seven steps to producing a literature review

Study resources
Calendar - Graduate
Calendar - Undergraduate
Class schedules
Class cancellations
Course registration
Important academic dates
More academic resources
Campus services
IT services
Job opportunities
Safety & prevention
Mental health support
Student Service Centre (Birks)
All campus services
Calendar of events
Latest news
Media Relations
Faculties, Schools & Colleges
Arts and Science
Gina Cody School of Engineering and Computer Science
John Molson School of Business
School of Graduate Studies
All Schools, Colleges & Departments.
Directories
Future students
Current students
Alumni & friends
Faculty & staff
Arts & culture
In the community
Sports & wellness
Student life
University affairs
Publications & reports
Our experts
News releases
The Conversation

7 easy steps to do a literature review

A literature review is a fundamental part of your thesis writing process. It critically informs you of the relevant literature by other scholars in your research area and situates your research in the conversation. Ultimately, the literature review helps you communicate how the new knowledge you are producing contributes to existing scholarship.

The process of scanning literature in your area allows you to identify overlooked or understudied topics in your research field, and identify scholarships that support your arguments. The literature review provides the theoretical framework, methodology, concepts and problems that frame your research design.

We attended the GradProSkills webinar Writing a Literature Review (GPLL37) , led by Joseph Brito, a Ph.D. Candidate in the Department of Religions and Cultures, to learn how to do a literature review efficiently and still be thorough. Joseph shared 7 steps to do a literature review in a stress-free manner:

1. Define your research scope

Establish the research area, topics and questions you want to address. Make a list of keywords (including synonyms) and main concepts linked to your research topic, and establish the connections between these concepts and your research question with a concept map . Then set some additional parameters to your searches like publication date, geographical coverage, and related disciplines.

2. Plan your research approach

Build a checklist with important aspects of your research area, like the existing scholarship covering your topic, under-researched or overlooked aspects by other researchers, and key scholars in the field. Identify where to search for research papers on Concordia’s online catalogue and databases , browse on Google Scholar , talk to a subject librarian or ask your advisor for tips. Identify credible scholarly publications like peer-reviewed journals, books from university presses and graduate thesis. If in doubt, seek your supervisor’s guidance to acceptable sources.

3. Search strategically: be efficient but thorough

Use the keywords and concepts you identified in your research and explore combinations with boolean operators (or, and, not, etc), and truncated terms (develop* returns results like development, developer). Enhance your research expertise with GradProSkills webinar Library Skills & Resources (GPLL231) or chat with Concordia's librarians .

Keep research logs with critical aspects of your search: date, database, terms used and their combinations, and results. Establish categories for important themes, and organize search results within these major themes.

4. Manage your literature with online tools

Keeping good referencing practices early on in your grad school saves you time during the writing phase. Zotero is a free online reference management tool to keep your citations and personal notes in one place. This software inserts the citation (author, date of publication, page number) into your word document and automatically creates a reference list as per the chosen citation style . Zotero training is available to grad students with GradProSkills webinar GPLL 243 - Using Zotero for Grads .

5. Critical reading and analysis

Before reading your text, consider the author's argumentation and evidence to support your research question. Skim read the abstract, conclusion, and the first sentence of each paragraph to eliminate non-relevant literature.

Keep an annotated bibliography for each source with its key points and importance to your research (about seven sentences), and place selected literature in conversation with each other. The literature review is an iterative process of searching, reading, taking notes and writing.

6. Benchmark from other literature reviews

Check existing literature reviews in the thesis and dissertations at Concordia’s Theses, dissertations, and research papers database . Organize the literature review keeping the connection between topics, with a smooth transition from one section to another. Avoid excessive direct quoting, and prefer to give your interpretation of other scholars’ perspectives in your research field.

7. Assemble the texts and write

Put all the sources together into your literature review when you are confident that you have covered the significant authors and debates in your field. You will know that you have reached this point when your search results and readings start repeating themselves, or if your advisor tells you to stop and write. A literature review is structured with an introduction, main body and conclusion. Concordia’s Student Success Centre shares handouts on how to structure essays and research papers .

Joseph recommends starting the literature review process sooner rather than later to give yourself time to gather and analyze your sources. Manage the process like a small project with specific goals and timelines to increase efficiency and reduce stress. You can learn how to work efficiently with our Productivity in Grad School (GPLL50) webinar.

Seven Steps to a Comprehensive Literature Review A Multimodal and Cultural Approach

Anthony J. Onwuegbuzie
Rebecca Frels - Lamar University, USA
Description

What makes this book unique:

Focuses on multimodal texts and settings such as observations, documents, social media, experts in the field and secondary data so that your review covers the full research environment
Puts mixed methods at the centre of the process
Shows you how to synthesize information thematically, rather than merely summarize the existing literature and findings
Brings culture into the process to help you address bias and understand the role of knowledge interpretation, guiding you through
Teaches the CORE of the literature review – Critical thinking, Organization, Reflections and Evaluation – and provides a guide for reflexivity at the end of each of the seven steps
Visualizes the steps with roadmaps so you can track progress and self-evaluate as you learn the steps

This book is the essential best practices guide for students and researchers, providing the understanding and tools to approach both the ‘how’ and ‘why’ of a rigorous, comprehensive, literature review.

This is by far the most comprehensive text on how to do comprehensive literature reviews! Onwuegbuzie and Frels skilfully demonstrate that review has a methodology of its own. Both novice and experienced scholars will benefit from detailed examples and step-by-step demonstrations of ways to maximize the effectiveness of literature reviews to build new theories and develop better explanations of behaviours and outcomes.

This is the most comprehensive and user-friendly book I’ve seen on how to conduct a literature review. The authors take the distinction of qualitative, quantitative, and mixed methods research seriously, showing how each adds something important and how being open-minded results in the use of literature based on all three approaches. Overall, the book provides a process theory of literature review, that is done before, during, and after each research study. It is a must read for both PhD students and research faculty.

With noteworthy scope of content, this book is a must-have resource for beginning and experienced researchers alike. In addition to its effective pedagogical features such as visuals and end of chapter questions, this resource enables researchers to make informed decisions about the purposes of and procedures for undertaking a literature review. In so doing, the authors innovate and advance our understandings of the processes and products involved in a comprehensive literature review and provide practical guidance for each of the steps. I have been seeking such a book and plan to make this required reading for the graduate students I instruct, mentor, and supervise.

Seven Steps to a Comprehensive Literature Review is a comprehensive text book written to instruct master’s-level students, doctoral-level students, and new and experienced researchers in the process of writing a comprehensive literature review... Hopefully, this book will become an important text used by instructors as they guide college students into the writing of the literature review.

Sadly this book never arrived despite me being very interested to adopt for my MSc students dissertation stage.

The literature review is one of the toughest parts of any proposal (or postgraduate piece of work) for students to complete successfully because it asks the student to engage with the theory they will be using from the perspective of ideas alone. IT also asks the student to investigate other academics' work in a manner that they haven't really experienced before. All these "firsts" make the literature review a very confusing and oftentimes daunting process. Fortunately, "Seven Steps" provides the specific guidance that so many students need to navigate this difficult process. The systematic way in which the book approaches a topic that can be said to change with each application (e.g. How do you go about it? What to include? What to leave out? and most importantly, Why?) is indispensable for anyone teaching students new to postgraduate work, or for researchers looking for an alternative approach to a process they are otherwise well-acquainted with.

Very accessible book for students who wish to increase their capabilites in working at the front end of their papers.

Comprehensive, well structured book, which will be very useful to students planning a literature review.

this book is more relevant for the MSc students. it will be a good supplement for the student who wants to go a little further

it was actually a little more complex than I was hoping for. the text is dense and it is big book. for my BSc students it is jut a little too much

Preview this book

Sample materials & chapters.

Chapter 1: Foundations of the Literature Review

For instructors

Select a purchasing option.

Electronic Order Options VitalSource Amazon Kindle Google Play eBooks.com Kobo

Related Products

Seven Steps to a Comprehensive Literature Review

A multimodal and cultural approach.

Request Instructor Sample
DESCRIPTION

What makes this book unique:

Focuses on multimodal texts and settings such as observations, documents, social media, experts in the field and secondary data so that your review covers the full research environment
Puts mixed methods at the centre of the process
Shows you how to synthesize information thematically, rather than merely summarize the existing literature and findings
Brings culture into the process to help you address bias and understand the role of knowledge interpretation, guiding you through
Teaches the CORE of the literature review – Critical thinking, Organization, Reflections and Evaluation – and provides a guide for reflexivity at the end of each of the seven steps
Visualizes the steps with roadmaps so you can track progress and self-evaluate as you learn the steps

Available formats

With noteworthy scope of content, this book is a must-have resource for beginning and experienced researchers alike. In addition to its effective pedagogical features such as visuals and end of chapter questions, this resource enables researchers to make informed decisions about the purposes of and procedures for undertaking a literature review. In so doing, the authors innovate and advance our understandings of the processes and products involved in a comprehensive literature review and provide practical guidance for each of the steps. I have been seeking such a book and plan to make this required reading for the graduate students I instruct, mentor, and supervise. Cheryl N. Poth Centre for for Research in Applied Measurement and Evaluation, University of Alberta

This is by far the most comprehensive text on how to do comprehensive literature reviews! Onwuegbuzie and Frels skilfully demonstrate that review has a methodology of its own. Both novice and experienced scholars will benefit from detailed examples and step-by-step demonstrations of ways to maximize the effectiveness of literature reviews to build new theories and develop better explanations of behaviours and outcomes. Abbas Tashakkori Department of Educational Psychology,University of North Texas

This is the most comprehensive and user-friendly book I’ve seen on how to conduct a literature review. The authors take the distinction of qualitative, quantitative, and mixed methods research seriously, showing how each adds something important and how being open-minded results in the use of literature based on all three approaches. Overall, the book provides a process theory of literature review, that is done before, during, and after each research study. It is a must read for both PhD students and research faculty. Burke Johnson Department of Professional Studies, University of South Alabama

Seven Steps to a Comprehensive Literature Review is a comprehensive text book written to instruct master’s-level students, doctoral-level students, and new and experienced researchers in the process of writing a comprehensive literature review... Hopefully, this book will become an important text used by instructors as they guide college students into the writing of the literature review. Jan Kirksey Williams The Qualitative Report

Session Timeout

Have a language expert improve your writing

Run a free plagiarism check in 10 minutes, generate accurate citations for free.

Knowledge Base

Methodology

How to Write a Literature Review | Guide, Examples, & Templates

How to Write a Literature Review | Guide, Examples, & Templates

Published on January 2, 2023 by Shona McCombes . Revised on September 11, 2023.

What is a literature review? A literature review is a survey of scholarly sources on a specific topic. It provides an overview of current knowledge, allowing you to identify relevant theories, methods, and gaps in the existing research that you can later apply to your paper, thesis, or dissertation topic .

There are five key steps to writing a literature review:

Search for relevant literature
Evaluate sources
Identify themes, debates, and gaps
Outline the structure
Write your literature review

A good literature review doesn’t just summarize sources—it analyzes, synthesizes , and critically evaluates to give a clear picture of the state of knowledge on the subject.

Instantly correct all language mistakes in your text

Upload your document to correct all your mistakes in minutes

What is the purpose of a literature review, examples of literature reviews, step 1 – search for relevant literature, step 2 – evaluate and select sources, step 3 – identify themes, debates, and gaps, step 4 – outline your literature review’s structure, step 5 – write your literature review, free lecture slides, other interesting articles, frequently asked questions, introduction.

Quick Run-through
Step 1 & 2

When you write a thesis , dissertation , or research paper , you will likely have to conduct a literature review to situate your research within existing knowledge. The literature review gives you a chance to:

Demonstrate your familiarity with the topic and its scholarly context
Develop a theoretical framework and methodology for your research
Position your work in relation to other researchers and theorists
Show how your research addresses a gap or contributes to a debate
Evaluate the current state of research and demonstrate your knowledge of the scholarly debates around your topic.

Writing literature reviews is a particularly important skill if you want to apply for graduate school or pursue a career in research. We’ve written a step-by-step guide that you can follow below.

Don't submit your assignments before you do this

The academic proofreading tool has been trained on 1000s of academic texts. Making it the most accurate and reliable proofreading tool for students. Free citation check included.

seven steps to producing a literature review

Try for free

Writing literature reviews can be quite challenging! A good starting point could be to look at some examples, depending on what kind of literature review you’d like to write.

Example literature review #1: “Why Do People Migrate? A Review of the Theoretical Literature” ( Theoretical literature review about the development of economic migration theory from the 1950s to today.)
Example literature review #2: “Literature review as a research methodology: An overview and guidelines” ( Methodological literature review about interdisciplinary knowledge acquisition and production.)
Example literature review #3: “The Use of Technology in English Language Learning: A Literature Review” ( Thematic literature review about the effects of technology on language acquisition.)
Example literature review #4: “Learners’ Listening Comprehension Difficulties in English Language Learning: A Literature Review” ( Chronological literature review about how the concept of listening skills has changed over time.)

You can also check out our templates with literature review examples and sample outlines at the links below.

Download Word doc Download Google doc

Before you begin searching for literature, you need a clearly defined topic .

If you are writing the literature review section of a dissertation or research paper, you will search for literature related to your research problem and questions .

Make a list of keywords

Start by creating a list of keywords related to your research question. Include each of the key concepts or variables you’re interested in, and list any synonyms and related terms. You can add to this list as you discover new keywords in the process of your literature search.

Social media, Facebook, Instagram, Twitter, Snapchat, TikTok
Body image, self-perception, self-esteem, mental health
Generation Z, teenagers, adolescents, youth

Search for relevant sources

Use your keywords to begin searching for sources. Some useful databases to search for journals and articles include:

Your university’s library catalogue
Google Scholar
Project Muse (humanities and social sciences)
Medline (life sciences and biomedicine)
EconLit (economics)
Inspec (physics, engineering and computer science)

You can also use boolean operators to help narrow down your search.

Make sure to read the abstract to find out whether an article is relevant to your question. When you find a useful book or article, you can check the bibliography to find other relevant sources.

You likely won’t be able to read absolutely everything that has been written on your topic, so it will be necessary to evaluate which sources are most relevant to your research question.

For each publication, ask yourself:

What question or problem is the author addressing?
What are the key concepts and how are they defined?
What are the key theories, models, and methods?
Does the research use established frameworks or take an innovative approach?
What are the results and conclusions of the study?
How does the publication relate to other literature in the field? Does it confirm, add to, or challenge established knowledge?
What are the strengths and weaknesses of the research?

Make sure the sources you use are credible , and make sure you read any landmark studies and major theories in your field of research.

You can use our template to summarize and evaluate sources you’re thinking about using. Click on either button below to download.

Take notes and cite your sources

As you read, you should also begin the writing process. Take notes that you can later incorporate into the text of your literature review.

It is important to keep track of your sources with citations to avoid plagiarism . It can be helpful to make an annotated bibliography , where you compile full citation information and write a paragraph of summary and analysis for each source. This helps you remember what you read and saves time later in the process.

To begin organizing your literature review’s argument and structure, be sure you understand the connections and relationships between the sources you’ve read. Based on your reading and notes, you can look for:

Trends and patterns (in theory, method or results): do certain approaches become more or less popular over time?
Themes: what questions or concepts recur across the literature?
Debates, conflicts and contradictions: where do sources disagree?
Pivotal publications: are there any influential theories or studies that changed the direction of the field?
Gaps: what is missing from the literature? Are there weaknesses that need to be addressed?

This step will help you work out the structure of your literature review and (if applicable) show how your own research will contribute to existing knowledge.

Most research has focused on young women.
There is an increasing interest in the visual aspects of social media.
But there is still a lack of robust research on highly visual platforms like Instagram and Snapchat—this is a gap that you could address in your own research.

There are various approaches to organizing the body of a literature review. Depending on the length of your literature review, you can combine several of these strategies (for example, your overall structure might be thematic, but each theme is discussed chronologically).

Chronological

The simplest approach is to trace the development of the topic over time. However, if you choose this strategy, be careful to avoid simply listing and summarizing sources in order.

Try to analyze patterns, turning points and key debates that have shaped the direction of the field. Give your interpretation of how and why certain developments occurred.

If you have found some recurring central themes, you can organize your literature review into subsections that address different aspects of the topic.

For example, if you are reviewing literature about inequalities in migrant health outcomes, key themes might include healthcare policy, language barriers, cultural attitudes, legal status, and economic access.

Methodological

If you draw your sources from different disciplines or fields that use a variety of research methods , you might want to compare the results and conclusions that emerge from different approaches. For example:

Look at what results have emerged in qualitative versus quantitative research
Discuss how the topic has been approached by empirical versus theoretical scholarship
Divide the literature into sociological, historical, and cultural sources

Theoretical

A literature review is often the foundation for a theoretical framework . You can use it to discuss various theories, models, and definitions of key concepts.

You might argue for the relevance of a specific theoretical approach, or combine various theoretical concepts to create a framework for your research.

Like any other academic text , your literature review should have an introduction , a main body, and a conclusion . What you include in each depends on the objective of your literature review.

The introduction should clearly establish the focus and purpose of the literature review.

Depending on the length of your literature review, you might want to divide the body into subsections. You can use a subheading for each theme, time period, or methodological approach.

As you write, you can follow these tips:

Summarize and synthesize: give an overview of the main points of each source and combine them into a coherent whole
Analyze and interpret: don’t just paraphrase other researchers — add your own interpretations where possible, discussing the significance of findings in relation to the literature as a whole
Critically evaluate: mention the strengths and weaknesses of your sources
Write in well-structured paragraphs: use transition words and topic sentences to draw connections, comparisons and contrasts

In the conclusion, you should summarize the key findings you have taken from the literature and emphasize their significance.

When you’ve finished writing and revising your literature review, don’t forget to proofread thoroughly before submitting. Not a language expert? Check out Scribbr’s professional proofreading services !

This article has been adapted into lecture slides that you can use to teach your students about writing a literature review.

Scribbr slides are free to use, customize, and distribute for educational purposes.

Open Google Slides Download PowerPoint

If you want to know more about the research process , methodology , research bias , or statistics , make sure to check out some of our other articles with explanations and examples.

Sampling methods
Simple random sampling
Stratified sampling
Cluster sampling
Likert scales
Reproducibility

Statistics

Null hypothesis
Statistical power
Probability distribution
Effect size
Poisson distribution

Research bias

Optimism bias
Cognitive bias
Implicit bias
Hawthorne effect
Anchoring bias
Explicit bias

A literature review is a survey of scholarly sources (such as books, journal articles, and theses) related to a specific topic or research question .

It is often written as part of a thesis, dissertation , or research paper , in order to situate your work in relation to existing knowledge.

There are several reasons to conduct a literature review at the beginning of a research project:

To familiarize yourself with the current state of knowledge on your topic
To ensure that you’re not just repeating what others have already done
To identify gaps in knowledge and unresolved problems that your research can address
To develop your theoretical framework and methodology
To provide an overview of the key findings and debates on the topic

Writing the literature review shows your reader how your work relates to existing research and what new insights it will contribute.

The literature review usually comes near the beginning of your thesis or dissertation . After the introduction , it grounds your research in a scholarly field and leads directly to your theoretical framework or methodology .

A literature review is a survey of credible sources on a topic, often used in dissertations , theses, and research papers . Literature reviews give an overview of knowledge on a subject, helping you identify relevant theories and methods, as well as gaps in existing research. Literature reviews are set up similarly to other academic texts , with an introduction , a main body, and a conclusion .

An annotated bibliography is a list of source references that has a short description (called an annotation ) for each of the sources. It is often assigned as part of the research process for a paper .

Cite this Scribbr article

If you want to cite this source, you can copy and paste the citation or click the “Cite this Scribbr article” button to automatically add the citation to our free Citation Generator.

McCombes, S. (2023, September 11). How to Write a Literature Review | Guide, Examples, & Templates. Scribbr. Retrieved September 9, 2024, from https://www.scribbr.com/dissertation/literature-review/

Is this article helpful?

Shona McCombes

Other students also liked, what is a theoretical framework | guide to organizing, what is a research methodology | steps & tips, how to write a research proposal | examples & templates, "i thought ai proofreading was useless but..".

I've been using Scribbr for years now and I know it's a service that won't disappoint. It does a good job spotting mistakes”

Write a Literature Review

1. narrow your topic and select papers accordingly, 2. search for literature, 3. read the selected articles thoroughly and evaluate them, 4. organize the selected papers by looking for patterns and by developing subtopics, 5. develop a thesis or purpose statement, 6. write the paper, 7. review your work.

Resources for Gathering and Reading the Literature
Resources for Writing and Revising
Other Useful Resources

Ask Us: Chat, email, visit or call

Get Assistance

The library offers a range of helpful services. All of our appointments are free of charge and confidential.

Book an appointment

Consider your specific area of study. Think about what interests you and what interests other researchers in your field.

Talk to your professor, brainstorm, and read lecture notes and recent issues of periodicals in the ﬁeld.

Limit your scope to a smaller topic area (ie. focusing on France's role in WWII instead of focusing on WWII in general).

Four Steps to Narrow Your Research Topic (Video) This 3-minute video provides instructions on how to narrow the focus of your research topic.
Developing a Research Question + Worksheet Use this worksheet to develop, assess, and refine your research questions. There is also a downloadable PDF version.

Define your source selection criteria (ie. articles published between a specific date range, focusing on a specific geographic region, or using a specific methodology).

Using keywords, search a library database.

Reference lists of recent articles and reviews can lead to other useful papers.

Include any studies contrary to your point of view.

Evaluate and synthesize the studies' ﬁndings and conclusions.

Note the following:

Assumptions some or most researchers seem to make
Methodologies, testing procedures, subjects, material tested researchers use
Experts in the ﬁeld: names/labs that are frequently referenced
Conflicting theories, results, methodologies
Popularity of theories and how this has/has not changed over time
Findings that are common/contested
Important trends in the research
The most influential theories

Tip: If your literature review is extensive, ﬁnd a large table surface, and on it place post-it notes or ﬁling cards to organize all your ﬁndings into categories.

Move them around if you decide that (a) they ﬁt better under different headings, or (b) you need to establish new topic headings.
Develop headings/subheadings that reflect the major themes and patterns you detected

Write a one or two sentence statement summarizing the conclusion you have reached about the major trends and developments you see in the research that has been conducted on your subject.

Templates for Writing Thesis Statements This template provides a two-step guide for writing thesis statements. There is also a downloadable PDF version.
5 Types of Thesis Statements Learn about five different types of thesis statements to help you choose the best type for your research. There is also a downloadable PDF version.
5 Questions to Strengthen Your Thesis Statement Follow these five steps to strengthen your thesis statements. There is also a downloadable PDF version.

Follow the organizational structure you developed above, including the headings and subheadings you constructed.

Make certain that each section links logically to the one before and after.

Structure your sections by themes or subtopics, not by individual theorists or researchers.

Tip: If you ﬁnd that each paragraph begins with a researcher's name, it might indicate that, instead of evaluating and comparing the research literature from an analytical point of view, you have simply described what research has been done.

Prioritize analysis over description.

For example, look at the following two passages and note that Student A merely describes the literature, whereas Student B takes a more analytical and evaluative approach by comparing and contrasting. You can also see that this evaluative approach is well signaled by linguistic markers indicating logical connections (words such as "however," "moreover") and phrases such as "substantiates the claim that," which indicate supporting evidence and Student B's ability to synthesize knowledge.

Student A: Smith (2000) concludes that personal privacy in their living quarters is the most important factor in nursing home residents' perception of their autonomy. He suggests that the physical environment in the more public spaces of the building did not have much impact on their perceptions. Neither the layout of the building nor the activities available seem to make much difference. Jones and Johnstone make the claim that the need to control one's environment is a fundamental need of life (2001), and suggest that the approach of most institutions, which is to provide total care, may be as bad as no care at all. If people have no choices or think that they have none, they become depressed.

Student B: After studying residents and staff from two intermediate care facilities in Calgary, Alberta, Smith (2000) came to the conclusion that except for the amount of personal privacy available to residents, the physical environment of these institutions had minimal if any effect on their perceptions of control (autonomy). However, French (1998) and Haroon (2000) found that availability of private areas is not the only aspect of the physical environment that determines residents' autonomy. Haroon interviewed 115 residents from 32 different nursing homes known to have different levels of autonomy (2000). It was found that physical structures, such as standardized furniture, heating that could not be individually regulated, and no possession of a house key for residents limited their feelings of independence. Moreover, Hope (2002), who interviewed 225 residents from various nursing homes, substantiates the claim that characteristics of the institutional environment such as the extent of resources in the facility, as well as its location, are features which residents have indicated as being of great importance to their independence.

How to Integrate Critical Voice into Your Literature Review (Video)
Look at the topic sentences of each paragraph. If you were to read only these sentences, would you ﬁnd that your paper presented a clear position, logically developed, from beginning to end? The topic sentences of each paragraph should indicate the main points of your literature review.
Make an outline of each section of the paper and decide whether you need to add information, to delete irrelevant information, or to re-structure sections.
Read your work out loud. That way you will be better able to identify where you need punctuation marks to signal pauses or divisions within sentences, where you have made grammatical errors, or where your sentences are unclear.
Since the purpose of a literature review is to demonstrate that the writer is familiar with the important professional literature on the chosen subject, check to make certain that you have covered all of the important, up-to-date, and pertinent texts. In the sciences and some of the social sciences it is important that your literature be quite recent; this is not so important in the humanities.
Make certain that all of the citations and references are correct and that you are referencing in the appropriate style for your discipline. If you are uncertain which style to use, ask your professor.
Check to make sure that you have not plagiarized either by failing to cite a source of information, or by using words quoted directly from a source. (Usually if you take three or more words directly from another source, you should put those words within quotation marks, and cite the page.)
Text should be written in a clear and concise academic style; it should not be descriptive in nature or use the language of everyday speech.
There should be no grammatical or spelling errors.
Sentences should ﬂow smoothly and logically.
<< Previous: Start Here
Next: Resources for Gathering and Reading the Literature >>
Last Updated: Aug 21, 2024 2:18 PM
URL: https://guides.lib.uoguelph.ca/LiteratureReview

Suggest an edit to this guide

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

How To Write An A-Grade Literature Review

3 straightforward steps (with examples) + free template.

By: Derek Jansen (MBA) | Expert Reviewed By: Dr. Eunice Rautenbach | October 2019

Quality research is about building onto the existing work of others , “standing on the shoulders of giants”, as Newton put it. The literature review chapter of your dissertation, thesis or research project is where you synthesise this prior work and lay the theoretical foundation for your own research.

Long story short, this chapter is a pretty big deal, which is why you want to make sure you get it right . In this post, I’ll show you exactly how to write a literature review in three straightforward steps, so you can conquer this vital chapter (the smart way).

Overview: The Literature Review Process

Understanding the “ why “
Finding the relevant literature
Cataloguing and synthesising the information
Outlining & writing up your literature review
Example of a literature review

But first, the “why”…

Before we unpack how to write the literature review chapter, we’ve got to look at the why . To put it bluntly, if you don’t understand the function and purpose of the literature review process, there’s no way you can pull it off well. So, what exactly is the purpose of the literature review?

Well, there are (at least) four core functions:

For you to gain an understanding (and demonstrate this understanding) of where the research is at currently, what the key arguments and disagreements are.
For you to identify the gap(s) in the literature and then use this as justification for your own research topic.
To help you build a conceptual framework for empirical testing (if applicable to your research topic).
To inform your methodological choices and help you source tried and tested questionnaires (for interviews ) and measurement instruments (for surveys ).

Most students understand the first point but don’t give any thought to the rest. To get the most from the literature review process, you must keep all four points front of mind as you review the literature (more on this shortly), or you’ll land up with a wonky foundation.

Okay – with the why out the way, let’s move on to the how . As mentioned above, writing your literature review is a process, which I’ll break down into three steps:

Finding the most suitable literature
Understanding , distilling and organising the literature
Planning and writing up your literature review chapter

Importantly, you must complete steps one and two before you start writing up your chapter. I know it’s very tempting, but don’t try to kill two birds with one stone and write as you read. You’ll invariably end up wasting huge amounts of time re-writing and re-shaping, or you’ll just land up with a disjointed, hard-to-digest mess . Instead, you need to read first and distil the information, then plan and execute the writing.

Step 1: Find the relevant literature

Naturally, the first step in the literature review journey is to hunt down the existing research that’s relevant to your topic. While you probably already have a decent base of this from your research proposal , you need to expand on this substantially in the dissertation or thesis itself.

Essentially, you need to be looking for any existing literature that potentially helps you answer your research question (or develop it, if that’s not yet pinned down). There are numerous ways to find relevant literature, but I’ll cover my top four tactics here. I’d suggest combining all four methods to ensure that nothing slips past you:

Method 1 – Google Scholar Scrubbing

Google’s academic search engine, Google Scholar , is a great starting point as it provides a good high-level view of the relevant journal articles for whatever keyword you throw at it. Most valuably, it tells you how many times each article has been cited, which gives you an idea of how credible (or at least, popular) it is. Some articles will be free to access, while others will require an account, which brings us to the next method.

Method 2 – University Database Scrounging

Generally, universities provide students with access to an online library, which provides access to many (but not all) of the major journals.

So, if you find an article using Google Scholar that requires paid access (which is quite likely), search for that article in your university’s database – if it’s listed there, you’ll have access. Note that, generally, the search engine capabilities of these databases are poor, so make sure you search for the exact article name, or you might not find it.

Method 3 – Journal Article Snowballing

At the end of every academic journal article, you’ll find a list of references. As with any academic writing, these references are the building blocks of the article, so if the article is relevant to your topic, there’s a good chance a portion of the referenced works will be too. Do a quick scan of the titles and see what seems relevant, then search for the relevant ones in your university’s database.

Method 4 – Dissertation Scavenging

Similar to Method 3 above, you can leverage other students’ dissertations. All you have to do is skim through literature review chapters of existing dissertations related to your topic and you’ll find a gold mine of potential literature. Usually, your university will provide you with access to previous students’ dissertations, but you can also find a much larger selection in the following databases:

Open Access Theses & Dissertations
Stanford SearchWorks

Keep in mind that dissertations and theses are not as academically sound as published, peer-reviewed journal articles (because they’re written by students, not professionals), so be sure to check the credibility of any sources you find using this method. You can do this by assessing the citation count of any given article in Google Scholar. If you need help with assessing the credibility of any article, or with finding relevant research in general, you can chat with one of our Research Specialists .

Alright – with a good base of literature firmly under your belt, it’s time to move onto the next step.

Need a helping hand?

Step 2: Log, catalogue and synthesise

Once you’ve built a little treasure trove of articles, it’s time to get reading and start digesting the information – what does it all mean?

While I present steps one and two (hunting and digesting) as sequential, in reality, it’s more of a back-and-forth tango – you’ll read a little , then have an idea, spot a new citation, or a new potential variable, and then go back to searching for articles. This is perfectly natural – through the reading process, your thoughts will develop , new avenues might crop up, and directional adjustments might arise. This is, after all, one of the main purposes of the literature review process (i.e. to familiarise yourself with the current state of research in your field).

As you’re working through your treasure chest, it’s essential that you simultaneously start organising the information. There are three aspects to this:

Logging reference information
Building an organised catalogue
Distilling and synthesising the information

I’ll discuss each of these below:

2.1 – Log the reference information

As you read each article, you should add it to your reference management software. I usually recommend Mendeley for this purpose (see the Mendeley 101 video below), but you can use whichever software you’re comfortable with. Most importantly, make sure you load EVERY article you read into your reference manager, even if it doesn’t seem very relevant at the time.

2.2 – Build an organised catalogue

In the beginning, you might feel confident that you can remember who said what, where, and what their main arguments were. Trust me, you won’t. If you do a thorough review of the relevant literature (as you must!), you’re going to read many, many articles, and it’s simply impossible to remember who said what, when, and in what context . Also, without the bird’s eye view that a catalogue provides, you’ll miss connections between various articles, and have no view of how the research developed over time. Simply put, it’s essential to build your own catalogue of the literature.

I would suggest using Excel to build your catalogue, as it allows you to run filters, colour code and sort – all very useful when your list grows large (which it will). How you lay your spreadsheet out is up to you, but I’d suggest you have the following columns (at minimum):

Author, date, title – Start with three columns containing this core information. This will make it easy for you to search for titles with certain words, order research by date, or group by author.
Categories or keywords – You can either create multiple columns, one for each category/theme and then tick the relevant categories, or you can have one column with keywords.
Key arguments/points – Use this column to succinctly convey the essence of the article, the key arguments and implications thereof for your research.
Context – Note the socioeconomic context in which the research was undertaken. For example, US-based, respondents aged 25-35, lower- income, etc. This will be useful for making an argument about gaps in the research.
Methodology – Note which methodology was used and why. Also, note any issues you feel arise due to the methodology. Again, you can use this to make an argument about gaps in the research.
Quotations – Note down any quoteworthy lines you feel might be useful later.
Notes – Make notes about anything not already covered. For example, linkages to or disagreements with other theories, questions raised but unanswered, shortcomings or limitations, and so forth.

If you’d like, you can try out our free catalog template here (see screenshot below).

2.3 – Digest and synthesise

Most importantly, as you work through the literature and build your catalogue, you need to synthesise all the information in your own mind – how does it all fit together? Look for links between the various articles and try to develop a bigger picture view of the state of the research. Some important questions to ask yourself are:

What answers does the existing research provide to my own research questions ?
Which points do the researchers agree (and disagree) on?
How has the research developed over time?
Where do the gaps in the current research lie?

To help you develop a big-picture view and synthesise all the information, you might find mind mapping software such as Freemind useful. Alternatively, if you’re a fan of physical note-taking, investing in a large whiteboard might work for you.

Mind mapping is a useful way to plan your literature review.

Step 3: Outline and write it up!

Once you’re satisfied that you have digested and distilled all the relevant literature in your mind, it’s time to put pen to paper (or rather, fingers to keyboard). There are two steps here – outlining and writing:

3.1 – Draw up your outline

Having spent so much time reading, it might be tempting to just start writing up without a clear structure in mind. However, it’s critically important to decide on your structure and develop a detailed outline before you write anything. Your literature review chapter needs to present a clear, logical and an easy to follow narrative – and that requires some planning. Don’t try to wing it!

Naturally, you won’t always follow the plan to the letter, but without a detailed outline, you’re more than likely going to end up with a disjointed pile of waffle , and then you’re going to spend a far greater amount of time re-writing, hacking and patching. The adage, “measure twice, cut once” is very suitable here.

In terms of structure, the first decision you’ll have to make is whether you’ll lay out your review thematically (into themes) or chronologically (by date/period). The right choice depends on your topic, research objectives and research questions, which we discuss in this article .

Once that’s decided, you need to draw up an outline of your entire chapter in bullet point format. Try to get as detailed as possible, so that you know exactly what you’ll cover where, how each section will connect to the next, and how your entire argument will develop throughout the chapter. Also, at this stage, it’s a good idea to allocate rough word count limits for each section, so that you can identify word count problems before you’ve spent weeks or months writing!

PS – check out our free literature review chapter template…

3.2 – Get writing

With a detailed outline at your side, it’s time to start writing up (finally!). At this stage, it’s common to feel a bit of writer’s block and find yourself procrastinating under the pressure of finally having to put something on paper. To help with this, remember that the objective of the first draft is not perfection – it’s simply to get your thoughts out of your head and onto paper, after which you can refine them. The structure might change a little, the word count allocations might shift and shuffle, and you might add or remove a section – that’s all okay. Don’t worry about all this on your first draft – just get your thoughts down on paper.

Once you’ve got a full first draft (however rough it may be), step away from it for a day or two (longer if you can) and then come back at it with fresh eyes. Pay particular attention to the flow and narrative – does it fall fit together and flow from one section to another smoothly? Now’s the time to try to improve the linkage from each section to the next, tighten up the writing to be more concise, trim down word count and sand it down into a more digestible read.

Once you’ve done that, give your writing to a friend or colleague who is not a subject matter expert and ask them if they understand the overall discussion. The best way to assess this is to ask them to explain the chapter back to you. This technique will give you a strong indication of which points were clearly communicated and which weren’t. If you’re working with Grad Coach, this is a good time to have your Research Specialist review your chapter.

Finally, tighten it up and send it off to your supervisor for comment. Some might argue that you should be sending your work to your supervisor sooner than this (indeed your university might formally require this), but in my experience, supervisors are extremely short on time (and often patience), so, the more refined your chapter is, the less time they’ll waste on addressing basic issues (which you know about already) and the more time they’ll spend on valuable feedback that will increase your mark-earning potential.

Literature Review Example

In the video below, we unpack an actual literature review so that you can see how all the core components come together in reality.

Let’s Recap

In this post, we’ve covered how to research and write up a high-quality literature review chapter. Let’s do a quick recap of the key takeaways:

It is essential to understand the WHY of the literature review before you read or write anything. Make sure you understand the 4 core functions of the process.
The first step is to hunt down the relevant literature . You can do this using Google Scholar, your university database, the snowballing technique and by reviewing other dissertations and theses.
Next, you need to log all the articles in your reference manager , build your own catalogue of literature and synthesise all the research.
Following that, you need to develop a detailed outline of your entire chapter – the more detail the better. Don’t start writing without a clear outline (on paper, not in your head!)
Write up your first draft in rough form – don’t aim for perfection. Remember, done beats perfect.
Refine your second draft and get a layman’s perspective on it . Then tighten it up and submit it to your supervisor.

Psst… there’s more!

This post is an extract from our bestselling short course, Literature Review Bootcamp . If you want to work smart, you don't want to miss this .

38 Comments

Thank you very much. This page is an eye opener and easy to comprehend.

This is awesome!

I wish I come across GradCoach earlier enough.

But all the same I’ll make use of this opportunity to the fullest.

Thank you for this good job.

Keep it up!

You’re welcome, Yinka. Thank you for the kind words. All the best writing your literature review.

Thank you for a very useful literature review session. Although I am doing most of the steps…it being my first masters an Mphil is a self study and one not sure you are on the right track. I have an amazing supervisor but one also knows they are super busy. So not wanting to bother on the minutae. Thank you.

You’re most welcome, Renee. Good luck with your literature review 🙂

This has been really helpful. Will make full use of it. 🙂

Thank you Gradcoach.

Really agreed. Admirable effort

thank you for this beautiful well explained recap.

Thank you so much for your guide of video and other instructions for the dissertation writing.

It is instrumental. It encouraged me to write a dissertation now.

Thank you the video was great – from someone that knows nothing thankyou

an amazing and very constructive way of presetting a topic, very useful, thanks for the effort,

It is timely

It is very good video of guidance for writing a research proposal and a dissertation. Since I have been watching and reading instructions, I have started my research proposal to write. I appreciate to Mr Jansen hugely.

I learn a lot from your videos. Very comprehensive and detailed.

Thank you for sharing your knowledge. As a research student, you learn better with your learning tips in research

I was really stuck in reading and gathering information but after watching these things are cleared thanks, it is so helpful.

Really helpful, Thank you for the effort in showing such information

This is super helpful thank you very much.

Thank you for this whole literature writing review.You have simplified the process.

I’m so glad I found GradCoach. Excellent information, Clear explanation, and Easy to follow, Many thanks Derek!

You’re welcome, Maithe. Good luck writing your literature review 🙂

Thank you Coach, you have greatly enriched and improved my knowledge

Great piece, so enriching and it is going to help me a great lot in my project and thesis, thanks so much

This is THE BEST site for ANYONE doing a masters or doctorate! Thank you for the sound advice and templates. You rock!

Thanks, Stephanie 🙂

This is mind blowing, the detailed explanation and simplicity is perfect.

I am doing two papers on my final year thesis, and I must stay I feel very confident to face both headlong after reading this article.

thank you so much.

if anyone is to get a paper done on time and in the best way possible, GRADCOACH is certainly the go to area!

This is very good video which is well explained with detailed explanation

Thank you excellent piece of work and great mentoring

Thanks, it was useful

Thank you very much. the video and the information were very helpful.

Good morning scholar. I’m delighted coming to know you even before the commencement of my dissertation which hopefully is expected in not more than six months from now. I would love to engage my study under your guidance from the beginning to the end. I love to know how to do good job

Thank you so much Derek for such useful information on writing up a good literature review. I am at a stage where I need to start writing my one. My proposal was accepted late last year but I honestly did not know where to start

Like the name of your YouTube implies you are GRAD (great,resource person, about dissertation). In short you are smart enough in coaching research work.

This is a very well thought out webpage. Very informative and a great read.

Very timely.

I appreciate.

Very comprehensive and eye opener for me as beginner in postgraduate study. Well explained and easy to understand. Appreciate and good reference in guiding me in my research journey. Thank you

Thank you. I requested to download the free literature review template, however, your website wouldn’t allow me to complete the request or complete a download. May I request that you email me the free template? Thank you.

Submit a Comment Cancel reply

Your email address will not be published. Required fields are marked *

Save my name, email, and website in this browser for the next time I comment.

Print Friendly

Find My Rep

Seven Steps to a Comprehensive Literature Review A Multimodal and Cultural Approach

Anthony j. onwuegbuzie.

Rebecca Frels - Lamar University, USA
Description
Author(s) / Editor(s)

What makes this book unique:

Focuses on multimodal texts and settings such as observations, documents, social media, experts in the field and secondary data so that your review covers the full research environment
Puts mixed methods at the centre of the process
Shows you how to synthesize information thematically, rather than merely summarize the existing literature and findings
Brings culture into the process to help you address bias and understand the role of knowledge interpretation, guiding you through
Teaches the CORE of the literature review – Critical thinking, Organization, Reflections and Evaluation – and provides a guide for reflexivity at the end of each of the seven steps
Visualizes the steps with roadmaps so you can track progress and self-evaluate as you learn the steps

Sadly this book never arrived despite me being very interested to adopt for my MSc students dissertation stage.

Very accessible book for students who wish to increase their capabilites in working at the front end of their papers.

Comprehensive, well structured book, which will be very useful to students planning a literature review.

this book is more relevant for the MSc students. it will be a good supplement for the student who wants to go a little further

it was actually a little more complex than I was hoping for. the text is dense and it is big book. for my BSc students it is jut a little too much

Preview this book

Sample materials & chapters.

Chapter 1: Foundations of the Literature Review

Rebecca Frels

Purchasing options.

Please select a format:

Order from:

Buy from SAGE

Literature Review: The What, Why and How-to Guide — Introduction

Getting Started
How to Pick a Topic
Strategies to Find Sources
Evaluating Sources & Lit. Reviews
Tips for Writing Literature Reviews
Writing Literature Review: Useful Sites
Citation Resources
Other Academic Writings

What are Literature Reviews?

So, what is a literature review? "A literature review is an account of what has been published on a topic by accredited scholars and researchers. In writing the literature review, your purpose is to convey to your reader what knowledge and ideas have been established on a topic, and what their strengths and weaknesses are. As a piece of writing, the literature review must be defined by a guiding concept (e.g., your research objective, the problem or issue you are discussing, or your argumentative thesis). It is not just a descriptive list of the material available, or a set of summaries." Taylor, D. The literature review: A few tips on conducting it . University of Toronto Health Sciences Writing Centre.

Goals of Literature Reviews

What are the goals of creating a Literature Review? A literature could be written to accomplish different aims:

To develop a theory or evaluate an existing theory
To summarize the historical or existing state of a research topic
Identify a problem in a field of research

Baumeister, R. F., & Leary, M. R. (1997). Writing narrative literature reviews . Review of General Psychology , 1 (3), 311-320.

What kinds of sources require a Literature Review?

A research paper assigned in a course
A thesis or dissertation
A grant proposal
An article intended for publication in a journal

All these instances require you to collect what has been written about your research topic so that you can demonstrate how your own research sheds new light on the topic.

Types of Literature Reviews

What kinds of literature reviews are written?

Narrative review: The purpose of this type of review is to describe the current state of the research on a specific topic/research and to offer a critical analysis of the literature reviewed. Studies are grouped by research/theoretical categories, and themes and trends, strengths and weakness, and gaps are identified. The review ends with a conclusion section which summarizes the findings regarding the state of the research of the specific study, the gaps identify and if applicable, explains how the author's research will address gaps identify in the review and expand the knowledge on the topic reviewed.

Example : Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework: 10.1177/08948453211037398

Systematic review : "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139). Nelson, L. K. (2013). Research in Communication Sciences and Disorders . Plural Publishing.

Example : The effect of leave policies on increasing fertility: a systematic review: 10.1057/s41599-022-01270-w

Meta-analysis : "Meta-analysis is a method of reviewing research findings in a quantitative fashion by transforming the data from individual studies into what is called an effect size and then pooling and analyzing this information. The basic goal in meta-analysis is to explain why different outcomes have occurred in different studies." (p. 197). Roberts, M. C., & Ilardi, S. S. (2003). Handbook of Research Methods in Clinical Psychology . Blackwell Publishing.

Example : Employment Instability and Fertility in Europe: A Meta-Analysis: 10.1215/00703370-9164737

Meta-synthesis : "Qualitative meta-synthesis is a type of qualitative study that uses as data the findings from other qualitative studies linked by the same or related topic." (p.312). Zimmer, L. (2006). Qualitative meta-synthesis: A question of dialoguing with texts . Journal of Advanced Nursing , 53 (3), 311-318.

Example : Women’s perspectives on career successes and barriers: A qualitative meta-synthesis: 10.1177/05390184221113735

Literature Reviews in the Health Sciences

UConn Health subject guide on systematic reviews Explanation of the different review types used in health sciences literature as well as tools to help you find the right review type
<< Previous: Getting Started
Next: How to Pick a Topic >>
Last Updated: Sep 21, 2022 2:16 PM
URL: https://guides.lib.uconn.edu/literaturereview

Writing a Literature Review

What is a Literature Review?
Step 1: Choosing a Topic
Step 2: Finding Information
Step 3: Evaluating Content
Step 4: Taking Notes
Step 5: Synthesizing Content
Step 6: Writing the Review
Step 7: Citing Your Sources
Meet the Library Team
Off-Campus & Mobile Access
Software, Printing, & IT Help
Other Helpful Guides

Library Hours

*Hours may differ on holidays and when classes are out of session. Up-to-date hours can be found here: https://library.llu.edu/all-library-hours .

Monday: 7:00am - 10:00pm

Tuesday: 7:00am - 10:00pm

Wednesday: 7:00am - 10:00pm

Thursday: 7:00am - 10:00pm

Friday: 7:00am - 4:00pm

Saturday: Closed

Sunday: 10:00am - 10:00pm

Steps To Write a Literature Review

<< Previous: What is a Literature Review?
Next: Step 1: Choosing a Topic >>
Last Updated: Sep 13, 2024 5:15 PM
URL: https://libguides.llu.edu/literaturereview

Harvey Cushing/John Hay Whitney Medical Library

Collections
Research Help

YSN Doctoral Programs: Steps in Conducting a Literature Review

Biomedical Databases
Global (Public Health) Databases
Soc. Sci., History, and Law Databases
Grey Literature
Trials Registers
Data and Statistics
Public Policy
Google Tips
Recommended Books
Steps in Conducting a Literature Review

What is a literature review?

A literature review is an integrated analysis -- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question. That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.

A literature review may be a stand alone work or the introduction to a larger research paper, depending on the assignment. Rely heavily on the guidelines your instructor has given you.

Why is it important?

A literature review is important because it:

Explains the background of research on a topic.
Demonstrates why a topic is significant to a subject area.
Discovers relationships between research studies/ideas.
Identifies major themes, concepts, and researchers on a topic.
Identifies critical gaps and points of disagreement.
Discusses further research questions that logically come out of the previous studies.

APA7 Style resources

APA Style Blog - for those harder to find answers

1. Choose a topic. Define your research question.

Your literature review should be guided by your central research question. The literature represents background and research developments related to a specific research question, interpreted and analyzed by you in a synthesized way.

Make sure your research question is not too broad or too narrow. Is it manageable?
Begin writing down terms that are related to your question. These will be useful for searches later.
If you have the opportunity, discuss your topic with your professor and your class mates.

2. Decide on the scope of your review

How many studies do you need to look at? How comprehensive should it be? How many years should it cover?

This may depend on your assignment. How many sources does the assignment require?

3. Select the databases you will use to conduct your searches.

Make a list of the databases you will search.

Where to find databases:

use the tabs on this guide
Find other databases in the Nursing Information Resources web page
More on the Medical Library web page
... and more on the Yale University Library web page

4. Conduct your searches to find the evidence. Keep track of your searches.

Use the key words in your question, as well as synonyms for those words, as terms in your search. Use the database tutorials for help.
Save the searches in the databases. This saves time when you want to redo, or modify, the searches. It is also helpful to use as a guide is the searches are not finding any useful results.
Review the abstracts of research studies carefully. This will save you time.
Use the bibliographies and references of research studies you find to locate others.
Check with your professor, or a subject expert in the field, if you are missing any key works in the field.
Ask your librarian for help at any time.
Use a citation manager, such as EndNote as the repository for your citations. See the EndNote tutorials for help.

Review the literature

Some questions to help you analyze the research:

What was the research question of the study you are reviewing? What were the authors trying to discover?
Was the research funded by a source that could influence the findings?
What were the research methodologies? Analyze its literature review, the samples and variables used, the results, and the conclusions.
Does the research seem to be complete? Could it have been conducted more soundly? What further questions does it raise?
If there are conflicting studies, why do you think that is?
How are the authors viewed in the field? Has this study been cited? If so, how has it been analyzed?

Tips:

Review the abstracts carefully.
Keep careful notes so that you may track your thought processes during the research process.
Create a matrix of the studies for easy analysis, and synthesis, across all of the studies.
<< Previous: Recommended Books
Last Updated: Jun 20, 2024 9:08 AM
URL: https://guides.library.yale.edu/YSNDoctoral

How to Write a Literature Review: Six Steps to Get You from Start to Finish

Writing-a-literature-review-six-steps-to-get-you-from-start-to-finish.

Tanya Golash-Boza, Associate Professor of Sociology, University of California

February 03, 2022

Writing a literature review is often the most daunting part of writing an article, book, thesis, or dissertation. “The literature” seems (and often is) massive. I have found it helpful to be as systematic as possible when completing this gargantuan task.

Sonja Foss and William Walters* describe an efficient and effective way of writing a literature review. Their system provides an excellent guide for getting through the massive amounts of literature for any purpose: in a dissertation, an M.A. thesis, or preparing a research article for publication in any field of study. Below is a summary of the steps they outline as well as a step-by-step method for writing a literature review.

How to Write a Literature Review

Step One: Decide on your areas of research:

Before you begin to search for articles or books, decide beforehand what areas you are going to research. Make sure that you only get articles and books in those areas, even if you come across fascinating books in other areas. A literature review I am currently working on, for example, explores barriers to higher education for undocumented students.

Step Two: Search for the literature:

Conduct a comprehensive bibliographic search of books and articles in your area. Read the abstracts online and download and/or print those articles that pertain to your area of research. Find books in the library that are relevant and check them out. Set a specific time frame for how long you will search. It should not take more than two or three dedicated sessions.

Step Three: Find relevant excerpts in your books and articles:

Skim the contents of each book and article and look specifically for these five things:

1. Claims, conclusions, and findings about the constructs you are investigating

2. Definitions of terms

3. Calls for follow-up studies relevant to your project

4. Gaps you notice in the literature

5. Disagreement about the constructs you are investigating

When you find any of these five things, type the relevant excerpt directly into a Word document. Don’t summarize, as summarizing takes longer than simply typing the excerpt. Make sure to note the name of the author and the page number following each excerpt. Do this for each article and book that you have in your stack of literature. When you are done, print out your excerpts.

Step Four: Code the literature:

Get out a pair of scissors and cut each excerpt out. Now, sort the pieces of paper into similar topics. Figure out what the main themes are. Place each excerpt into a themed pile. Make sure each note goes into a pile. If there are excerpts that you can’t figure out where they belong, separate those and go over them again at the end to see if you need new categories. When you finish, place each stack of notes into an envelope labeled with the name of the theme.

Step Five: Create Your Conceptual Schema:

Type, in large font, the name of each of your coded themes. Print this out, and cut the titles into individual slips of paper. Take the slips of paper to a table or large workspace and figure out the best way to organize them. Are there ideas that go together or that are in dialogue with each other? Are there ideas that contradict each other? Move around the slips of paper until you come up with a way of organizing the codes that makes sense. Write the conceptual schema down before you forget or someone cleans up your slips of paper.

Step Six: Begin to Write Your Literature Review:

Choose any section of your conceptual schema to begin with. You can begin anywhere, because you already know the order. Find the envelope with the excerpts in them and lay them on the table in front of you. Figure out a mini-conceptual schema based on that theme by grouping together those excerpts that say the same thing. Use that mini-conceptual schema to write up your literature review based on the excerpts that you have in front of you. Don’t forget to include the citations as you write, so as not to lose track of who said what. Repeat this for each section of your literature review.

Once you complete these six steps, you will have a complete draft of your literature review. The great thing about this process is that it breaks down into manageable steps something that seems enormous: writing a literature review.

I think that Foss and Walter’s system for writing the literature review is ideal for a dissertation, because a Ph.D. candidate has already read widely in his or her field through graduate seminars and comprehensive exams.

It may be more challenging for M.A. students, unless you are already familiar with the literature. It is always hard to figure out how much you need to read for deep meaning, and how much you just need to know what others have said. That balance will depend on how much you already know.

For people writing literature reviews for articles or books, this system also could work, especially when you are writing in a field with which you are already familiar. The mere fact of having a system can make the literature review seem much less daunting, so I recommend this system for anyone who feels overwhelmed by the prospect of writing a literature review.

*Destination Dissertation: A Traveler's Guide to a Done Dissertation

Image Credit/Source: Goldmund Lukic/Getty Images

Watch our Webinar to help you get published

Please enter your Email Address

Please enter valid email address

Please Enter your First Name

Please enter your Last Name

Please enter your Questions or Comments.

Please enter the Privacy

Please enter the Terms & Conditions

Leveraging user research to improve author guidelines at the Council of Science Editors Annual Meeting

How research content supports academic integrity

Finding time to publish as a medical student: 6 tips for Success

Software to Improve Reliability of Research Image Data: Wiley, Lumina, and Researchers at Harvard Medical School Work Together on Solutions

Driving Research Outcomes: Wiley Partners with CiteAb

ISBN, ISSN, DOI: what they are and how to find them

Image Collections for Medical Practitioners with TDS Health

How do you Discover Content?

Writing for Publication for Nurses (Mandarin Edition)

Get Published - Your How to Webinar

Finding time to publish as a medical student: 6 tips for success

How to Easily Access the Most Relevant Research: A Q&A With the Creator of Scitrus

Atypon launches Scitrus, a personalized web app that allows users to create a customized feed of the latest research.

FOR INDIVIDUALS

FOR INSTITUTIONS & BUSINESSES

WILEY NETWORK

ABOUT WILEY

Corporate Responsibility

Corporate Governance

Leadership Team

Cookie Preferences

Rights & Permissions

Latest Posts
LSE Authors
Choose a Book for Review
Submit a Book for Review
Bookshop Guides

Dr Ana Raquel Nunes

August 26th, 2016, book review: seven steps to a comprehensive literature review: a multimodal and cultural approach by anthony j. onwuegbuzie and rebecca frels.

3 comments | 2 shares

Estimated reading time: 10 minutes

In Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach , Anthony J. Onwuegbuzie and Rebecca Frels offer a new guide on how to produce a comprehensive literature review through seven key steps that incorporate rigour, validity and reliability. Ana Raquel Nunes recommends this helpful, well-informed and well-organised book to those undertaking literature reviews as well as those reflecting on research methodologies more broadly.

Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach. Anthony J. Onwuegbuzie and Rebecca Frels . Sage. 2016.

According to the authors, literature reviews should be systematic , defined ‘as a set of rigorous routines, documentation of such routines, and the way the literature reviewer negotiates particular biases throughout these routines’ (10). The authors acknowledge that this definition differs from the definitions of systematic literature reviews used in the health sciences. Instead, this book defines a comprehensive literature review (CLR) as an integrative review, being the combination of narrative review (i.e. theoretical, historical, general and methodological reviews) and systematic review (i.e. meta-analysis, meta-summary, rapid review and meta-synthesis).

Seven Steps to a Comprehensive Literature Review purposefully addresses CLR as ‘a methodological, culturally progressive approach involving the practice of documenting the process of inquiry into the current state of knowledge about a selected topic’ (18). Additionally, the authors’ approach to the CLR takes into account the researcher’s philosophical stance, research methods and practices which, when combined, create a framework for collecting, analysing and evaluating the information that will form the basis for conducting a literature review. The book thus presents five types of information – MODES: namely, Media; Observation(s); Documents; Experts(s); and Secondary Sources – that help the researcher in their journey through the literature review landscape, which in the end will produce either a separate output or inform primary research within a bigger research project.

Seven Steps to a Comprehensive Literature Review is an effective tool for an iterative process denoting a structured and chronological approach to conducting literature reviews. The book covers a range of research topics and practical examples arising from the authors’ own research including education, counselling and health systems research. Through these, the authors report an in-depth model characterised by a series of qualitative, quantitative and mixed research approaches, methods and techniques used to collect, analyse and evaluate data/information for the creation of new knowledge.

As its title suggests, the book is organised around seven sequential steps within three phases: the Exploration Phase includes Steps 1-5 (Exploring Beliefs and Topics; Initiating the Search; Storing and Organising Information; Selecting/Deselecting Information; and Expanding the Search (MODES)); the Interpretation Phase includes Step 6 (Analysing and Synthesising Information); and the Communication Phase includes Step 7 (Presenting the CLR Report). As the argument of the book develops, the differences between traditional literature reviews and the CLR become evident as the seven steps are unveiled. Traditional literature reviews are encapsulated within Steps 1-4, whilst a CLR goes further through the addition of Steps 5-7.

One of the steps that was of particular interest to me was Step 6 on analysing and synthesising information. The book advances research methodology knowledge and practice on the different elements of empirical data and how both qualitative and quantitative information can be analysed and synthesised to inform a CLR. In Step 6, the authors go to great lengths to explain and exemplify how users can perform qualitative and quantitative data analyses of information, as well as the level of integration that can be achieved when doing mixed methods analyses. Additionally, the authors explore the nature of data analysis and identify three levels or layers that need to be taken into consideration: namely, the research approach (e.g. grounded theory); the research method (e.g. measures if regression); and the research technique (e.g. content analysis) used. This is found to be essential as data analysis is considered to be a product of the research method used, which in turn is linked to the research approach.

Seven Steps to a Comprehensive Literature Review is not merely intended for those conducting a literature review, but it also works as a research methodology book as it addresses an extensive number of research methodologies, methods and techniques. The book offers a theoretically and practically informed discussion of increased integration of research processes, practices and products, raising important quality standards assurances necessary for a CLR, but also for research more generally. This is a very well-organised book which cleverly and effectively uses tables, figures and boxes throughout to illustrate and help contextualise detailed examples of the different steps involved in conducting a literature review.

Accordingly, readers seeking a tool or a guide on conducting literature reviews will find this a very helpful book. It will also be of use to a broader readership interested in research methodology more generally as it encompasses the different research traditions (qualitative, quantitative and mixed methods) as well as the stages of the research process (the research problem, the literature review, research design, data collection, data analysis and interpretation and report writing). For the reasons above, it will appeal widely to students, academics and practitioners interested in conducting literature reviews within the social, behavioural and health sciences. It is suitable for different levels of experience in conducting literature reviews and doing research in general. Furthermore, this is a book that should be at-hand and used as a guide each time one decides to conduct a piece of research that includes a literature review as it will provide new ideas and directions depending on the topic and disciplinary perspective.

Note: This review gives the views of the author, and not the position of the LSE Review of Books blog, or of the London School of Economics. The LSE RB blog may receive a small commission if you choose to make a purchase through the above Amazon affiliate link. This is entirely independent of the coverage of the book on LSE Review of Books.

Image Credit: ( Ines Hegedus-Garcia CC BY 2.0 ).

About the author

Dr Ana Raquel Nunes is a Research Fellow in the Division of Health Sciences at the Warwick Medical School, University of Warwick, and a Research Methodologist and Adviser for the National Institute for Health Research (NIHR) Research Design Service (RDS). She is an interdisciplinary and mixed methods researcher working at the interface between public health, environmental science and social science. Her active interests include human vulnerability, resilience and adaptation to stresses and threats (e.g. climate change), housing and health, and fuel poverty. You can find more about her research here.

Pingback: Impact of Social Sciences – Book Review: Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach by Anthony J. Onwuegbuzie and Rebecca Frels
Pingback: Why should essay creating continue to be taught in schools? | Hayatder
Pingback: How you can study research papers quickly? – NCTaps

Book Review: Taking Control of Writing Your Thesis: A Guide to Get You to the End by Kay Guccione and Jerry Wellington

February 1st, 2019.

Twelve Top Tips for Writing an Academic Book Blurb

March 19th, 2020.

Literature Review: Conducting & Writing

Steps for Conducting a Lit Review

1. Choose a topic. Define your research question.

2. decide on the scope of your review., 3. select the databases you will use to conduct your searches., 4. conduct your searches and find the literature. keep track of your searches, 5. review the literature..

Finding "The Literature"
Organizing/Writing
APA Style This link opens in a new window
Chicago: Notes Bibliography This link opens in a new window
MLA Style This link opens in a new window
Sample Literature Reviews

Disclaimer!!

Conducting a literature review is usually recursive, meaning that somewhere along the way, you'll find yourself repeating steps out-of-order.

That is actually a good sign.

Reviewing the research should lead to more research questions and those questions will likely lead you to either revise your initial research question or go back and find more literature related to a more specific aspect of your research question.

Your literature review should be guided by a central research question. Remember, it is not a collection of loosely related studies in a field but instead represents background and research developments related to a specific research question, interpreted and analyzed by you in a synthesized way.

Make sure your research question is not too broad or too narrow. Is it manageable?
Begin writing down terms that are related to your question. These will be useful for searches later.
If you have the opportunity, discuss your topic with your professor.

How many studies do you need to look at? How comprehensive should it be? How many years should it cover?

Tip: This may depend on your assignment. How many sources does the assignment require?

Make a list of the databases you will search. Remember to include comprehensive databases such as WorldCat and Dissertations & Theses, if you need to.

Where to find databases:

Find Databases by Subject UWF Databases categorized by discipline
Find Databases via Research Guides Librarians create research guides for all of the disciplines on campus! Take advantage of their expertise and see what discipline-specific search strategies they recommend!
Review the abstracts of research studies carefully. This will save you time.
Write down the searches you conduct in each database so that you may duplicate them if you need to later (or avoid dead-end searches that you'd forgotten you'd already tried).
Use the bibliographies and references of research studies you find to locate others.
Ask your professor or a scholar in the field if you are missing any key works in the field.
Use RefWorks to keep track of your research citations. See the RefWorks Tutorial if you need help.

Some questions to help you analyze the research:

What was the research question of the study you are reviewing? What were the authors trying to discover?
Was the research funded by a source that could influence the findings?
What were the research methodologies? Analyze its literature review, the samples and variables used, the results, and the conclusions. Does the research seem to be complete? Could it have been conducted more soundly? What further questions does it raise?
If there are conflicting studies, why do you think that is?
How are the authors viewed in the field? Has this study been cited?; if so, how has it been analyzed?

Tips:

Again, review the abstracts carefully.
Keep careful notes so that you may track your thought processes during the research process.
<< Previous: Home
Next: Finding "The Literature" >>
Last Updated: Sep 11, 2024 1:37 PM
URL: https://libguides.uwf.edu/litreview

Seven Steps to a Comprehensive Literature Review A Multimodal and Cultural Approach

Anthony j. onwuegbuzie.

Rebecca Frels - Lamar University, USA

Format	Published Date	ISBN	Price
Hardcover	02/25/2016	9781446248911	$164.00
Paperback	02/25/2016	9781446248928	$56.00
Electronic Version	03/28/2016	9781446299463	$50.00
Electronic Version	03/13/2016	9781473944121	$50.00
Electronic Version	03/13/2016	9781473944121	$50.00
Electronic Version	02/28/2016	9781473944138	$50.00
Electronic Version	03/13/2016	9781473944121	$28.00
Electronic Version	03/13/2016	9781473944121	$31.00
Electronic Version	03/13/2016	9781473944121	$34.00

Sadly this book never arrived despite me being very interested to adopt for my MSc students dissertation stage.

Rebecca Frels

Graduate Research: Guide to the Literature Review

"Literature review" defined
Research Communication Graphic
Literature Review Steps
Search techniques
Finding Additional "Items
Evaluating information
Citing Styles
Ethical Use of Information
Research Databases This link opens in a new window
Get Full Text
Reading a Scholarly Article
Author Rights
Selecting a publisher

Introduction to Research Process: Literature Review Steps

When seeking information for a literature review or for any purpose, it helps to understand information-seeking as a process that you can follow. 5 Each of the six (6) steps has its own section in this web page with more detail. Do (and re-do) the following six steps:

1. Define your topic. The first step is defining your task -- choosing a topic and noting the questions you have about the topic. This will provide a focus that guides your strategy in step II and will provide potential words to use in searches in step III.

2. Develop a strategy. Strategy involves figuring out where the information might be and identifying the best tools for finding those types of sources. The strategy section identifies specific types of research databases to use for specific purposes.

3. Locate the information . In this step, you implement the strategy developed in II in order to actually locate specific articles, books, technical reports, etc.

4. Use and Evaluate the information. Having located relevant and useful material, in step IV you read and analyze the items to determine whether they have value for your project and credibility as sources.

5. Synthesize. In step V, you will make sense of what you've learned and demonstrate your knowledge. You will thoroughly understand, organize and integrate the information --become knowledgeable-- so that you are able to use your own words to support and explain your research project and its relationship to existing research by others.

6. Evaluate your work. At every step along the way, you should evaluate your work. However, this final step is a last check to make sure your work is complete and of high quality.

Continue below to begin working through the process.

5. Eisenberg, M. B., & Berkowitz, R. E. (1990). Information Problem-Solving: the Big Six Skills Approach to Library & Information Skills Instruction . Norwood, NJ: Ablex Publishing.

1. Define your topic.

I. Define your topic

A. Many students have difficulty selecting a topic. You want to find a topic you find interesting and will enjoy learning more about.

B. Students often select a topic that is too broad. You may have a broad topic in mind initially and will need to narrow it.

1. To help narrow a broad topic :

a. Brainstorm.

1). Try this technique for brainstorming to narrow your focus.

a) Step 1. Write down your broad topic.

b) Step 2. Write down a "specific kind" or "specific aspect" of the topic you identified in step 1.

c) Step 3. Write down an aspect --such as an attribute or behavior-- of the "specific kind" you identified in step 2.

d) Step 4. Continue to add levels of specificity as needed to get to a focus that is manageable. However, you may want to begin researching the literature before narrowing further to give yourself the opportunity to explore what others are doing and how that might impact the direction that you take for your own research.

2) Three examples of using the narrowing technique. These examples start with very, very broad topics, so the topic at step 3 or 4 in these examples would be used for a preliminary search in the literature in order to identify a more specific focus. Greater specificity than level 3 or 4 will ultimately be necessary for developing a specific research question. And we may discover in our preliminary research that we need to alter the direction that we originally were taking.

a) Example 1.

Step 1. information security

Step 2. protocols

Step 3. handshake protocol

Brainstorming has brought us to focus on the handshake protocol.

b) Example 2.

Step 1. information security

Step 2. single sign-on authentication

Step 3. analyzing

Step 4. methods

Brainstorming has brought us to focus on methods for analyzing the security of single sign-on authentication

c) Example 3. The diagram below is an example using the broad topic of "software" to show two potential ways to begin to narrow the topic.

C. Once you have completed the brainstorming process and your topic is more focused, you can do preliminary research to help you identify a specific research question .

1) Examine overview sources such as subject-specific encyclopedias and textbooks that are likely to break down your specific topic into sub-topics and to highlight core issues that could serve as possible research questions. [See section II. below on developing a strategy to learn how to find these encyclopedias]

2). Search the broad topic in a research database that includes scholarly journals and professional magazines (to find technical and scholarly articles) and scan recent article titles for ideas. [See section II. below on developing a strategy to learn how to find trade and scholarly journal articles]

D. Once you have identified a research question or questions, ask yourself what you need to know to answer the questions. For example,

1. What new knowledge do I need to gain?

2. What has already been answered by prior research of other scholars?

E. Use the answers to the questions in C. to identify what words to use to describe the topic when you are doing searches.

1. Identify key words

a. For example , if you are investigating "security audits in banking", key terms to combine in your searches would be: security, audits, banking.

2. Create a list of alternative ways of referring to a key word or phrase

a.For example , "information assurance" may be referred to in various ways such as: "information assurance," "information security," and "computer security."

b. Use these alternatives when doing searches.

3. As you are searching, pay attention to how others are writing about the topic and add new words or phrases to your searches if appropriate.

2. Develop a strategy.

II. Develop a strategy for finding the information.

A. Start by considering what types of source might contain the information you need . Do you need a dictionary for definitions? a directory for an address? the history of a concept or technique that might be in a book or specialized encyclopedia? today's tech news in an online tech magazine or newspaper? current research in a journal article? background information that might be in a specialized encyclopedia? data or statistics from a specific organization or website? Note that you will typically have online access to these source types.

B. This section provides a description of some of the common types of information needed for research.

1. For technical and business analysis , look for articles in technical and trade magazines . These articles are written by information technology professionals to help other IT professionals do their jobs better. Content might include news on new developments in hardware or software, techniques, tools, and practical advice. Technical journals are also likely to have product ads relevant to information technology workers and to have job ads. Examples iof technical magazines include Network Computing and IEEE Spectrum .

2. To read original research studies , look for articles in scholarly journals and conference proceedings . They will provide articles written by information technology professionals who are reporting original research; that is, research that has been done by the authors and is being reported for the first time. The audience for original research articles is other information technology scholars and professionals. Examples of scholarly journals include Journal of Applied Security Research , Journal of Management Information Systems , IEEE Transactions on Computers , and ACM Transactions on Information and System Security .

3. For original research being reported to funding agencies , look for technical reports on agency websites. Technical reports are researcher reports to funding agencies about progress on or completion of research funded by the agency.

4. For in-depth, comprehensive information on a topic , look for book-length volumes . All chapters in the book might be written by the same author(s) or might be a collection of separate papers written by different authors.

5. To learn about an unfamiliar topic , use textbooks , specialized encyclopedias and handbooks to get get overviews of topics, history/background, and key issues explained.

6. For instructions for hardware, software, networking, etc., look for manuals that provide step-by-step instructions.

7. For technical details about inventions (devices, instruments, machines), look for patent documents .

C. NOTE - In order to search for and find original research studies, it will help if you understand how information is produced, packaged and communicated within your profession. This is explained in the tab "Research Communication: Graphic."

3. Locate the information.

III. Locate the information

A. Use search tools designed to find the sources you want. Types of sources were described in section II. above.

Always feel free to Ask a librarian for assistance when you have questions about where and how locate the information you need.

B. Evaluate the search results (no matter where you find the information)

1. Evaluate the items you find using at least these 5 criteria:

a. accuracy -- is the information reliable and error free?

1) Is there an editor or someone who verifies/checks the information?

2) Is there adequate documentation: bibliography, footnotes, credits?

3) Are the conclusions justified by the information presented?

b. authority -- is the source of the information reputable?

1) How did you find the source of information: an index to edited/peer-reviewed material, in a bibliography from a published article, etc.?

2) What type of source is it: sensationalistic, popular, scholarly?

c. objectivity -- does the information show bias?

1) What is the purpose of the information: to inform, persuade, explain, sway opinion, advertise?

2) Does the source show political or cultural biases?

d. currency -- is the information current? does it cover the time period you need?

e. coverage -- does it provide the evidence or information you need?

2. Is the search producing the material you need? -- the right content? the right quality? right time period? right geographical location? etc. If not, are you using

a. the right sources?

b. the right tools to get to the sources?

c. are you using the right words to describe the topic?

3. Have you discovered additional terms that should be searched? If so, search those terms.

4. Have you discovered additional questions you need to answer? If so, return to section A above to begin to answer new questions.

4. Use and evaluate the information.

IV. Use the information.

A. Read, hear or view the source

1. Evaluate: Does the material answer your question(s)? -- right content? If not, return to B.

2. Evaluate: Is the material appropriate? -- right quality? If not, return to B.

B. Extract the information from the source : copy/download information, take notes, record citation, keep track of items using a citation manager.

1. Note taking (these steps will help you when you begin to write your thesis and/or document your project.):

a. Write the keywords you use in your searches to avoid duplicating previous searches if you return to search a research database again. Keeping track of keywords used will also save you time if your search is interrupted or you need return and do the search again for some other reason. It will help you remember which search terms worked successfully in which databases

b. Write the citations or record the information needed to cite each article/document you plan to read and use, or make sure that any saved a copy of the article includes all the information needed to cite it. Some article pdf files may not include all of the information needed to cite, and it's a waste of your valuable time to have to go back to search and find the items again in order to be able to cite them. Using citation management software such as EndNote will help keep track of citations and help create bibliographies for your research papers.

c. Write a summary of each article you read and/or why you want to use it.

5. Synthesize.

V. Synthesize.

A. Organize and integrate information from multiple sources

B. Present the information (create report, speech, etc. that communicates)

C. Cite material using the style required by your professor or by the venue (conference, publication, etc.). For help with citation styles, see Guide to Citing Sources . A link to the citing guide is also available in the "Get Help" section on the left side of the Library home page

6. Evaluate your work.

VI. Evaluate the paper, speech, or whatever you are using to communicate your research.

A. Is it effective?

B. Does it meet the requirements?

C. Ask another student or colleague to provide constructive criticism of your paper/project.

<< Previous: Research Communication Graphic
Next: Search techniques >>
Last Updated: Sep 11, 2024 3:08 PM
URL: https://library.dsu.edu/graduate-research

University of Texas Libraries

Literature Reviews

Steps in the literature review process.

What is a literature review?
Define your research question
Determine inclusion and exclusion criteria
Choose databases and search
Review Results
Synthesize Results
Analyze Results
Librarian Support
Artificial Intelligence (AI) Tools
You may need to some exploratory searching of the literature to get a sense of scope, to determine whether you need to narrow or broaden your focus
Identify databases that provide the most relevant sources, and identify relevant terms (controlled vocabularies) to add to your search strategy
Finalize your research question
Think about relevant dates, geographies (and languages), methods, and conflicting points of view
Conduct searches in the published literature via the identified databases
Check to see if this topic has been covered in other discipline's databases
Examine the citations of on-point articles for keywords, authors, and previous research (via references) and cited reference searching.
Save your search results in a citation management tool (such as Zotero, Mendeley or EndNote)
De-duplicate your search results
Make sure that you've found the seminal pieces -- they have been cited many times, and their work is considered foundational
Check with your professor or a librarian to make sure your search has been comprehensive
Evaluate the strengths and weaknesses of individual sources and evaluate for bias, methodologies, and thoroughness
Group your results in to an organizational structure that will support why your research needs to be done, or that provides the answer to your research question
Develop your conclusions
Are there gaps in the literature?
Where has significant research taken place, and who has done it?
Is there consensus or debate on this topic?
Which methodological approaches work best?
For example: Background, Current Practices, Critics and Proponents, Where/How this study will fit in
Organize your citations and focus on your research question and pertinent studies
Compile your bibliography

Note: The first four steps are the best points at which to contact a librarian. Your librarian can help you determine the best databases to use for your topic, assess scope, and formulate a search strategy.

Videos Tutorials about Literature Reviews

This 4.5 minute video from Academic Education Materials has a Creative Commons License and a British narrator.

How to Use AI for Literature Review (2024): Complete 7 Step Guide for Researchers

Jc Chaithanya

13 min read

What is a Literature Review and Why Does It Matter?

Different types of literature review, method 1: using multiple ai tools for literature review, method 2: using elephas for literature review, advantages of using ai for literature review, the traditional approach: manual literature review, the new kid on the block: ai literature review, comparing the two approaches, common concerns and misconceptions about ai in literature review, things to keep in mind while using ai for literature review, conclusion , 1. can gpt-4 do a literature review , 2. can you use ai to do a literature review, 3. what is the ai tool to summarize the literature review.

Literature reviews are a crucial yet time-consuming part of academic research.

With the advent of artificial intelligence (AI), researchers now have tools that can significantly streamline this process. This guide explores how AI can be effectively utilized to enhance and accelerate literature reviews.

We'll cover the following key aspects:

The role of AI in literature reviews
Specific AI tools designed for academic research, such as Elephas
Best practices for integrating AI into your research workflow
Potential benefits and limitations of AI-assisted literature reviews

Whether you're a seasoned researcher or a student embarking on your first major project, this guide will provide practical insights on leveraging AI to improve your literature review process.

So let's get started.

When researchers start a new project , they don't just jump in blindly. They first look at what others have already figured out. That's where a literature review comes in handy.

It's like piecing together a puzzle. You gather all the bits of information from different studies, articles, and books. Then you start to see the big picture. What do we know so far? Where are the gaps? Are there any hot debates going on?

All these will translate to

It connects their work to the bigger conversation in their field

It stops researchers from reinventing the wheel

It helps them spot new angles to explore

It shows they've done their homework

By digging into existing research, scholars can push knowledge forward. They're not starting from scratch, but building on what's already there. Plus, a good literature review is super helpful for other researchers too.

It gives them a quick way to catch up on a topic without having to read through piles of separate studies. This saves time and helps guide future research efforts.

Literature reviews can take on various forms depending on their purpose and approach. Below are some of the most popular types of literature reviews:

Narrative Review: This review gives a broad summary of existing studies on a topic but doesn't adhere to a rigid structure. It's often used to provide general insights without analyzing the specifics deeply.

Systematic Review: A systematic review follows a well-defined method to gather, assess, and interpret all available research on a particular question, aiming to reduce bias and provide a more accurate picture of the subject.

Meta-Analysis: This method uses statistical techniques to combine findings from several studies. The goal is to derive a stronger conclusion by merging the data and providing more robust results.

Scoping Review: A scoping review maps out the main ideas and gaps in a field of research, helping to identify where more studies are needed and suggesting potential directions for future research .

Critical Review: This type of review critically examines the strengths and weaknesses of existing research, offering new perspectives or challenging previously accepted theories.

Well, each type offers unique insights based on the research objective, shaping the direction of further inquiry of the research.

Step-by-Step Guide on How to Use AI for Literature Review

Using AI for literature review can significantly streamline your research process. Let's explore two methods: a multi-tool approach and using Elephas, an all-in-one assistant.

Using Multiple AI Tools for Literature Review

1. Identify Your Research Topic and Keywords

The first step is defining your research area. Use Perplexity AI for topic exploration and generating research questions. This AI tool helps you uncover new angles for research topics by analyzing vast amounts of data quickly.

2. Search for Relevant Articles

Start your literature search by heading to Elicit.org. Export the articles based on categories like abstract, author, title, and publication date. You can also use other AI-powered search tools like Semantic Scholar or Google Scholar to broaden your sources.

3. Generate Summaries and Key Themes with GPT-4o

After gathering your articles, use GPT-4o to analyze the abstracts and generate key themes. Input the abstracts with prompts like, “ Please summarize the key themes from these articles. ” This step saves hours of manual reading and gives you a thematic overview.

4. Draft an Initial Literature Review with Copy.ai

Use Copy.ai to create a first draft of your literature review. Its AI-powered writing features allow you to generate sections of the review quickly and in a structured format. Copy.ai can assist in writing specific sections, such as background or methodology, based on the keywords and themes you provide.

5. Refine with Smart Writing Tools

Use AI tools like Jasper or Writesonic to refine your literature review. These tools help to paraphrase content, improve readability, and adapt the tone to meet academic standards. The rewrites from these tools can help make the content more engaging and coherent.

6. Organise References Using Reference Managers

As you finalise your draft, integrate reference management tools like Mendeley or Zotero. These tools can store and organise all the references cited in your paper, and AI integration allows for easy reference generation.

7. Use Perplexity AI for Final Checks

Before submission, use Perplexity AI again to check for any gaps in the research or identify potential new areas to explore. It can provide suggestions based on the latest publications and research trends.

Elephas offers an all-in-one solution for conducting literature reviews. Here’s how you can use it:

1. Search the Web with Elephas

Elephas’ web search feature allows you to find relevant articles directly within the tool. Simply input your research terms, and it will pull up related papers, articles, and sources for you to analyse.

2. Analyse Key Themes

Using integrated AI models like GPT-4 or Claude, you can analyse the abstracts or summaries of these papers to identify key themes.

3. Generate a Literature Review

With Elephas’ Smart Write feature, you can create a well-structured literature review in just a few prompts. It pulls in the key themes and drafts a coherent review, ensuring that all relevant abstracts are referenced accurately.

4. Organise with Super Brain

Elephas’ Super Brain feature helps you manage the knowledge from the papers, documents, and research you’re using. It organises and categorises the data for easy access during the writing process.

5. Refine and Customise Tone

Elephas allows you to refine the review by using its multiple writing modes (Zinsser, Friendly, Professional, or Viral Mode). You can ensure that the literature review matches your preferred tone and style.

6. Manage References and Citations

With the help of Super Brain, you can manage references and citations within the text, simplifying the process of creating a bibliography.

By using Elephas, you can significantly speed up the literature review process while maintaining high quality. It’s a comprehensive all-in-one AI tool, making it one of the best solutions for conducting literature reviews.

Advantages of Using AI for Literature Review

AI is changing the game for researchers tackling literature reviews. Now, we've got smart tools that can do a lot of the heavy lifting for us. Let's explore some advantages of using AI for literature review.

Time Efficiency: AI dramatically speeds up the review process. It can analyze thousands of articles in minutes, a task that would take humans days or weeks to complete.

Comprehensive Coverage: AI can thoroughly scan vast databases, ensuring no relevant study slips through the cracks.

Pattern Recognition: AI literature tools excel at identifying trends and connections across multiple studies, often spotting insights that humans might overlook.

Bias Reduction: AI approaches each piece of literature objectively, helping to minimize human biases that can creep into manual reviews.

Multilingual Capabilities: Language barriers become less of an issue. AI can process and analyze research in multiple languages, broadening the scope of reviews.

Data Visualization: Many AI tools can generate clear, insightful visualizations of complex data, making it easier to grasp key findings at a glance.

Continuous Updating: In rapidly evolving fields, AI can keep literature reviews current by continuously incorporating newly published research.

While AI brings these impressive benefits to the table, it's important to remember that it's not a wise move to use AI extensively and limit your human touch in the review.

The ideal approach is to combine AI with your critical thinking and domain knowledge. As AI technology continues to advance, its role in streamlining and improving literature reviews is only set to grow, opening up exciting new possibilities for more comprehensive and efficient research processes.

Manual Literature Review vs AI Literature Review

In the world of research, literature reviews play a crucial role. They help researchers understand what's already known about a topic and identify gaps in knowledge. Today, we're seeing a shift in how these reviews are conducted, with AI tools coming in and helping researchers to reduce their overall workflow. But what is actually better: manual literature review or AI-assisted literature reviews?

Manual literature reviews have been the standard for a long time. Here's what they typically involve:

They take detailed notes on each source

Researchers spend hours reading through papers and articles

Key themes and patterns are identified through careful analysis

Connections between different studies are made based on the expertise

This method has its strengths. It allows for deep understanding and critical thinking. Researchers can pick up on subtle nuances that might be important. However, it's also very time-consuming and can be limited by the researcher's ability to process large amounts of information.

AI-assisted literature reviews are changing the game. Here's how they work:

AI tools can quickly scan thousands of articles

Key themes and patterns are automatically extracted

They use advanced algorithms to identify relevant studies

Connections between studies are made based on data analysis

The speed and efficiency of AI reviews are impressive. They can process far more information than a human could in the same amount of time. This means researchers can get a broader view of their field quickly. AI tools are also great at spotting trends and connections that humans might miss.

When we look at manual and AI literature reviews side by side, we see some interesting differences:

Time efficiency: AI is much faster, potentially saving weeks of work

Scope: AI can cover a broader range of sources

Depth of analysis: Manual reviews often provide deeper insights

Bias: AI can help reduce human bias, but may have its own algorithmic biases

Flexibility: Manual reviews can adapt more easily to unique research needs

Language: AI can work across multiple languages, expanding the scope of research

It's important to note that AI isn't perfect. It might miss context or nuances that a human would catch. That's why many researchers are now using a hybrid approach.

They use AI to do the initial heavy lifting, then apply their own expertise to refine and interpret the results.

In the end, whether manual or AI-assisted, the goal of a literature review remains the same: to build a solid foundation for new research and contribute to the advancement of knowledge in the field.

There are many concerns and misconceptions about using AI in literature reviews. It's natural to have doubts about new technology, especially when it comes to something as crucial as research.

One big worry is that AI might replace human researchers. But that's not really the case. AI is a powerful tool, but it can't match the critical thinking and deep understanding that humans bring to the table, at least for now. It's more of a helper than a replacement.

Accuracy Concerns: There's a misconception that AI might misinterpret or miss important information. Modern AI tools are actually quite accurate, but they do need proper setup and oversight to perform at their best.

Over-reliance on Technology: Some worry researchers might become too dependent on AI, losing their own analytical skills. In reality, AI frees up time for deeper analysis and creative thinking.

Data Privacy Issues: Concerns about data security and privacy are valid. It's crucial to use AI tools that adhere to strict data protection standards.

Limited to Quantitative Analysis: Many think AI can only handle numbers and statistics. Actually, advanced AI can process qualitative data too, including complex text analysis.

High Costs: While some AI tools can be expensive, many affordable options exist. The efficiency gains often outweigh the initial investment.

Complexity of Use: There's a belief that AI tools are too complicated for the average researcher. In fact, many are designed with user-friendly interfaces.

When using AI for literature reviews, there are several key points to keep in mind. Let's check out these important considerations that might get you into trouble if not checked properly when using AI for a literature review.

Quality Control: While using AI, you need to always double-check the results it generates. Take the time to review the selected articles and ensure they're truly relevant to your research.

Ethical Considerations: The use of AI in academic work is still a hot topic. Be mindful of ethical concerns, particularly around plagiarism and AI-generated content. Make sure your work is original and properly cited.

Stay Updated: Keep an eye on the latest developments in AI tools for literature reviews. What's new in the AI market and what’s outdated will help inform you to make the most of these tools.

Define Clear Parameters: Be specific about your research questions, keywords, and inclusion criteria. The more precise your input, the more relevant your results will be.

Understand AI Limitations: AI is great at processing large amounts of data, but it might miss nuances or context that a human would catch.

Maintain a Critical Perspective: Don't accept AI-generated summaries or analyses at face value. Apply your critical thinking skills. Question the results, look for potential biases, and consider alternative interpretations.

Document Your Process: Keep detailed records of how you used AI in your review. Note which tools you used, what parameters you set, and how you verified the results. This transparency is vital for the credibility of your work.

These tips may be generic and known to everyone, but many researchers, while using AI in their literature writing or revising process, still make these mistakes. Using AI is not wrong, but it's about finding the right balance between technological assistance and human expertise.

You know, it's pretty amazing how AI is shaking things up in the world of research. If you're knee-deep in literature reviews, learning to use AI could be a game-changer for you. It's like having a super-smart assistant who never gets tired and can spot connections you might miss.

There are a bunch of ways to go about it - you could mix and match different AI tools, or go for an all-in-one solution. The trick is finding what clicks for you. Just remember, AI is incredibly helpful, but it's not all good. You've still got to bring your expertise to the table.

As AI keeps evolving, it's opening up new possibilities for research. Who knows what breakthroughs we might see? So, getting comfortable with AI for literature reviews now could really set you up for the future.

It's an exciting time to be a researcher, that's for sure!

Yes, GPT-4 can help with a literature review by summarizing research papers, analyzing content, and identifying key themes. It speeds up the process by offering relevant insights from sources, but human expertise is still needed to ensure accuracy and a comprehensive understanding.

Yes, AI can assist in conducting a literature review by automating tasks such as summarizing research papers, analyzing large amounts of data, and highlighting important findings. This aids in streamlining the review process, although human judgment is essential for interpreting and validating the results effectively.

AI tools like Elephas, designed for summarizing literature reviews, help streamline the process by providing features such as offline support, multiple language models, and web search integration. These tools can quickly summarize key insights and trends across academic papers and other research sources.

AI assistant

Sign up now

Get a deep dive into the most important AI story of the week. Deliverd to your inbox for free!

Elephas helps you write faster and smarter on Mac - It's the best AI powered writing assistant for your Apple devices - Mac, iPhone and iPad.

You may also want to read

Top 10 Best AI Tools for Literature Review (Free + Paid)

Pinned Post

What’s New from Apple? iPhone 16 with AI, Apple Watch Series 10, and More!

iPhone Productivity

Jenni AI Review HONEST Review (2024): Is it the Best AI Writing Assistant for Research Papers

Open access
Published: 09 September 2024

Targeting the EphA2 pathway: could it be the way for bone sarcomas?

Giorgia Giordano 1 , 2 ,
Cristina Tucciarello 1 , 3 ,
Alessandra Merlini 2 ,
Santina Cutrupi 3 &
Ymera Pignochino 1 , 3

Cell Communication and Signaling volume 22 , Article number: 433 ( 2024 ) Cite this article

66 Accesses

Metrics details

Bone sarcomas are malignant tumors of mesenchymal origin. Complete surgical resection is the cornerstone of multidisciplinary treatment. However, advanced, unresectable forms remain incurable. A crucial step towards addressing this challenge involves comprehending the molecular mechanisms underpinning tumor progression and metastasis, laying the groundwork for innovative precision medicine-based interventions. We previously showed that tyrosine kinase receptor Ephrin Type-A Receptor 2 (EphA2) is overexpressed in bone sarcomas. EphA2 is a key oncofetal protein implicated in metastasis, self-renewal, and chemoresistance. Molecular, genetic, biochemical, and pharmacological approaches have been developed to target EphA2 and its signaling pathway aiming to interfere with its tumor-promoting effects or as a carrier for drug delivery. This review synthesizes the main functions of EphA2 and their relevance in bone sarcomas, providing strategies devised to leverage this receptor for diagnostic and therapeutic purposes, with a focus on its applicability in the three most common bone sarcoma histotypes: osteosarcoma, chondrosarcoma, and Ewing sarcoma.

Introduction

Bone sarcomas belong to a rare and heterogeneous group of malignant mesenchymal primary tumors originating from the osseous tissue, representing less than 1% of all malignancies [ 1 ]. Osteosarcoma (OS) and Ewing sarcoma (ES) occur mainly in adolescents and young adults, while chondrosarcoma (CS) has a peak incidence in the seventh decade of age [ 2 ]. Surgical excision of the tumor combined with radiotherapy and chemotherapy can achieve good results as first-line treatment; however, 40% of patients affected by bone sarcomas still die of the disease due to poor histological response to therapy, onset of multiple metastases, and relapses [ 3 ]. Several targeted therapies and immunotherapies against advanced unresectable bone sarcomas have been investigated in preclinical and clinical studies. Still, among innovative agents, only mifamurtide has entered the clinical management of OS until now [ 4 , 5 ]. Identifying novel molecular targets will be instrumental in overcoming the current impasse in treating relapsing disease. Receptor tyrosine kinases (RTKs) have been extensively studied as therapeutic targets in bone sarcoma, being implicated in several steps of their onset and progression [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Among them, the erythropoietin-producing hepatocellular (Eph) tyrosine kinases receptor family member 2 (EphA2) is a driver oncofetal protein implicated in self-renewal, chemoresistance, and metastasis [ 14 , 15 , 16 ] so that its targeting is now under preclinical and clinical investigation [ 17 , 18 , 19 , 20 , 21 ]. We previously showed that bone sarcoma patient-derived models overexpressed EphA2 and are sensitive to its inhibition [ 7 , 13 ]. In the present work, we combined a thorough overview of the literature to pursue the current knowledge of EphA2 functions in different tumors, focusing on bone sarcomas, and the main strategies developed so far for its specific targeting, exploring its potential applicability in these settings.

Eph receptors signaling and ephrins

Eph receptors belong to a large subfamily of RTKs expressed in various cell types in developing and mature tissues [ 22 , 23 ]. They have a highly conserved overall structure and are subdivided into two classes: EphA and EphB, based on their extracellular domain sequence homology and ligand binding specificity. In humans, nine EphA (A1-8, A10) and five EphB (B1-4, B6) receptors were identified with eight related ligands (Ephrin-A1-5 and Ephrin-B1-3) [ 24 , 25 ]. The EphA receptor members bind preferentially to Ephrin-A ligands, while the EphB receptors bind to Ephrin-Bs, with some exceptions of cross-class binding such as EphA4, which interacts with Ephrin-B2 and B3, while EphB2 with Ephrin-A5 [ 26 ].

Eph receptors are single transmembrane proteins constituted by an extracellular side, which exerts ligand-binding activity and an intracellular side with intrinsic enzymatic properties [ 26 ]. Starting from the N-terminal, the extracellular side of Eph receptors is composed of a ligand-binding domain (LBD) followed by a Cys-rich domain composed of the Sushi and the Epidermal Growth Factor (EGF)-like domains, and two fibronectin (FN) domains. The intracellular part of the Eph receptor is composed of the transmembrane (TM) region, the tyrosine kinase (TK) domain, the Sterile Alpha Motif (SAM), and the common structural PDZ domain (Fig. 1 ). The Eph ligands, Ephrins, are anchored to the cell membrane of interacting cells and share a conserved extracellular N-terminal receptor-binding domain (RBD) [ 25 ]. Class A is linked to the membrane through a glycosylphosphatidylinositol (GPI) linkage, whereas class B has a TM domain and an intracellular tail ending with a PDZ domain [ 24 ]. The interaction between Eph receptors and their ligands leads to the phosphorylation of various tyrosine (Tyr) residues between the TM and SAM domains. These post-translational modifications are crucial for the occurrence of the biological responses triggered by Eph signaling (Fig. 1 ).

Schematic representation of the structural and functional domains of Eph receptor and its ligands. Eph receptors are single transmembrane proteins constituted by an extracellular and an intracellular side. The extracellular side is composed of a ligand-binding domain (LBD), a Cys-rich domain made of the Sushi and the Epidermal Growth Factor (EGF)-like domains, and two fibronectin (FN1 and FN2) domains. The intracellular side is composed of the transmembrane (TM) region, the tyrosine kinase (TK) domain, the Sterile Alpha Motif (SAM), and the PDZ domain. Ephrin ligands are constituted by a receptor-binding domain (RBD). Class A Ephrins are linked to the membrane through the GPI linkage, while class B Ephrins have a TM domain and an intracellular tail ending with a PDZ domain. Ephrins can be released from the cell surface by proteolytic cleavage done by proteases such as MMPs and ADAMs and can activate Eph receptors in a paracrine manner. (Created with BioRender.com)

Physiologically, the Eph-Ephrin signaling pathway intervenes in multiple biological events such as axon guidance, tissue patterning, and blood vessel development in embryonic cells [ 27 , 28 ]. It is strictly dependent on cell type and microenvironment and works bi-directionally. Namely, it can affect both the receptor-expressing and the ligand-expressing cells [ 4 , 22 , 24 ]. Indeed, when the Eph receptor interacts with its ligand Ephrin on the adjacent cell, it initiates bidirectional signaling, which can be categorized as “forward” or “reverse” depending on the direction of signal flow. The classical forward signal (Ephrin: Eph) is often cell repulsive, dependent on Eph kinase activity and it propagates in the Eph receptor-expressing cell; conversely, the reverse signal (Eph: Ephrin) is dependent on Fyn, a kinase belonging to the Src family, and it propagates in the Ephrin-expressing cell [ 27 , 28 ] (Fig. 2 A). Furthermore, as both Eph receptors and Ephrins can function concurrently as receptors and ligands when present on opposing cells, we can distinguish between simultaneous parallel or antiparallel signaling based on the direction of signal propagation. Signaling is deemed “parallel” if the Eph-Ephrin complex transmits the signal in the same direction and “antiparallel” if it transmits the signal in opposite directions [ 22 , 29 ] (Fig. 2 B).

Schematic representation of the directional signaling evoked by Eph-Ephrin binding between adjacent interacting cells. ( A ) Eph receptor interacts with its ligand Ephrin on the adjacent cell, initiating a bidirectional signal, “forward” or “reverse”, based on the direction of signal flow. ( B ) The signal could also be “parallel” or “antiparallel”, if the Eph-Ephrin complex transmits the signal in the same or opposite directions, respectively. (Created with BioRender.com)

Proteolytic cleavage serves as a feedback mechanism of this signaling process. However, the extracellular portions of shed Eph and Ephrin can interact with distant cells autonomously, independent of cell-cell contact, resulting in paracrine effects [ 30 , 31 ]. For instance, they may act as monomeric inhibitors of bidirectional signaling [ 32 ]. Alternatively, cleaved ligands activate Eph receptors in an endocrine way. Soluble A-type Ephrin oligomers produced by the cleavage of GPI-anchored Ephrin-A1 on the plasma membrane by matrix metalloproteases (MMPs) or proteases of the A disintegrin and metalloproteinase (ADAM) family have the potential to activate EphA receptors, disrupting cell-cell contacts and increasing endothelial permeability which facilitates tumor metastasis to lungs [ 33 , 34 ]. Soluble B-type Ephrins are involved in pathological conditions such as fibrosis and cancers [ 35 ] (Fig. 1 ).

EphA2 is an oncofetal protein

Among Eph receptors, EphA2 is the most widely overexpressed in different tumor types [ 29 ]. EphA2 is a 130 kDa transmembrane glycoprotein of 976 amino acids encoded by the gene EPHA2 in the human genome on chromosome 1p36 [ 36 ]. EphA2 could be described as a fetal oncoprotein since it physiologically plays key roles in several biological processes during development, including embryonic lens and inner ear formation, mammary epithelial branching morphogenesis, kidney development, and bone homeostasis, and it is aberrantly reactivated in several solid tumors [ 37 , 38 , 39 , 40 ].

EphA2 interacts with all the Ephrin-A family ligands with preferential binding to Ephrin-A1 (EFNA1), a Tumor Necrosis Factor (TNF)-α–inducible gene product [ 41 ]. During embryogenesis, its physiological functions following cell-cell contact rely on the binding with EFNA1 on the neighboring cells generating both reverse and forward signaling [ 27 , 42 ]. During oncogenesis, EphA2 is overexpressed and signal transduction leads to modifications in cytoskeleton dynamics, cell adhesion, migration, metastasis, proliferation, and angiogenesis [ 43 ].

During normal development, the ligand-dependent EphA2 activation suppresses the Extracellular signal-regulated Kinases (ERKs), the Akt, and Focal Adhesion Kinase (FAK) signaling pathways inhibiting cell proliferation, resistance to apoptosis, and migration [ 44 ] (Fig. 3 A). However, in cancers, EphA2 is involved in a non-canonical activation through different mechanisms: (i) the dimerization with other RTKs such as the Epidermal Growth Factor Receptor (EGFR); the Human Epidermal Growth Factor Receptor-2 (HER2) [ 45 , 46 ]; some members of the Fibroblast Growth Factor Receptors (FGFRs); and Vascular Endothelial Growth Factor Receptors, (VEGFRs), or with cell adhesion molecules (e.g. E-cadherin and integrins) [ 47 , 48 ]; (ii) the direct binding with growth factors (e.g. the Platelet-Derived Growth Factor subunit A, PDGFA [ 49 ]; iii.) the direct phosphorylation of Serine-897 (P-Ser897 EphA2) located between the TK and SAM intracellular domains by intracellular oncogenic activated kinases, such as ERK Akt, and the Ribosomal S6 Kinase (RSK) [ 50 , 51 , 52 ]. P-Ser897 EphA2 recruits Ephexin4, a guanine nucleotide exchange factor, promoting resistance to the extracellular matrix detachment induced-cell death (anoikis), engaging the small GTPase Ras Homolog Gene Family Member G (Rho G)-Akt pathway activation (Fig. 3 B) [ 53 , 54 ]. EphA2 also plays a key role in integrin-mediated cell adhesion and migration through its association with FAK. In prostate cancer cells, the constitutive active EphA2/FAK complex is disassembled by the treatment with soluble EFNA1 that stimulates EphA2 Tyrosine phosphorylation and FAK dephosphorylation leading to the complex disassemble and the inhibition of cell migration [ 55 , 56 ]. However, the inhibitory effect of EFNA1-induced tyrosine phosphorylation of EphA2 is reversed by the action of the Low Molecular Weight Phospho-Tyrosine Phosphatase (LMW-PTP), a protein frequently overexpressed in cancer [ 57 ]. Moreover, LMW-PTP inhibits the p190 RhoGAP, (a Rho-GTP inhibitor), destabilizing adherent junctions via a RhoA-dependent mechanism inducing cell detachment and migration [ 58 ] (Fig. 3 B).

Ligand-dependent and ligand-independent EphA2 signal transduction, in normal and cancer cells, respectively. ( A ) In normal cells, the ligand-dependent EphA2 activation induced Tyrosine (Y) and Serine (S) phosphorylation, the Epha2 clustering, suppresses the proliferation, survival, and migration signaling pathways (ERK, Akt, FAK) inhibiting cell proliferation, resistance to apoptosis, and migration, and activates c-Cbl -mediated endosomal degradation and EphA2 recycling ( B ) In cancers, the non-canonical ligand-independent activation of EphA2 occurs through the dimerization with other RTKs (EGFR, HER2, FGFRs, VEGFRs) or cell adhesion molecules (E-cadherin, integrins); the direct binding with other ligands such as growth factors (e.g. platelet-derived growth factor A, PDGFA); or is mediated by intracellular oncogenic kinases (Akt, PKA, PKC, ERK). This induces the phosphorylation of Ser897, promoting cell proliferation, adhesion, and migration, other than drug resistance, protection to apoptosis and anoikis. (Created with BioRender.com)

The involvement of EphA2 in several solid tumors including melanoma, bone sarcomas, glioblastoma, lung, colorectal, prostate, pancreatic, endometrial, breast, and gastric cancers is widely demonstrated [ 16 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. In these tumors, EphA2 was shown to correlate with tumor stages, cancer aggressiveness, metastatic potential, and poor patient survival, so that could be considered a biomarker of poor prognosis [ 73 , 74 , 75 , 76 , 77 ]. Moreover, some evidence has recently shown that EphA2 is implicated in tumor-microenvironment crosstalk, promotion of metastasis, and chemoresistance [ 17 , 78 , 79 , 80 , 81 ]. EphA2 has been correlated with cancer-associated fibroblasts (CAFs) in many tumors. In gastric cancer, CAFs promote tumorigenesis through the EphA2 signaling pathway, and the treatment with the selective EphA2 inhibitor (ALW-II-41-27) or EphA2 silencing decreased the CAF-induced tumorigenesis [ 82 ]. Moreover, the EphA2-PI3K signaling pathway is involved in the CAF-induced vascular mimicry inducing gastric cancer cells to generate an endothelial-free blood delivery channel [ 83 ]. In addition, EphA2 may promote tumor-induced endothelial cell migration and angiogenesis, through its direct interaction with Caveolin-1 (CAV-1) and the consequent Akt activation and basic FGF (bFGF) production [ 84 ].

EphA2 as a potential therapeutic target in bone sarcoma

In the realm of rare tumors, bone sarcomas remain a particularly challenging category, often labeled as “drug-orphan tumors”, because of the lack of effective treatments for advanced disease. This is mainly due to their heterogeneity and rarity, which pose significant obstacles to drug discovery and the development of innovative therapy. In this context, exploring EphaA2 targeting emerges as a promising avenue [ 85 ].

Our group has provided evidence suggesting that EphA2 might be an effective molecular target in the three main bone sarcomas (OS, ES, and CS). Through a combination of in silico analyses, and in vitro experiments using bone sarcoma cell lines and patient-derived xenografts, we observed significant overexpression of EphA2 compared to healthy controls [ 13 ]. Furthermore, our studies revealed that inhibiting EphA2 directly with ALW-II-41-27 or decreasing its expression impaired bone sarcoma growth [ 7 , 13 ].

EphA2 in osteosarcoma

OS is the most common primary bone tumor [ 3 ]. It mainly affects children and young adults under 25 years old. Still, a second peak of incidence usually arises at the age of 60 years with a frequency of 0.2–0.3 and 0.8/1.1 cases per 100,000 people per year in the general population and at the age of 15–19, respectively, and with a 1.4 male/female ratio [ 86 , 87 , 88 ]. There are 3 main types of primary osteosarcoma: intramedullary, juxtacortical, and extraskeletal osteosarcoma. The intramedullary osteosarcoma develops in the medullary cavity of a long bone is the most common (80%) and can be further divided into osteoblastic, condroblastic, fibroblastic, small-cell, and epithelioid based on main cell types. The juxtacortical osteosarcoma (10–15%) develops on the outer surface of the bones or the periosteum. The extraskeletal osteosarcoma is the rarest (< 5%) originates in soft tissues and can be induced by radiotherapy. Differences in clinical behavior and treatment choice for each subtype were exhaustively reviewed elsewhere [ 89 ]. OS is characterized by complex genetic changes and instability which result in recurrent amplifications and DNA copy number variations at different chromosomal regions [ 90 ]. Two recurrent somatic mutations implicated in the genesis of this tumor result from the progressive accumulation of genetic defects: a mutation in the Retinoblastoma Protein 1 (RB1) gene associated with retinoblastoma at 13q14 and mutations in the Tumor Protein 53 (TP53) gene associated with Li-Fraumeni syndrome at 17p13 [ 91 ]. These known tumor suppressor genes are key players in bone oncogenesis [ 92 ]. However, efficient targetingof RB1 and TP53 alterations remains elusive, and druggable gene alterations are still lacking. The standard therapeutic approach in localized OS combines surgery and polychemotherapy; in advanced disease with lung metastases, repeated lung metastasectomy can achieve a permanent cure in a subset of selected patients [ 93 ] but the overall prognosis remains dismal [ 94 ]. Fritsche-Guenther et al. showed a high overexpression of the EphA2 and its ligand in human OS samples analyzed by microarray [ 62 ]. Though EFNA1 was strongly upregulated in tumor tissues, it was also detected in fetal and normal adult human bone tissue. On the contrary, an EphA2 de novo expression has been observed in OS tumor tissue only. Furthermore, preclinical data demonstrated that this pathway activation is involved in OS progression. Therefore, the upregulation of EphA2 and its ligand in OS contributes to oncogenic signaling and might stimulate the OS metastasis process [ 62 ]. This target is also strongly expressed at the proteomic level as shown by PosthumaDeBoer et al. which observed that EphA2 was one of the most abundant and highly expressed proteins in OS cell lines and human OS samples. Furthermore, they underscored the significance of EphA2 expression in patients by establishing correlations with clinical parameters and demonstrating its association with poor overall survival [ 95 ]. Our group confirmed the pro-tumorigenic role of EphA2 in OS cells demonstrating that EphA2 silencing significantly reduced cell proliferation and migration [ 7 ]. We showed for the first time that the inhibition of EphA2 occurred after treatments with two receptor tyrosine kinase inhibitors, pazopanib and trametinib [ 7 ]. Using bioinformatic analysis, we explored the EphA2 gene expression level in 10 OS cell lines of the whole Cancer Cell Line Encyclopedia (CCLE) and its relation to patient characteristics and clinical outcomes in 88 OS samples deposited in Gene Expression Omnibus (GEO). We observed a higher expression of EphA2 in tumors with a higher Huvos grade than in the lower [ 13 ]. These findings allow us to speculate that, despite the good outcome of chemotherapy (high Huvos grade), persister cells surviving after/tolerant to chemotherapy and typically responsible for disease relapse, express higher levels of EphA2, suggesting that EphA2 could be a good target for second-line therapy, or its targeting could be combined with first-line chemotherapy to overcome drug resistance. In addition, significant upregulation of EphA2 in males compared to females was observed [ 13 ]. Considering that a worse prognosis was registered in male OS patients [ 96 ], this could be attributed to higher EphA2 expression. Overall, these data rationally support the exploration of the EphA2 targeting in OS.

EphA2 in ewing sarcoma

ES is the second most frequent malignant bone tumor among children and adolescents with a median age at diagnosis of 15 years, slightly more common in males, and an incidence of 0.3 cases per 100,000 people per year, burdened by dismal prognosis in advanced stages [ 97 ]. The survival rate is 66% at 5 years and 20% at 5 years for poor responders [ 88 ]. Genetically, they are characterized by chromosomal translocation t(11;22)(q24;q29) in which the gene encoding for the RNA-binding protein EWS (EWSR1) is fused with the ETS transcription factor FLI1 resulting in EWSR1–FLI1 fusion gene. However, although rarely, few recurrent somatic mutations were found in ES, involving Cohesin Complex Component (STAG2), TP53, and Cyclin-Dependent Kinase inhibitor 2 A (CDKN2A) or else Kinase Insert Domain Receptor (KDR), Serine/Threonine Kinase 11 (STK11), DNA mismatch repair protein Mlh1 (MLH1), Kirsten rat sarcoma virus (KRAS), and Tyrosine-Protein Phosphatase Non-Receptor Type 11 (PTPN11) [ 98 , 99 , 100 ]. ESs are aggressive tumors, frequently displaying micrometastases at presentation [ 101 ]. These tumors exhibit a high sensitivity to chemotherapy and nearly 2/3 of the patients can be cured through multimodal treatment strategies, based on surgery and poli-chemotherapy with vincristine, doxorubicin, cyclophosphamide, and ifosfamide. Nevertheless, advanced/metastatic forms displayed poor outcomes [ 102 ]. ES family tumors do not benefit from established targeted therapies, emphasizing the imperative to uncover alternative therapeutic strategies. Recently, a phase I/II trial, conducted in a total of 85 patients not preselected for the ES molecular subtype, has shown good tolerability and limited activity of TK216, a small molecule inhibitor of EWS: FLI1 fusion protein inhibiting its function by preventing binding to RNA Helicase A [ 103 ].

Sáinz-Jaspeado et al. demonstrated the high expression of EphA2 protein in ES cell lines and patient samples investigating its association with the key membrane trafficking controlling protein CAV-1. CAV-1 contributes to angiogenesis in different tumors [ 104 , 105 ]. In ES angiogenesis, CAV-1 increases EphA2 activation and signaling influencing its membrane localization [ 84 , 106 ]. The formation of the EphA2/CAV1 complex also promoted the expression and secretion of bFGF, increasing tumor-induced migration of endothelial cells. These results suggest that in ES, EphA2-induced angiogenesis is dependent on CAV-1 [ 84 ]. In another study of the same group, EphA2 was reaffirmed as a significant contributor to the metastatic progression of ES owing to its involvement in cell signaling, mobility, and survival; moreover, the EphA2 phosphorylation at Ser897 was associated with ES aggressiveness [ 16 ]. Consistently, silencing EphA2 led to reductions in tumorigenicity, migration, invasiveness, and pulmonary metastatic progression in ES preclinical models. Finally, the knockdown of the metalloproteinase ADAM19, a downstream effector of EphA2 receptor signaling, negatively affects cell migration [ 16 , 107 ].

Furthermore, our previous study investigated the mRNA expression levels of EphA2 in 12 ES cell lines from the CCLE and its correlation with tissue type, patient characteristics, and clinical outcomes within a cohort of 246 ES patients archived in GEO database. Specifically, we observed a significantly higher expression of EphA2 in tumor samples compared to normal tissues, with higher levels observed in male patients than females [ 13 ]. As for OS also for ES, male patients display a worse prognosis than females [ 108 , 109 ]. These findings suggest that EphA2 might be related to more aggressive tumor behavior. Additionally, targeted inhibition of EphA2 resulted in a notable reduction of ES cell viability [ 13 ]. These experimental and computational findings collectively provide compelling evidence to support the hypothesis that targeting EphA2 overexpression may represent a viable therapeutic strategy for evaluation in advanced ES patients.

EphA2 in chondrosarcoma

CS represents a malignant mesenchymal tumor and is the third most common among bone sarcomas across all age groups, yet it predominates in adults. Unlike OS and ES, it mainly occurs during adulthood in patients over the age of 40, with an average incidence of 0.2 cases per 100,000 people per year, both male and female [ 2 , 3 ]. Most CSs arise as primary, low-grade, locally aggressive, non-metastasizing tumors (grade I) rather than high-grade (grades II-III). The histologic subtypes of CS include conventional, clear cell, mesenchymal, and dedifferentiated CS [ 3 ]. Patients with dedifferentiated CS are more likely to develop metastases and have a dismal prognosis with a 5-year overall survival of 7–24%. It is characterized by varied differentiated cells producing chondroid matrices, reflecting its high heterogeneity and association with intricate cytogenetic alterations [ 88 ]. Notably, mutations in Isocitrate Dehydrogenase (IDH) genes, specifically IDH1 and IDH2, are frequently observed, along with mutations in genes associated with cancer progression, such as TP53 [ 110 ]. CSs generally exhibit resistance to conventional chemotherapy regimens. Standard chemotherapy protocols yield poor results, and in cases in which surgical intervention becomes unviable, the prognosis is extremely poor. Recently, inhibition of IDH1 has shown some degree of activity [99]. Nevertheless, the clinical challenges posed by advanced CSs remain truly unmet in this context. The cornerstone of treatment for CS remains surgery and the result depends on the grade and location. Apart from low-grade CS of the extremities which are treated with extensive intralesional resection associated with local adjuvant treatment (high-speed burr, phenolization or cryotherapy, lavage with a high-pressure pulsatile system, and packing the defect with cement or bone graft). Generally, no adjuvant treatment is recommended in conventional CS due to its low sensitivity to radio and chemotherapy. Some retrospective reports suggest that mesenchymal CS is more chemo-sensitive, and may be considered for adjuvant or neoadjuvant therapy, mainly with Ewing-like regimens [ 111 ].

Zhang et al. evaluated the phosphorylation status of 42 RTKs in five CS cell lines showing that EphA2 was highly phosphorylated and constitutively activated in two of them [ 112 ]. Nevertheless, the EphA2 expression in CS tumor samples has not yet been extensively studied. In our previous work, we explored the EphA2 gene expression level in 4 CS cell lines belonging to the CCLE and its relationship with clinical and molecular features in a total of 102 CS patients from publicly available datasets. We observed a significantly higher expression of EphA2 in dedifferentiated CS samples with a worse prognosis than in better ones, and EphA2-specific inhibition impinged CS cell viability [ 13 ].

Considering these findings, there is a compelling rationale to pursue targeted therapy directed at EphA2 in advanced CS patients. Current therapeutic options for advanced CS remain notably inadequate, emphasizing the need for novel treatment strategies and EphA2 may represent a promising tool.

Therapeutic strategies for targeting EphA2 in solid tumors

A plethora of molecular, genetic, epigenetic, biochemical, pharmacological, and immunotherapeutic strategies targeting EphA2 and its signaling pathways have been developed. This review explored a wide range of interventions, including small molecule inhibitors, monoclonal antibodies, drug or toxin-conjugated antibodies or peptides, chimeric antigen receptor T lymphocytes (CAR-T), and dendritic cell (DC) vaccines investigated in cancer preclinical models and clinical trials, providing valuable insights into their potential efficacy and translation applications also for bone tumors (Fig. 4 ).

Schematic diagram summarizing the therapeutic targeting of EphA2 in solid tumors. EphA2 could be exploited as a molecular target ( pink ring): the disruption of its signaling through the inhibition of its expression by siRNAs, miRNAs, YSA-peptides, siRNA-loaded liposomes, and HDAC inhibitors; the promotion of its degradation by monoclonal antibodies, soluble EFNA1, mimetic peptides, EFNA1-Fc, disrupting SAM-SAM interaction peptides; or blocking its activation by EFNA1 antagonists, monoclonal antibodies, tyrosine kinase inhibitors; as a theranostic target (green ring) by using antibodies or peptides conjugates to exotoxins (MEDI547, BT5528, PE38KDEL-1F12, EFNA1-PE38QQR), chemotherapeutic agents (peptides-drug conjugated), nanotherapeutic agents (immunoliposomes or PEGylated nanoliposomes), or radiolabeled probes (radiolabeled antibodies or peptides); or as immunotherapeutic target (blue ring) by DC-vaccines, adoptive cell therapy approaches (CAR-T), or peptides conjugated with immunomodulators (bicyclic peptides). (Created with BioRender.com)

EphA2 as a molecular target

Among the different strategies that have been evaluated to disrupt EphA2 signaling, direct molecular targeting is by far the most investigated one. Indeed, several agents were shown to be able to bind the receptor and interfere with its tumor-promoting effects by different mechanisms such as inhibiting EphA2 expression, promoting its degradation, or blocking its activation [ 17 ](Fig. 4 ).

Inhibiting EphA2 expression

Short interfering RNAs (siRNAs) for gene knockdown have been used for EphA2 silencing and suppressing its expression in human cancer cells. Several studies showed that decreasing the levels of EphA2, through silencing by specific siRNAs, significantly induces antitumor activity, reducing tumor growth and promoting apoptosis, both in in vitro [ 7 ] and in vivo models including lung cancer, breast cancer, and glioma [ 113 , 114 , 115 , 116 ]. We showed that the silencing of EphA2 reduced OS cell proliferation and migration [ 7 ] (Fig. 5 ). Moreover, Zhou et al. demonstrated that combining an EphA2 siRNA with either cisplatin, etoposide, or minustine hydrochloride significantly enhanced the antitumor effect against glioma cells [ 116 ]. However, although siRNAs have shown good results in vitro, their activity in vivo was limited by the difficulties of obtaining efficient delivery, cellular uptake, and good stability in body fluids [ 117 ]. Aiming to overcome this limitation and improve siRNA delivery, EphA2-specific siRNA was incorporated into neutral 1,2-dioleoyl-sn-glycerol-3-phosphatidylcholine (DOPC) liposomes resulting in an efficient tumor growth reduction in ovarian cancer mouse xenograft models when administered both as a single agent or in combination with paclitaxel [ 118 ]. Later, siRNA-DOPC was tested in murine and primate models, showing good safety and feasibility [ 119 ], and prompting a phase 1 clinical trial (NCT01591356). A different strategy to improve the EphA2 transcription silencing was proposed by Choi et al. who synthesized the p19-YSA fusion protein, composed of p19 RNA-binding protein and the EFNA1 mimetic YSA peptide as a siRNA delivery strategy. Specifically, YSA is a short amino acid sequence (YSAYPDSVPMMS) that binds with high affinity and selectivity to EphA2, while p19 can bind with high stability to siRNAs, protecting them from external RNAses [ 120 , 121 ]. More recently, Oner et al. successfully developed a novel, safe, and efficient delivery system based on cationic solid lipid nanoparticles (cSLN) to enhance the bioavailability of EphA2-siRNAs in tumors. They used the dimethyldioctadecylammonium bromide (DDAB) to induce the reduction of the nanoparticle (NP) size and showed that siEphA2-loaded DDAB-cSLN displayed improved cellular uptake and EphA2 silencing [ 122 ].

List of the therapies targeting EphA2 tested preclinically in osteosarcoma, chondrosarcomas, and Ewing sarcomas. (Created with BioRender.com)

Other than siRNA, miRNAs seem to be a good strategy to inhibit the EphA2 expression in many tumors. Different miRNAs are involved in the regulation of the EphA2 oncogene, varying according to the tumor type. At first, Tsouko et al. identified miR-200a as a direct repressor of EphA2 in triple-negative breast cancer, while Li et al. showed the antitumor effect of miR-26b on hepatocellular carcinoma cells [ 123 , 124 ]. Subsequent research revealed that the overexpression of miR-200c downregulates EphA2 in malignant glioma, breast cancer, and lung carcinoma cells displaying efficient tumor-suppressive properties [ 125 ]. Similar tumor suppressive effects were observed with miR-141 in glioma cells, miRNA520d-3p and miR-302b in gastric cancers, and miR-519a on non-small cell lung cancer (NSCLC) cells [ 126 , 127 , 128 , 129 ]. Conversely, some miRNAs, such as miR-451a and miR-125a‐5p, naturally upregulate the expression of EphA2, making their inhibition a potential strategy to downregulate the oncogene expression. The reduction of miR-451a and miR125a-5p inhibits cell growth and metastasis in bladder carcinoma, and gastric cancer preclinical models, respectively [ 130 , 131 ].

The overexpression of EphA2 stems from transcriptional activation through regulatory regions controlled by epigenetic regulators. EphA2 is associated with super-enhancers (SEs) activation in tumors [ 132 , 133 ]. SEs are large clusters of enhancers that recruit multiple transcription factors and are implicated in the transcription of oncogenes [ 134 ]. Bioinformatic screening of Cancer Databases identified cancer-associated SEs by analyzing genomic regions with enriched histone 3 lysine 27 acetylation (H3K27Ac) marks. CRISPR technology targeting SE-associated EphA2 genes inhibits cell growth and metastasis. TCF7L2 and FOSL2 transcription factors were found to be recruited at SE-associated EphA2 loci during breast cancer progression [ 132 ]. Transcription factors exhibit cell-type-specific functions across different cancer types. Testicular nuclear Receptor 4 regulates EphA2 transcription in hepatocellular carcinoma and controls metastasis [ 135 ]. Changes in histone 3 lysine27 acetylation levels correspond to gene transcription regulation, with histone deacetylases (HDACs) playing a pivotal role in this process. HDACs are enzymes that modulate gene expression, making treatment with HDAC inhibitors a viable strategy to impede cancer progression. Notably, EphA2 expression was downregulated in advanced breast cancer following HDAC inhibitor treatment [ 115 ]. Furthermore, combining EphA2 and HDAC inhibitors enhanced the anti-tumor effects, underscoring the importance of identifying specific pathways in individual tumors to select optimal therapeutic approaches and develop personalized medicine [ 136 ].

Promoting EphA2 degradation

Soluble ligands or monoclonal antibodies (mAbs) that bind to EphA2 may disrupt oncogenic signaling by promoting receptor internalization and degradation [ 14 ]. Two independent studies showed that soluble EphA2 ligands in comparison with Fc-mAbs conjugated with EFNA1 induced EphA2 Tyr phosphorylation and proteasomal degradation, displaying tumor-suppressing properties in several tumor types including glioblastoma multiforme (GBM), gastric and breast adenocarcinoma [ 72 , 137 ]. Additionally, Xu et al. demonstrated that mEA1-EYFP-H10, a fusion protein consisting of monomeric EFNA1 (mEA1) conjugate with an enhanced yellow fluorescent protein and linked to a supported lipid bilayer via a 10-histidine (H10) anchor, induced the Tyr phosphorylation of EphA2, and subsequent degradation [ 138 ]. Similarly, two short EFNA1 mimetic peptides, YSA and SWL, have been utilized to specifically target EphA2 LBD, inducing Tyr phosphorylation and signaling activation, albeit with less potency compared to soluble ligands and Fc conjugates [ 139 ]. Subsequent structural modifications of these peptides have led to improved derivatives capable of acting as both EphA2 agonist and antagonist and serving as pharmacological carriers [ 140 ].

Otherwise, Alves et al., take advantage of the acidic extracellular medium of solid tumors and created a highly soluble conditional peptide, called TYPE7, designed based on the sequence of the TM domain of EphA2, which binds the EphA2 endogenous domain acting as a molecular clamp that envelopes dimers of EphA2. TYPE7 reduced Akt phosphorylation and inhibited cell migration, mimicking the EFNA1 effect [ 141 , 142 ]. Furthermore, the EphA2 SAM domain at the C-terminus facilitates interactions with regulators of receptor stability such as the lipid phosphatases Ship2 and the adaptor Odin. Ship2 decreased EphA2 endocytosis and consequent degradation, producing pro-oncogenic outcomes. In this setting, Mercurio et al. first discovered that the Ship2-SAM domain interaction promotes pro-oncogenic effects, identifying the peptide region involved in this interaction [ 143 ]. By computational and experimental approaches, they developed and tested several cyclic peptides that interfered with this complex and showed high serum stability and enhanced efficacy [ 144 , 145 ]. Another strategy to modulate EphA2 activation regards the development of mAbs and other agonists acting as EFNA1 mimetics and eventually inducing receptor internalization and degradation [ 14 ]. For example, Carles-Kinch et al. identified EA1.2 mAb which recognizes specific epitopes of the EphA2 extracellular domain, inhibiting metastatic features on breast cancer cells, while sparing normal breast epithelial cells [ 146 ]. Different mAbs displayed similar results in several solid tumors. Coffman et al. showed that EA2 and B233 EphA2-specific mAbs promote EphA2 phosphorylation and degradation in breast and lung cancer cells, reducing cell growth in mice models, while Ansuini et al. developed and tested IgG25, another specific EphA2 mAb that promotes receptor endocytosis and subsequent degradation in pancreatic cancer in vitro and in vivo models, particularly reducing EphA2 protein levels and the phosphorylation of FAK on Tyr576 [ 147 , 148 ]. Similarly, Jackson et al. generated an EphA2-specific fully humanized IgG1 mAb 1C1 able to induce receptor phosphorylation, internalization, and degradation [ 149 ]. DS-8895a is another new afucosylated humanized specific mAb which recognizes the extracellular juxtamembrane region of EphA2, interacting with both the full-length and truncated forms of the receptor. DS-8895a induces antibody-dependent cellular cytotoxicity, inhibiting tumor growth in both in vitro and in vivo models of breast and gastric cancers. Moreover, it potentiates the antitumor effect of cisplatin when administered in combination [ 150 ]. More recently, Sakamoto et al. produced three mAbs recognizing EphA2, showing that SHM16 inhibited migration and invasion of melanoma cells efficiently [ 151 ].

Blocking EphA2 activation

Agents binding to EphA2 or its ligand EFNA1 act as antagonists and suppress signaling, inhibiting Eph-Ephrin interaction or directly the receptor activity [ 17 ]. Dobrzanski et al. showed that the administration of EphA2/Fc soluble receptors, composed of EphA2 fused with the Fc region of human IgG1 antibody, functions as a decoy for activating ligands preventing their binding, and blocking the EphA2 signaling, thereby reducing tumor cell growth and invasiveness in preclinical models of pancreatic carcinoma [ 152 ]. Meanwhile, Ansuini et al. developed and tested a specific EphA2 mAb called IgG28 that impedes the binding to EFNA1, thereby impairing tumor vascularization in preclinical models of pancreatic cancer [ 148 ].

Another strategy was based on lithocholic acid (LCA), a secondary bile acid produced from chenodeoxycholic acid by colon bacterial activity. LCA is a competitive and reversible EphA2 antagonist that inhibits EphA2-EFNA1 interaction, blocking the receptor phosphorylation and activation; however, it does not discriminate between different combinations of Eph-Ephrin binding [ 153 ]. Several attempts were made to obtain and even increase the selectivity for EphA2 [ 154 , 155 , 156 , 157 ]. First, Giorgio et al. showed that LCA inhibited EphA2 phosphorylation in prostate and colon adenocarcinoma cell lines, without affecting other tested receptor tyrosine kinases [ 153 ]. They also discovered that the carboxylate group of LCA is critical for disrupting the EFNA1 ligand binding to EphA2 and identified the cholanic acid as a more competitive inhibitor than LCA [ 154 ]. Later, they synthesized a set of LCA derivatives that efficiently antagonized EphA2 in prostate cancer cells at low µM concentrations [ 155 , 156 , 157 ]. Finally, they designed and tested UniPR129, the L-homo-tryptophan conjugate of LCA that disrupted EphA2-EFNA1 interaction, inhibiting EphA2 activation and angiogenesis in prostate cancer cells [ 158 ]. Another derivative of 3β-hydroxy-D5-cholenic acid and L-tryptophan called UniPR1331 was active at low molecular concentration, showed good tolerability in GBM preclinical models, and potentiated the antitumor effect of bevacizumab when administered in combination [ 159 ]. Tognolini’s group efficiently demonstrated that the structural requirements for a small molecule to bind different receptors, among which Epha2, Farnesoid X receptor, and the G-protein-coupled receptor 5, are similar [ 160 ]. They selected and tested different Farnesoid X receptor agonists, among which Cilofexor, showing that they bind specifically and reversibly to EphA2 and interfere with EphA2 oncogenic phosphorylation in prostate adenocarcinoma cells [ 160 ].

Other researchers focused on tyrosine kinase inhibitors (TKI) and their potential to bind the EphA2 inner part, preventing its downstream signaling. Dasatinib, an oral multi-TKI, was the first studied in this context [ 161 , 162 , 163 ]. Chang et al. observed that, after EFNA1 stimulation, dasatinib inhibited EphA2 phosphorylation [ 163 ]. In addition, Buettner et al. showed that dasatinib inhibited the EphA2 tyrosine kinases activity, blocking migration and invasion, but not proliferation and survival, in human melanoma cell lines [ 161 ], while Ishigaki et al. observed that dasatinib exclusively inhibited the proliferation of EphA2-positive small-cell lung cancer (SCLC) cells, suggesting feasibility for clinical settings [ 114 ]. Dasatinib, either alone or in combination with chemotherapy, has been assessed in several clinical trials for advanced solid tumors (NCT00162214, NCT00792545), including SCLC (NCT00470054), squamous cell carcinoma (NCT00563290), endometrial cancer (NCT01440998) and in combination with radiotherapy in GBM (NCT00895960). Notably, this inhibitor has shown a broad range of targets making it challenging to interpret biological and clinical data [ 164 , 165 , 166 ]. However, these findings guided a chemical proteomics approach to designing and synthesizing new EphA2 inhibitors based on dasatinib structure. This approach seeks to exploit the ATP and the ribose pockets as binding epitopes in EphA2 kinase, improving its targeting profile. Compounds with an improved selectivity profile and potent anti-proliferative effect against GBM were obtained [ 167 ]. Similarly, Ho et al., using an orthogonal biological phenotypic screening approach, identified a group of newly synthesized benzylidene-indolinones able to inhibit multiple tyrosine kinases such as IGF-1R, Tyro3, and EphA2 phosphorylation. Among different candidates, they selected the most effective TKI which displayed a good safety profile and potent anti-proliferative, anti-migratory, and pro-apoptotic activities in hepatocellular carcinoma preclinical models [ 168 ]. Sitravatinib (MGCD516) is another multi-TKI inhibiting EphA2 [ 169 ]. Patwardhan et al. showed that this molecule promotes the blockade of RTK phosphorylation and induced tumor growth suppression in different sarcoma models, among which OS and ES, acting also in TKI-resistant models (Fig. 5 ) [ 170 ]. Based on these preclinical findings, a phase 1 clinical trial (NCT02219711) was conducted by Bauer et al. in patients with advanced solid tumors to evaluate its safety, pharmacokinetic, metabolism, pharmacodynamic, and clinical activity profiles, showing feasibility with only limited manageable side effects in these patients [ 171 ]. Several other clinical trials are currently ongoing to test the efficacy of sitravatinib in different types of cancers such as NSCLC (NCT03906071), liposarcoma (NCT02978859), squamous cell carcinoma (NCT03575598) and urothelial carcinoma (NCT03606174), as monotherapy or combination therapy.

Speaking of selective TKI targeting EphA2, ALW-II-41-27 showed promising antitumor effects in preclinical models of lung cancers, inducing time and dose-dependent apoptosis and tumor regression in NSCLC models, among which the EGFR-inhibitor-resistant ones, and inhibiting exclusively the proliferation of EphA2-positive SCLC models [ 113 , 114 , 172 ]. Furthermore, ALW-II-41-27 has been administered in combination with cetuximab reverting both primary and acquired drug resistance and resulting in proliferation inhibition, apoptosis induction, and tumor growth blockade in preclinical models of colorectal cancer [ 114 ]. This inhibitor is also effective in nasopharyngeal carcinoma cells, and in cervical cancer cells, reducing tumor growth, cell proliferation, migration, and invasion [ 173 , 174 , 175 ]. We also explored the effect of ALW-II-41-27 in OS, CS, and ES preclinical models, showing that it inhibited cell growth in a dose-dependent manner (Fig. 5 ) [ 13 ].

EphA2 as a target for theranostic applications

The overexpression of EphA2 in tumor cells and its relatively low expression level in normal tissue makes EphA2 an ideal target for tumor-specific delivery of chemotherapy or toxins while sparing healthy cells [ 14 , 38 ]. Various types of antibodies-drug or peptides-drug conjugates have been developed and tested to hit EphA2-expressing tumor cells (Fig. 4 ).

Peptide/antibody exotoxin-conjugates

Derivatives of the highly cytotoxic exotoxin A of Pseudomonas aeruginosa were developed and conjugated with EFNA1 or with fragments of mAb recognizing EphA2 showing antitumor effects in preclinical models with limited side effects [ 176 , 177 ]. In addition, Sakamoto et al. used the SHM16 mAb to deliver the saporin toxin in melanoma cells [ 151 ].

Another approach involves the conjugation of anti-EphA2 1C1 mAb with the toxin monomethyl auristatin phenylalanine (MMAF) via a stable maleimidocaproyl linker, known as MEDI-547 [ 149 ]. Upon EphA2 binding, this conjugate undergoes internalization and enzymatic cleavage, releasing MMAF that binds to tubulin, inhibiting its polymerization and inducing cell cycle arrest and apoptosis. MEDI-547 triggers activation of caspase-3/7 and cell death, EphA2 degradation, and tumor growth inhibition with minimal side effects in tumor preclinical models [ 178 , 179 ]. Despite these encouraging results, in a phase I clinical trial (NCT00796055) testing MEDI-547, severe dose-limiting toxicity was observed arresting any further development of this strategy [ 180 ]. Then, novel EphA2-selective bicycle toxin-conjugates (BTC) were developed by Bicycle Therapeutics to avoid side effects. Mudd et al. used a phage display selection to generate a BTC with another potent microtubule inhibitor, the cytotoxin mertansine (DM1) via a cleavable linker, able to bind the EphA2-LBD at a low nanomolar range. After chemical optimization, they showed that it displayed potent antitumor activity and was well tolerated in xenograft models [ 181 ]. The most promising is BT5528 composed of the antimitotic agent MMAE linked via a chemical scaffold, capable of binding to EphA2 with high affinity and stability, avoiding off-target effect. Compared to MEDI-547, Bicycle toxins are much smaller and display a “fast-in and fast-out” mechanism of action exposing much less drug to the normal tissues [ 182 ]. MEDI-547 and BT5528 both carrying MMAE were compared: the BTC displayed potent antitumor activity avoiding hematologic adverse effects in animal models first, and in humans later, showing manageable side effects [ 182 ]. Moreover, the administration of BT5528, alone or in combination with nivolumab, in patients with solid tumors is ongoing in a phase I/II clinical trial (NCT04180371).

Peptide/antibody chemotherapy conjugates

The conjugation of peptides or antibodies that selectively bind EphA2 and induce its internalization provides a vehicle for targeting chemotherapeutic agents specifically to cancer cells sparing healthy tissues. Recently, Wang et al. conjugated the EphA2 agonist short peptide YSA with the cytotoxic agent paclitaxel (PTX) showing that it is significantly more effective than chemotherapy alone in a prostate cancer xenograft model [ 183 ]. Later, they optimized the drug-like properties of this delivery system by introducing non-natural amino acids, synthesizing, and testing two new PTX-conjugates EphA2 targeting peptides. In particular, dYNH-PTX displayed higher stability in mouse serum and significantly reduced tumor volume in prostate and renal cancer preclinical models [ 184 ]. Next, they investigated the chemical determinants responsible for the stability and degradation of these agents in plasma and introduced modifications to obtain more long-lived and more effective agents [ 185 ]. Despite their efficacy, these short peptides are often degraded and eliminated too rapidly in vivo. Therefore, Wu et al. developed 123B9-PTX, a novel tumor-homing agent that targets the EphA2-LBD, conjugated with PTX via a stable linker which displayed good efficacy in a pancreatic cancer xenograft and melanoma lung colonization and metastases models [ 186 ]. To overcome the limit due to the high concentrations required, they also developed a dimeric version of this compound (123B92–L2–PTX) which acted at nanomolar concentrations, targeting circulating tumor cells and inhibiting lung metastasis in breast cancer models [ 187 ]. The same strategy was adopted to conjugate gemcitabine with EphA2 targeting agents, developing YNH-L2-Gem and 123B9-L2-Gem, which showed good results in pancreatic cancer models [ 188 ]. Finally, more recently, Baggio et al. developed Targefrin-PTX, a novel agent targeting the EphA2-LBD that efficiently delivered to pancreatic cancers xenograft models reducing tumor volume and circulating tumor cells [ 189 ].

Peptide/antibody nanotherapeutic agent conjugates

The abovementioned peptides and antibodies can also be conjugated with PEGylated nanoliposomes and loaded with different drugs, such as the MEK inhibitor trametinib and the chemotherapeutic agent doxorubicin [ 190 , 191 ]. This delivery approach allows drug release after internalization in tumor cells expressing EphA2, reducing circulating free-drug, and minimizing the off-target toxicity [ 190 ]. Fu et al. showed that the YSA-trametinib-loaded PEGylated nanoliposomes (YTPL) complex displayed the desired cytotoxicity against melanoma cells with higher uptake in vemurafenib-sensitive cells compared to its resistant counterpart [ 190 ]. Similarly, Haghilralsadat et al. showed that the YSA-doxorubicin-loaded PEGylated nanoliposomes (YSA-L-DOX) efficiently targeted the EphA2 receptor on human SAOS-2 OS cell line, promoting dose reduction and a higher cytotoxic activity (Fig. 5 ) [ 191 ]. Later, they developed a dual-targeted approach which consisted of targeting OS cell lines both extracellularly, against EphA2, and intracellularly against JNK-interacting protein 1 (JIP1) using YSA-PEGylated cationic liposomes loaded with doxorubicin and siRNA against JIP1 protein (YSA-L-JIP1siRNA-DOX). This strategy efficiently induced a reduction of JIP1 expression and the induction of apoptosis at the cellular level [ 192 ]. More recently, in collaboration with Carofiglio et al., we proposed to conjugate and with YSA peptide the iron-droplet zinc oxide (ZnO) nanoparticles coated with a 3 C lipidic shell and conjugated (FZ-3 C-YSA-NPs), to potentiate the specific targeting of OS. This construct triggers a specific cytotoxic effect that suppresses OS cell growth by increasing reactive oxygen species only when remotely activated by a mechanical pressure stimulation through ultrasound irradiation (Fig. 5 ) [ 193 ].

Another type of antibody-directed nanotherapeutics is MM-310. This is constituted by immunoliposomes loaded with the precursor form of docetaxel and conjugate with the anti-EphA2 scFv-3 peptide. Kamoun et al. tested the preclinical efficacy of MM-310 in bladder cancer xenograft models, both as a monotherapy and in combination with gemcitabine, showing that the combination improved tumor growth control [ 194 ]. Moreover, they studied the combination activity of MM-310 with the immune checkpoint inhibitors anti-PD1 and anti-PD-L1 in breast, colon, lung carcinoma, and in fibrosarcoma syngeneic mouse models, demonstrating the synergistic and immunomodulatory effects of the combination, mainly in breast cancer tumor models [ 195 ]. Based on these findings, a phase I clinical trial is ongoing to study the maximum tolerated dose and the safety profile of MM-310 in patients with advanced solid tumors, including soft tissue sarcoma (NCT03076372) [ 196 ].

Peptide/antibody imaging or therapeutic radiolabeled probe conjugates

Thanks to its high expression in both cancer cells and tumor vasculature compared to normal tissue, EphA2 can also be used as a target to deliver imaging agents for diagnostic and therapeutic purposes [ 197 ]. In this context, several specific probes consisting of radiolabeled peptides or antibodies binding EphA2 were developed for molecular imaging [ 198 ].

The first quantitative radioimmuno-positron emission tomography (PET) imaging of EphA2 was performed by Cai et al. in tumor-bearing mice, using the 64Cu-DOTA-1C1 compound, which consists of the 1C1 EphA2 antibody labeled with copper-64 (64Cu) through the chelating agent DOTA (1,4,7,10-tetraazacyclododecane N, N′,N″,N″′-tetra-acetic acid). This tracer showed promising results for clinical purpose investigation [ 199 ]. Similarly, Puttick et al. conjugated the 4B3 EphA2 antibody, labeled with 64Cu, with the chelating agent NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) to perform PET imaging. They observed that 64Cu-NOTA-4B3 effectively delineates tumor burden, displaying both qualitatively and quantitatively better high-contrast images compared to other clinical standards imaging tools, in GBM mice models [ 200 ]. Later, Pyo et al. conjugated the same compound with another EphA2 antibody, E1, and observed that 64Cu-NOTA-E1 tracer displayed high tumor uptake and retention in human cancer prostate cells, rapid clearance in xenograft mice models and low background values in other tissues [ 201 ]. In addition, Burvenich et al. labeled another EphA2-specific antibody, DS-8895 A, with three different radio-isotypes: iodine-125 (125I), indium-111 (111In) and zirconium-89 (89Zr). They showed that 111In and 89Zr radio-conjugates displayed the highest uptake in EphA2-expressing tumors because of their entrapment inside the cell; on the contrary, 125I resulted in the lowest tumor uptake due to its internalization, translocation to lysosomes and subsequent degradation which release 125I-catabolites from the cells. Moreover, they observed that molecular imaging of DS-8895a tumor uptake, in particular using the [ 89 ]Zr-Df-Bz-NCS-DS-8895a compound, allows noninvasive measurement of EphA2 expression and determination of its saturation in xenograft models [ 202 ]. These considerations lead this compound in phase-I bio-imaging clinical trials, evaluating its dose assessment and patient response, showing that it is safe and well tolerated in patients with advanced solid tumors (NCT02004717; NCT02252211) [ 203 , 204 ]. In the phase Ib study of DS-8895 A in patients with advanced/metastatic EphA2-positive cancers, no dose-limiting toxicities or treatment-related adverse events were reported. Observed non-drug related, treatment-emergent adverse events (grade ≤ 2) included fatigue ( n = 3, 43%), diarrhea ( n = 2, 29%), thrombocytopenia ( n = 2, 29%), and decreased appetite ( n = 2, 29%) [ 204 ].

Furthermore, Furukawa et al. recently developed and tested a novel imaging tracer to perform single-photon emission computed tomography (SPECT) of the EphA2 receptor. They conjugated the EphA2-230-1 mAb with the bifunctional chelator p-SCN-BnDTPA and labeled it with [111In], evaluating its affinity and pharmacokinetics. This [111In]In-BnDTPA-EphA2-230-1 tracer exhibited high tumor accumulation and successfully showed the tumor during the SPECT imaging on GBM mice models [ 205 ].

In analogy, radiolabeled peptides could be used for diagnostic imaging and eventually targeted radiotherapy. For instance, Pretze et al. synthesized [18 F]AFP-SWL, a new radiolabeled peptide consisting of the EphA2 specific SWL peptide conjugated with the bioorthogonal radiolabeling building block [18 F]AFP (1-(3-azidopropyl)-4-(3-fluoropropyl)piperazine). They were the first to perform a radio-pharmacological characterization of this radiotracer, evaluating its metabolic stability [ 206 ]. However, a more promising tracer was developed by Liu et al. conjugating technetium-99 m (99mTc) with the same peptide, resulting in the 99mTc-HYNIC-SWL tracer which displayed rapid blood clearance by renal excretion in lung cancer and melanoma in vivo preclinical models [ 207 ]. Moreover, Furukawa et al. developed [123I]ETB, a SPECT imaging tracer for the EphA2 receptor which consists of an ALW-II-4127 EphA2 inhibitor derivative (ETB), labeled with gamma-emitting iodine-123 (I-123), showing that it selectively bound and inhibited EphA2 and also revealed an efficient tumor uptake in GBM mice models [ 208 ].

EphA2 as a target for immunotherapy

The extraordinary developments in immunotherapy make the preferential expression of EphA2 in solid tumors an attractive possible target for anticancer immunotherapy. Indeed, thanks to its membrane expression, EphA2 can be a good target for vaccines and adoptive cell therapy approaches, such as the CAR-T strategy [ 209 ] (Fig. 4 ).

EphA2 redirected CAR-T

Nowadays, a very promising immunotherapy strategy is based on autologous T lymphocytes extracted from patient blood samples, genetically engineered ex vivo to express artificial chimeric antigen receptors (CAR) recognizing a specific tumor antigen and then re-infused into the patient to obtain a T-cell dependent tumor cell killing. The definition of a selective and tumor-specific target is crucial to avoid side effects [ 210 ]. CAR-T cells specifically directed against EphA2 have been developed and studied against different tumors, such as NSCLC, esophageal squamous cell carcinoma (ESCC), GBM, and pediatric bone sarcomas [ 211 , 212 , 213 , 214 ]. At first, Chow et al. developed EphA2-specific T cells constituted by EphA2-CAR with a CD28-ζ endodomain which induced a potent anti-cancer activity on GBM cells and the regression of GBM xenograft in SCID mice, prolonging their survival [ 213 ]. Then, Yi et al. generated and compared different EphA2-specific CAR-T against GBM models, showing that T cells expressing both the endo-domains CD28.ζ and 41BB.ζ CARs with short spacers efficiently improve the CAR-T cell function, compared to incorporating the 41BB domain into CD28.ζ CARs [ 215 ]. Similarly, a second generation of efficient specific EphA2.CAR-T with the co-stimulatory receptor 4-1BB was developed and tested in NSCLC and ESCC in vitro and in vivo models [ 211 , 212 ]. Hsu et al. tested EphA2 CAR-T therapy against OS and ES, demonstrating its anti-tumor activity in metastatic murine models both in vitro and in vivo ( Fig. 5 ) [ 214 ]. Moreover, Lange et al. recently developed GM18, a novel CAR consisting of the GM-CSF receptor extracellular domains and the IL18 transmembrane domains, that links CAR-T cell activation to MYD88 signaling. It was developed to sustain the CAR-T cell function after repeated exposure to tumor cells, by activating an antigen-dependent autocrine loop. They showed that CAR.GM18-T cells significantly increase the expansion and production of cytokines in vitro and induce tumor regression in ES and OS in vivo models, compared to standard CAR-T (Fig. 5 ) [ 216 ]. Finally, a recent advancement in CAR-T therapy involves the development of TanCAR-T cells to enhance the treatment of GBM both in vitro and in vivo. TanCAR-T cells are engineered with a tandem arrangement of IL13 (4MS) and EphA2 scFv, as well as both targets when present on cancer cells. Importantly, TanCAR-T cells are programmed to spare normal cells that express only the IL13Ra1/IL4Ra receptor, thereby minimizing off-target effects and enhancing the specificity of the therapy [ 217 ].

In the first clinical trial with EphA2-redirected CAR-T cells, the reported toxicities in the first 3 treated patients were pulmonary edema with cytokine release syndrome in 2 out of 3 patients. This might be due to the physiological expression of EphA2 by lung epithelial cells [ 218 ]. Unfortunately, our relatively little knowledge on EphA2 expression by adult healthy tissues further complicates our ability to predict which other organ sites could be affected by on-tumor, off-target side effects.

DC-vaccines

Despite its physiological expression in normal tissues, the relatively low distribution of the EphA2 receptor in adult cells, compared to cancer cells, renders it an almost ideal target for vaccine-based strategies. In this scenario, DC-based vaccines emerge as a promising therapeutic approach in cancer immunotherapy since they promote antitumor response taking advantage of each patient’s immune system [ 219 ]. Indeed, DCs are proficient antigen-presenting cells specialized to capture, process, and present antigens on major histocompatibility complex molecules [ 220 ]. Moreover, DCs play key roles in the communication between innate and adaptive immunity and are responsible for the antigen-specific adaptive immune response initiation stimulating both helper T cells and cytotoxic T lymphocytes (CTLs) that recognize specifically tumor cells [ 221 ]. The first evidence to support the potential of EphA2-based vaccine therapies was realized by Hatano et al., they demonstrated that EphA2-derived peptide vaccination promoted immunity and induced therapeutic anti-tumor effects in mice models. Furthermore, they observed that this vaccination effectively prevented tumor establishment or growth in EphA2-positive syngeneic glioma, sarcoma, and melanoma models and that EphA2 vaccines could also be directed to EphA2-negative target cells, targeting tumor-associated vascular endothelial cells expressing EphA2, as different tumor-associated antigens [ 222 , 223 ]. In addition, to improve the CTL-mediated immune response against glioma cells, Chen et al. developed and tested a novel vaccine containing EphA2883–891 peptide and LIGHT plasmid in HLA-A2 transgenic mice. They observed that this vaccine induced a robust cellular anti-tumor immunity against U251 glioma cells and inhibited tumor growth [ 224 ]. As well, Yeung et al. demonstrated that an increased expression of tumor-associated antigens such as EphA2, IL-13Rα2, and Survivin, allowed the basis for the utilization of an established multiple peptide vaccine in pediatric and adult ependymomas [ 225 ]. Therefore, Pollack et al. worked on a pilot study of subcutaneous vaccinations using these glioma-associated antigens epitope peptides emulsified in Montanide-ISA-51. They showed good tolerability and immunogenic activity with preliminary evidence of efficacy ascribing this as a promising strategy [ 226 ]. The results obtained with vaccines in glioma tumors were later confirmed in other models. Yamaguchi et al. evaluated the immunotherapy efficacy of DCs pulsed with EphA2-derived peptide on murine MC38 colon cancer models. They demonstrated that this strategy inhibited tumor growth in EphA2-positive colon cancer xenografts but not in EphA2-negative melanoma ones. Moreover, they observed that natural killer cells, but not CD4 + and CD8 + T lymphocytes, were necessary for immunizations and the vaccine had long-term anti-tumor immunity [ 227 , 228 ]. Additionally, the researchers observed heightened tumor-specific CTL activity in both colon cancer and melanoma mice models [ 229 ]. Therefore, EphA2-DCs and EphA2-NPs vaccines warrant further studies in selected EphA2-expressing tumors. Furthermore, in a recent phase II trial, Storkus et al. demonstrated that dasatinib is a potent adjuvant in specific vaccination against overexpressed and non-mutated tumor blood vessel antigens, including EphA2. The active recruitment of T cells in tumor sites lowered myeloid-derived suppressor cells and regulatory T cell abundance extending the patient’s overall survival. This vaccination combined with dasatinib was safe and resulted in immunologic and clinical responses in melanoma patients [ 230 ].

Peptide/antibody immunomodulator conjugates

Another strategy to take advantage of EphA2 specificity is the stimulation of the immune cells exclusively at the tumor site, exploiting a specific binding to EphA2 tumor cells and immune cells infiltrating the nearby microenvironment. BCY12491, a tumor-targeted immune cell agonist (TICA) exemplifies a new class of fully synthetic immunomodulators consisting of two bicyclic peptides, constricted each other, targeting respectively EphA2 as tumor antigen, and a co-stimulatory molecule CD137 or 4-1BB, a member of the tumor necrosis factor receptor superfamily. Upadhyaya et al. showed that BCY12491 is a highly specific and potent immune cell stimulator through CD137 agonism, in EphA2-overexpressing tumors that avoid systemic activation. Preclinical data confirmed that BCY12491 showed potent EphA2-dependent immunomodulatory activity in vitro and induced local tumor regression, complete responses, immunogenic memory, and significant modulation of the tumor immune microenvironment in preclinical syngeneic mouse models [ 231 ]. These findings provide a strong rationale to further develop the first-in-class Bicycle TICAs to potentially treat EphA2-expressing cancers.

Conclusions

In conclusion, targeting EphA2 in bone sarcomas is a promising therapeutic strategy due to its highly tumor-specific expression and pivotal role in tumor progression and metastasis. The development of advanced drug delivery systems, such as NP-based carriers, antibody-drug conjugates, small molecule inhibitors, and gene therapy approaches, enhances the precision and efficacy of EphA2-targeted therapies. These methods not only improve drug delivery to the tumor site but could also help minimize systemic toxicity. However, given the lack of data on EphA2 protein expression in adult normal tissues [ 38 ], considerations on potential on-target, off-tumor effects should be considered cautiously. Despite its benefits, targeting EphA2 and its delivery system might lead to off-target effects, immune reactions, and toxicity. Disrupting normal cellular functions of EphA2 and the potential development of resistance are additional concerns. Hematologic toxicity, affecting blood cell counts and bone marrow function, is also a risk. Ongoing research and clinical trials are crucial to optimize these therapies, addressing the challenges and ensuring safe and effective treatment options for patients with bone sarcomas. EphA2 overexpression in bone tumors compared to normal tissues and its involvement in key tumor processes (e.g., proliferation, migration, and angiogenesis) supports its validity as a therapeutic target. EphA2 targeting can work synergistically with other treatments, potentially lowering the risk of resistance development, which typically ensues with all single-agent targeted treatments. Continued investigation into the mechanisms of EphA2 in cancer biology and the refinement of delivery methods will be key to realizing the full therapeutic potential of EphA2 targeting bone sarcomas. Dedicated clinical trials of EphA2 targeting in the diverse histotypes of each bone sarcoma are still missing, and the study of EphA2 protein expression in the different bone sarcoma subtypes can be useful for predicting the efficacy of EphA2 targeting strategies. These strong preclinical and early clinical studies of multifaceted targeting of EphA2 give rise to encouraging results of efficient novel therapeutic strategies against EphA2-expressing tumors. The distinct expression patterns of EphA2 and its pivotal role in promoting tumor progression render this protein an attractive target for therapy across various cancers. This includes advanced bone sarcomas which remain challenging to treat and lacks effective therapeutic options so far. These findings open the way toward novel therapeutic avenues for addressing these aggressive, rare, and currently “drug-orphan” diseases.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Ephrin Type-A Receptor 2

Osteosarcoma

Ewing sarcoma

Chondrosarcoma

Receptor tyrosine kinases

Erythropoietin-producing hepatocellular

Ligand-binding domain

Epidermal growth factor

Fibronectin

Transmembrane

Tyrosine kinase

Sterile alpha motif

Receptor-binding domain

Glycosylphosphatidylinositol

Tumor necrosis factor

Extracellular signal -regulated kinases

Focal adhesion kinase

Ras homolog gene family, member G

Cancer associated fibroblast

Low molecular weight phospho-tyrosine phosphatase

Cancer cell line encyclopedia

Gene expression omnibus

RNA-binding protein EWS

STAG2 cohesin complex component

Tumor protein 53

Cyclin-dependent kinase inhibitor 2 A

Kinase insert domain receptor

Serine/threonine kinase 11

DNA mismatch repair protein Mlh1

Kirsten rat sarcoma virus

Tyrosine-protein phosphatase non-receptor type 11

Isocitrate dehydrogenase

Chimeric antigen receptor T lymphocytes

Dendritic cell

1,2-Dioleoyl-sn-glycerol-3-phosphatidylcholine

Cationic solid lipid nanoparticles

Nanoparticle

Non-small cell lung cancer

Dimethyldioctadecylammonium bromide

Super-enhancers

Histone deacetylases

Glioblastoma

Monoclonal antibodies

Monomeric EFNA1

Lithocholicacid

Tyrosine kinase inhibitors

Small-cell lung cancer

Monomethyl auristatin phenylalanine

Bicycle toxin-conjugated

YSA-trametinib-loaded PEGylated nanoliposomes

YSA-doxorubicine-loaded PEGylated nanoliposomes

Positron emission tomography

1,4,7,10-Tetraazacyclododecane N, N′,N″,N″′-tetra-acetic acid

1,4,7-triazacyclononane-1,4,7-triacetic acid

Zirconium-89

Single-photon emission computed tomography

1-(3-azidopropyl)-4-(3-fluoropropyl)piperazine

Technetium-99 m

Epha2 inhibitor derivative

Tumor-targeted immune cell agonists

Esophageal squamous cellcarcinoma

Cytotoxic T lymphocytes

Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, et al. Bone sarcomas: ESMO-PaedCan-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv79–95.

Article PubMed CAS Google Scholar

Redondo A, Bagué S, Bernabeu D, Ortiz-Cruz E, Valverde C, Alvarez R, et al. Malignant bone tumors (other than Ewing’s): clinical practice guidelines for diagnosis, treatment and follow-up by Spanish Group for Research on Sarcomas (GEIS). Cancer Chemother Pharmacol. 2017;80(6):1113–31.

Article PubMed PubMed Central Google Scholar

Board WCoTE. Soft tissue and Bone Tumours. WHO Classification of Tumours tE; 2020.

Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 2005;23(9):2004–11.

Meyers PA, Schwartz CL, Krailo MD, Healey JH, Bernstein ML, Betcher D, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival–a report from the children’s Oncology Group. J Clin Oncol. 2008;26(4):633–8.

Pignochino Y, Dell’Aglio C, Inghilleri S, Zorzetto M, Basiricò M, Capozzi F, et al. The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma. BMC Cancer. 2015;15:374.

Chiabotto G, Grignani G, Todorovic M, Martin V, Centomo ML, Prola E et al. Pazopanib and Trametinib as a synergistic strategy against Osteosarcoma: preclinical activity and molecular insights. Cancers (Basel). 2020;12(6).

Fioramonti M, Fausti V, Pantano F, Iuliani M, Ribelli G, Lotti F, et al. Cabozantinib affects Osteosarcoma Growth through a direct effect on Tumor cells and modifications in bone microenvironment. Sci Rep. 2018;8(1):4177.

Article PubMed PubMed Central CAS Google Scholar

Grignani G, Palmerini E, Ferraresi V, D’Ambrosio L, Bertulli R, Asaftei SD, et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 2015;16(1):98–107.

Pignochino Y, Dell’Aglio C, Basiricò M, Capozzi F, Soster M, Marchiò S, et al. The combination of Sorafenib and Everolimus abrogates mTORC1 and mTORC2 upregulation in osteosarcoma preclinical models. Clin Cancer Res. 2013;19(8):2117–31.

Grignani G, Palmerini E, Dileo P, Asaftei SD, D’Ambrosio L, Pignochino Y, et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann Oncol. 2012;23(2):508–16.

Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S, et al. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer. 2009;8:118.

Giordano G, Merlini A, Ferrero G, Mesiano G, Fiorino E, Brusco S et al. EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma. Cells. 2021;10(11).

Binda E, Visioli A, Giani F, Lamorte G, Copetti M, Pitter KL, et al. The EphA2 receptor drives self-renewal and tumorigenicity in stem-like tumor-propagating cells from human glioblastomas. Cancer Cell. 2012;22(6):765–80.

Fan J, Wei Q, Koay EJ, Liu Y, Ning B, Bernard PW, et al. Chemoresistance Transmission via exosome-mediated EphA2 transfer in pancreatic Cancer. Theranostics. 2018;8(21):5986–94.

Garcia-Monclús S, López-Alemany R, Almacellas-Rabaiget O, Herrero-Martín D, Huertas-Martinez J, Lagares-Tena L, et al. EphA2 receptor is a key player in the metastatic onset of ewing sarcoma. Int J Cancer. 2018;143(5):1188–201.

Xiao T, Xiao Y, Wang W, Tang YY, Xiao Z, Su M. Targeting EphA2 in cancer. J Hematol Oncol. 2020;13(1):114.

Limited B. Study BT5528-100 in Patients With Advanced Solid Tumors Associated With EphA2 Expression [ https://clinicaltrials.gov/study/NCT04180371?term=epha2&rank=5&tab=table

Hospital CPG. Combination of CAR-DC Vaccine and ICIs in Malignant Tumors [ https://clinicaltrials.gov/study/NCT05631886?term=epha2&rank=3

Center MDAC. EphA2 siRNA in Treating Patients With Advanced or Recurrent Solid Tumors [ https://clinicaltrials.gov/study/NCT01591356?term=epha2&rank=1

Wilson K, Shiuan E, Brantley-Sieders DM. Oncogenic functions and therapeutic targeting of EphA2 in cancer. Oncogene. 2021;40(14):2483–95.

Kania A, Klein R. Mechanisms of ephrin-eph signalling in development, physiology and disease. Nat Rev Mol Cell Biol. 2016;17(4):240–56.

Atlas THP. Eph receptors [ https://www.proteinatlas.org/search/eph+receptors

Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol. 2013;5(9).

Liang LY, Patel O, Janes PW, Murphy JM, Lucet IS. Eph receptor signalling: from catalytic to non-catalytic functions. Oncogene. 2019;38(39):6567–84.

Pasquale EB. Eph-ephrin promiscuity is now crystal clear. Nat Neurosci. 2004;7(5):417–8.

Murai KK, Pasquale EB. Eph’ective signaling: forward, reverse and crosstalk. J Cell Sci. 2003;116(Pt 14):2823–32.

Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10(3):165–80.

Pasquale EB. Eph receptors and ephrins in cancer progression. Nat Rev Cancer. 2024;24(1):5–27.

Gatto G, Morales D, Kania A, Klein R. EphA4 receptor shedding regulates spinal motor axon guidance. Curr Biol. 2014;24(20):2355–65.

Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, et al. Cytoplasmic relaxation of active eph controls ephrin shedding by ADAM10. PLoS Biol. 2009;7(10):e1000215.

Barquilla A, Pasquale EB. Eph receptors and ephrins: therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2015;55:465–87.

Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, et al. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene. 2014;33(17):2179–90.

Alford SC, Bazowski J, Lorimer H, Elowe S, Howard PL. Tissue transglutaminase clusters soluble A-type ephrins into functionally active high molecular weight oligomers. Exp Cell Res. 2007;313(20):4170–9.

Lagares D, Ghassemi-Kakroodi P, Tremblay C, Santos A, Probst CK, Franklin A, et al. ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis. Nat Med. 2017;23(12):1405–15.

EMBL-EBI Er -M, Gene. EPHA2 ENSG00000142627 2024 [ https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000142627;r=1:16126401-16158135

Park JE, Son AI, Zhou R. Roles of EphA2 in Development and Disease. Genes (Basel). 2013;4(3):334–57.

Article PubMed Google Scholar

Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, et al. Differential gene expression of eph receptors and ephrins in benign human tissues and cancers. Clin Chem. 2004;50(3):490–9.

Ieguchi K, Maru Y. Roles of EphA1/A2 and ephrin-A1 in cancer. Cancer Sci. 2019;110(3):841–8.

Noberini R, de la Rubio E, Pasquale EB. Profiling eph receptor expression in cells and tissues: a targeted mass spectrometry approach. Cell Adh Migr. 2012;6(2):102–12.

Himanen JP, Goldgur Y, Miao H, Myshkin E, Guo H, Buck M, et al. Ligand recognition by A-class eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex. EMBO Rep. 2009;10(7):722–8.

Zhou Y, Sakurai H. Emerging and diverse functions of the EphA2 noncanonical pathway in Cancer Progression. Biol Pharm Bull. 2017;40(10):1616–24.

Tandon M, Vemula SV, Mittal SK. Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin Ther Targets. 2011;15(1):31–51.

Ireton RC, Chen J. EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets. 2005;5(3):149–57.

Kim J, Chang IY, You HJ. Interactions between EGFR and EphA2 promote tumorigenesis through the action of Ephexin1. Cell Death Dis. 2022;13(6):528.

Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, et al. The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest. 2008;118(1):64–78.

Paul MD, Grubb HN, Hristova K. Quantifying the strength of heterointeractions among receptor tyrosine kinases from different subfamilies: implications for cell signaling. J Biol Chem. 2020;295(29):9917–33.

Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Differ. 1999;10(9):629–38.

PubMed CAS Google Scholar

Gai QJ, Fu Z, He J, Mao M, Yao XX, Qin Y, et al. EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma. Signal Transduct Target Ther. 2022;7(1):33.

Hamaoka Y, Negishi M, Katoh H. EphA2 is a key effector of the MEK/ERK/RSK pathway regulating glioblastoma cell proliferation. Cell Signal. 2016;28(8):937–45.

Barquilla A, Lamberto I, Noberini R, Heynen-Genel S, Brill LM, Pasquale EB. Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation. Mol Biol Cell. 2016;27(17):2757–70.

Gehring MP, Pasquale EB. Protein kinase C phosphorylates the EphA2 receptor on serine 892 in the regulatory linker connecting the kinase and SAM domains. Cell Signal. 2020;73:109668.

Kawai H, Kobayashi M, Hiramoto-Yamaki N, Harada K, Negishi M, Katoh H. Ephexin4-mediated promotion of cell migration and anoikis resistance is regulated by serine 897 phosphorylation of EphA2. FEBS Open Bio. 2013;3:78–82.

Harada K, Hiramoto-Yamaki N, Negishi M, Katoh H. Ephexin4 and EphA2 mediate resistance to anoikis through RhoG and phosphatidylinositol 3-kinase. Exp Cell Res. 2011;317(12):1701–13.

Beauchamp A, Debinski W. Ephs and ephrins in cancer: ephrin-A1 signalling. Semin Cell Dev Biol. 2012;23(1):109–15.

Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000;2(2):62–9.

Kikawa KD, Vidale DR, Van Etten RL, Kinch MS. Regulation of the EphA2 kinase by the low molecular weight tyrosine phosphatase induces transformation. J Biol Chem. 2002;277(42):39274–9.

Fang WB, Ireton RC, Zhuang G, Takahashi T, Reynolds A, Chen J. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J Cell Sci. 2008;121(Pt 3):358–68.

Udayakumar D, Zhang G, Ji Z, Njauw CN, Mroz P, Tsao H. EphA2 is a critical oncogene in melanoma. Oncogene. 2011;30(50):4921–9.

Parri M, Taddei ML, Bianchini F, Calorini L, Chiarugi P. EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res. 2009;69(5):2072–81.

Mo J, Zhao X, Dong X, Liu T, Zhao N, Zhang D, et al. Effect of EphA2 knockdown on melanoma metastasis depends on intrinsic ephrinA1 level. Cell Oncol (Dordr). 2020;43(4):655–67.

Fritsche-Guenther R, Noske A, Ungethüm U, Kuban RJ, Schlag PM, Tunn PU, et al. De novo expression of EphA2 in osteosarcoma modulates activation of the mitogenic signalling pathway. Histopathology. 2010;57(6):836–50.

Wykosky J, Gibo DM, Stanton C, Debinski W. EphA2 as a novel molecular marker and target in glioblastoma multiforme. Mol Cancer Res. 2005;3(10):541–51.

Liu F, Park PJ, Lai W, Maher E, Chakravarti A, Durso L, et al. A genome-wide screen reveals functional gene clusters in the cancer genome and identifies EphA2 as a mitogen in glioblastoma. Cancer Res. 2006;66(22):10815–23.

Kinch MS, Moore MB, Harpole DH. Jr. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res. 2003;9(2):613–8.

Martini G, Cardone C, Vitiello PP, Belli V, Napolitano S, Troiani T, et al. EPHA2 is a predictive biomarker of resistance and a potential therapeutic target for improving Antiepidermal Growth factor receptor therapy in Colorectal Cancer. Mol Cancer Ther. 2019;18(4):845–55.

Walker-Daniels J, Coffman K, Azimi M, Rhim JS, Bostwick DG, Snyder P, et al. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate. 1999;41(4):275–80.

Mudali SV, Fu B, Lakkur SS, Luo M, Embuscado EE, Iacobuzio-Donahue CA. Patterns of EphA2 protein expression in primary and metastatic pancreatic carcinoma and correlation with genetic status. Clin Exp Metastasis. 2006;23(7–8):357–65.

PubMed PubMed Central CAS Google Scholar

Wu D, Suo Z, Kristensen GB, Li S, Troen G, Holm R, et al. Prognostic value of EphA2 and EphrinA-1 in squamous cell cervical carcinoma. Gynecol Oncol. 2004;94(2):312–9.

Brannan JM, Sen B, Saigal B, Prudkin L, Behrens C, Solis L, et al. EphA2 in the early pathogenesis and progression of non-small cell lung cancer. Cancer Prev Res (Phila). 2009;2(12):1039–49.

Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 2001;61(5):2301–6.

Nakamura R, Kataoka H, Sato N, Kanamori M, Ihara M, Igarashi H, et al. EPHA2/EFNA1 expression in human gastric cancer. Cancer Sci. 2005;96(1):42–7.

Fang WB, Brantley-Sieders DM, Parker MA, Reith AD, Chen J. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene. 2005;24(53):7859–68.

Dunne PD, Dasgupta S, Blayney JK, McArt DG, Redmond KL, Weir JA, et al. EphA2 expression is a key driver of Migration and Invasion and a poor prognostic marker in Colorectal Cancer. Clin Cancer Res. 2016;22(1):230–42.

Kurose H, Ueda K, Kondo R, Ogasawara S, Kusano H, Sanada S, et al. Elevated expression of EPHA2 is Associated with Poor Prognosis after radical prostatectomy in prostate Cancer. Anticancer Res. 2019;39(11):6249–57.

Kamat AA, Coffey D, Merritt WM, Nugent E, Urbauer D, Lin YG, et al. EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer. Cancer. 2009;115(12):2684–92.

Miyazaki T, Kato H, Fukuchi M, Nakajima M, Kuwano H. EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int J Cancer. 2003;103(5):657–63.

Takasugi M, Okada R, Takahashi A, Virya Chen D, Watanabe S, Hara E. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat Commun. 2017;8:15729.

Wei Q, Wei L, Zhang J, Li Z, Feng H, Ren L. EphA2–enriched exosomes promote cell migration and are a potential diagnostic serum marker in pancreatic cancer. Mol Med Rep. 2020;22(4):2941–7.

Yamashita T, Kamada H, Kanasaki S, Nagano K, Inoue M, Higashisaka K, et al. Ephrin type-A receptor 2 on tumor-derived exosomes enhances angiogenesis through the activation of MAPK signaling. Pharmazie. 2019;74(10):614–9.

Liu X, Li Y, Chen C, Dong J, Zhou J, Tong D, et al. Exosomal EphA2 promotes tumor metastasis of triple-negative breast cancer by damaging endothelial barrier. Clin Exp Metastasis. 2023;40(1):105–16.

Hong HN, Won YJ, Shim JH, Kim HJ, Han SH, Kim BS, et al. Cancer-associated fibroblasts promote gastric tumorigenesis through EphA2 activation in a ligand-independent manner. J Cancer Res Clin Oncol. 2018;144(9):1649–63.

Kim HS, Won YJ, Shim JH, Kim HJ, Kim BS, Hong HN. Role of EphA2-PI3K signaling in vasculogenic mimicry induced by cancer-associated fibroblasts in gastric cancer cells. Oncol Lett. 2019;18(3):3031–8.

Sáinz-Jaspeado M, Huertas-Martinez J, Lagares-Tena L, Martin Liberal J, Mateo-Lozano S, de Alava E, et al. EphA2-induced angiogenesis in ewing sarcoma cells works through bFGF production and is dependent on caveolin-1. PLoS ONE. 2013;8(8):e71449.

Hadjimichael AC, Pergaris A, Kaspiris A, Foukas AF, Kokkali S, Tsourouflis G et al. The EPH/Ephrin System in Bone and Soft Tissue Sarcomas’ Pathogenesis and Therapy: New Advancements and a Literature Review. Int J Mol Sci. 2022;23(9).

Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and end results program. Cancer. 2009;115(7):1531–43.

Zhao X, Wu Q, Gong X, Liu J, Ma Y. Osteosarcoma: a review of current and future therapeutic approaches. Biomed Eng Online. 2021;20(1):24.

Brown HK, Schiavone K, Gouin F, Heymann MF, Heymann D. Biology of Bone Sarcomas and New Therapeutic developments. Calcif Tissue Int. 2018;102(2):174–95.

Rothzerg E, Xu J, Wood D. Different subtypes of Osteosarcoma: histopathological patterns and clinical Behaviour. J Mol Pathol. 2023;4(2):99–108.

Article CAS Google Scholar

Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012;2012:627254.

Morrow JJ, Khanna C. Osteosarcoma Genetics and epigenetics: emerging Biology and candidate therapies. Crit Rev Oncog. 2015;20(3–4):173–97.

Liu W, Wang R, Zhang Y, Wang H, Huang Z, Jin T, et al. Whole-exome sequencing in osteosarcoma with distinct prognosis reveals disparate genetic heterogeneity. Cancer Genet. 2021;256–257:149–57.

Pastorino U, Palmerini E, Porcu L, Luksch R, Scanagatta P, Meazza C, et al. Lung metastasectomy for osteosarcoma in children, adolescents, and young adults: proof of permanent cure. Tumori. 2023;109(1):79–85.

Smeland S, Bielack SS, Whelan J, Bernstein M, Hogendoorn P, Krailo MD, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer. 2019;109:36–50.

Posthumadeboer J, Piersma SR, Pham TV, van Egmond PW, Knol JC, Cleton-Jansen AM, et al. Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery. Br J Cancer. 2013;109(8):2142–54.

Cole S, Gianferante DM, Zhu B, Mirabello L, Osteosarcoma. A surveillance, epidemiology, and end results program-based analysis from 1975 to 2017. Cancer. 2022;128(11):2107–18.

Williams RF, Fernandez-Pineda I, Gosain A. Pediatric Sarcomas. Surg Clin North Am. 2016;96(5):1107–25.

Bühnemann C, Li S, Yu H, Branford White H, Schäfer KL, Llombart-Bosch A, et al. Quantification of the heterogeneity of prognostic cellular biomarkers in ewing sarcoma using automated image and random survival forest analysis. PLoS ONE. 2014;9(9):e107105.

Zhang N, Liu H, Yue G, Zhang Y, You J, Wang H. Molecular Heterogeneity of Ewing Sarcoma as detected by Ion Torrent sequencing. PLoS ONE. 2016;11(4):e0153546.

Brohl AS, Solomon DA, Chang W, Wang J, Song Y, Sindiri S, et al. The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet. 2014;10(7):e1004475.

Zöllner SK, Amatruda JF, Bauer S, Collaud S, de Álava E, DuBois SG et al. Ewing Sarcoma-Diagnosis, treatment, Clinical challenges and Future perspectives. J Clin Med. 2021;10(8).

Franzetti GA, Laud-Duval K, van der Ent W, Brisac A, Irondelle M, Aubert S, et al. Cell-to-cell heterogeneity of EWSR1-FLI1 activity determines proliferation/migration choices in ewing sarcoma cells. Oncogene. 2017;36(25):3505–14.

Meyers PA, Federman N, Daw N, Anderson PM, Davis LE, Kim A et al. Open-Label, Multicenter, Phase I/II, First-in-human trial of TK216: a First-Generation EWS::FLI1 Fusion protein antagonist in Ewing Sarcoma. J Clin Oncol. 2024:Jco2400020.

Zhang ZB, Cai L, Zheng SG, Xiong Y, Dong JH. Overexpression of caveolin-1 in hepatocellular carcinoma with metastasis and worse prognosis: correlation with vascular endothelial growth factor, microvessel density and unpaired artery. Pathol Oncol Res. 2009;15(3):495–502.

Yang G, Addai J, Wheeler TM, Frolov A, Miles BJ, Kadmon D, et al. Correlative evidence that prostate cancer cell-derived caveolin-1 mediates angiogenesis. Hum Pathol. 2007;38(11):1688–95.

Sáinz-Jaspeado M, Lagares-Tena L, Lasheras J, Navid F, Rodriguez-Galindo C, Mateo-Lozano S, et al. Caveolin-1 modulates the ability of Ewing’s sarcoma to metastasize. Mol Cancer Res. 2010;8(11):1489–500.

Jin W. The role of Tyrosine Kinases as a critical prognostic parameter and its targeted therapies in Ewing Sarcoma. Front Cell Dev Biol. 2020;8:613.

Duchman KR, Gao Y, Miller BJ. Prognostic factors for survival in patients with Ewing’s sarcoma using the surveillance, epidemiology, and end results (SEER) program database. Cancer Epidemiol. 2015;39(2):189–95.

Jagodzinska-Mucha P, Raciborska A, Kosela-Paterczyk H, Kozak K, Bilska K, Switaj T et al. Age as a prognostic factor in patients with Ewing sarcoma-the Polish Sarcoma Group Experience. J Clin Med. 2021;10(16).

Sandberg AA. Genetics of chondrosarcoma and related tumors. Curr Opin Oncol. 2004;16(4):342–54.

Frezza AM, Cesari M, Baumhoer D, Biau D, Bielack S, Campanacci DA, et al. Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. Eur J Cancer. 2015;51(3):374–81.

Zhang YX, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, et al. Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res. 2013;19(14):3796–807.

Amato KR, Wang S, Hastings AK, Youngblood VM, Santapuram PR, Chen H, et al. Genetic and pharmacologic inhibition of EPHA2 promotes apoptosis in NSCLC. J Clin Invest. 2014;124(5):2037–49.

Ishigaki H, Minami T, Morimura O, Kitai H, Horio D, Koda Y, et al. EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest. Biochem Biophys Res Commun. 2019;519(4):846–53.

Zhang T, Li J, Ma X, Yang Y, Sun W, Jin W, et al. Inhibition of HDACs-EphA2 Signaling Axis with WW437 demonstrates promising Preclinical Antitumor activity in breast Cancer. EBioMedicine. 2018;31:276–86.

Zhou Z, Yuan X, Li Z, Tu H, Li D, Qing J, et al. RNA interference targeting EphA2 inhibits proliferation, induces apoptosis, and cooperates with cytotoxic drugs in human glioma cells. Surg Neurol. 2008;70(6):562–8. discussion 8–9.

Corydon IJ, Fabian-Jessing BK, Jakobsen TS, Jørgensen AC, Jensen EG, Askou AL, et al. 25 years of maturation: a systematic review of RNAi in the clinic. Mol Ther Nucleic Acids. 2023;33:469–82.

Landen CN Jr., Chavez-Reyes A, Bucana C, Schmandt R, Deavers MT, Lopez-Berestein G, et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 2005;65(15):6910–8.

Wagner MJ, Mitra R, McArthur MJ, Baze W, Barnhart K, Wu SY, et al. Preclinical mammalian Safety studies of EPHARNA (DOPC Nanoliposomal EphA2-Targeted siRNA). Mol Cancer Ther. 2017;16(6):1114–23.

Choi KM, Park GL, Hwang KY, Lee JW, Ahn HJ. Efficient siRNA delivery into tumor cells by p19-YSA fusion protein. Mol Pharm. 2013;10(2):763–73.

Ozcan G, Ozpolat B, Coleman RL, Sood AK, Lopez-Berestein G. Preclinical and clinical development of siRNA-based therapeutics. Adv Drug Deliv Rev. 2015;87:108–19.

Oner E, Kotmakci M, Baird AM, Gray SG, Debelec Butuner B, Bozkurt E, et al. Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small-molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids. J Nanobiotechnol. 2021;19(1):71.

Tsouko E, Wang J, Frigo DE, Aydoğdu E, Williams C. miR-200a inhibits migration of triple-negative breast cancer cells through direct repression of the EPHA2 oncogene. Carcinogenesis. 2015;36(9):1051–60.

Li H, Sun Q, Han B, Yu X, Hu B, Hu S. MiR-26b inhibits hepatocellular carcinoma cell proliferation, migration, and invasion by targeting EphA2. Int J Clin Exp Pathol. 2015;8(5):4782–90.

PubMed PubMed Central Google Scholar

Koo T, Cho BJ, Kim DH, Park JM, Choi EJ, Kim HH, et al. MicroRNA-200c increases radiosensitivity of human cancer cells with activated EGFR-associated signaling. Oncotarget. 2017;8(39):65457–68.

Li G, Huang M, Cai Y, Ke Y, Yang Y, Sun X. miR–141 inhibits glioma vasculogenic mimicry by controlling EphA2 expression. Mol Med Rep. 2018;18(2):1395–404.

Li R, Yuan W, Mei W, Yang K, Chen Z. MicroRNA 520d-3p inhibits gastric cancer cell proliferation, migration, and invasion by downregulating EphA2 expression. Mol Cell Biochem. 2014;396(1–2):295–305.

Tang L, Hu H, He Y, McLeod HL, Xiao D, Chen P, et al. The relationship between miR-302b and EphA2 and their clinical significance in gastric cancer. J Cancer. 2018;9(17):3109–16.

Gong S, Li Y, Lv L, Men W. Restored microRNA-519a enhances the radiosensitivity of non-small cell lung cancer via suppressing EphA2. Gene Ther. 2022;29(10–11):588–600.

Liu B, Sun W, Gao W, Li L, Cao Z, Yang X, et al. microRNA-451a promoter methylation regulated by DNMT3B expedites bladder cancer development via the EPHA2/PI3K/AKT axis. BMC Cancer. 2020;20(1):1019.

Li R, Hu Z, Wang Z, Zhu T, Wang G, Gao B, et al. miR-125a-5p promotes gastric cancer growth and invasion by regulating the Hippo pathway. J Clin Lab Anal. 2021;35(12):e24078.

Cui S, Wu Q, Liu M, Su M, Liu S, Shao L, et al. EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2. Cell Death Dis. 2021;12(3):264.

Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934–47.

Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–19.

Jin R, Lin H, Li G, Xu J, Shi L, Chang C, et al. TR(4) nuclear receptor suppresses HCC cell invasion via downregulating the EphA2 expression. Cell Death Dis. 2018;9(3):283.

Joseph R, Dasari SK, Umamaheswaran S, Mangala LS, Bayraktar E, Rodriguez-Aguayo C et al. EphA2- and HDAC-Targeted combination therapy in Endometrial Cancer. Int J Mol Sci. 2024;25(2).

Wykosky J, Palma E, Gibo DM, Ringler S, Turner CP, Debinski W. Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene. 2008;27(58):7260–73.

Xu Q, Lin WC, Petit RS, Groves JT. EphA2 receptor activation by monomeric Ephrin-A1 on supported membranes. Biophys J. 2011;101(11):2731–9.

Koolpe M, Dail M, Pasquale EB. An ephrin mimetic peptide that selectively targets the EphA2 receptor. J Biol Chem. 2002;277(49):46974–9.

Gomez-Soler M, Petersen Gehring M, Lechtenberg BC, Zapata-Mercado E, Hristova K, Pasquale EB. Engineering Nanomolar peptide ligands that differentially modulate EphA2 receptor signaling. J Biol Chem. 2019;294(22):8791–805.

Alves DS, Westerfield JM, Shi X, Nguyen VP, Stefanski KM, Booth KR et al. A novel pH-dependent membrane peptide that binds to EphA2 and inhibits cell migration. Elife. 2018;7.

Westerfield JM, Sahoo AR, Alves DS, Grau B, Cameron A, Maxwell M, et al. Conformational clamping by a membrane ligand activates the EphA2 receptor. J Mol Biol. 2021;433(18):167144.

Mercurio FA, Di Natale C, Pirone L, Iannitti R, Marasco D, Pedone EM, et al. The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors. Sci Rep. 2017;7(1):17474.

Mercurio FA, Di Natale C, Pirone L, Marasco D, Calce E, Vincenzi M, et al. Design and analysis of EphA2-SAM peptide ligands: a multi-disciplinary screening approach. Bioorg Chem. 2019;84:434–43.

Mercurio FA, Pirone L, Di Natale C, Marasco D, Pedone EM, Leone M. Sam domain-based stapled peptides: structural analysis and interaction studies with the Sam domains from the EphA2 receptor and the lipid phosphatase Ship2. Bioorg Chem. 2018;80:602–10.

Carles-Kinch K, Kilpatrick KE, Stewart JC, Kinch MS. Antibody targeting of the EphA2 tyrosine kinase inhibits malignant cell behavior. Cancer Res. 2002;62(10):2840–7.

Coffman KT, Hu M, Carles-Kinch K, Tice D, Donacki N, Munyon K, et al. Differential EphA2 epitope display on normal versus malignant cells. Cancer Res. 2003;63(22):7907–12.

Ansuini H, Meola A, Gunes Z, Paradisi V, Pezzanera M, Acali S, et al. Anti-EphA2 antibodies with distinct in Vitro Properties have equal in vivo efficacy in pancreatic Cancer. J Oncol. 2009;2009:951917.

Jackson D, Gooya J, Mao S, Kinneer K, Xu L, Camara M, et al. A human antibody-drug conjugate targeting EphA2 inhibits tumor growth in vivo. Cancer Res. 2008;68(22):9367–74.

Hasegawa J, Sue M, Yamato M, Ichikawa J, Ishida S, Shibutani T, et al. Novel anti-EPHA2 antibody, DS-8895a for cancer treatment. Cancer Biol Ther. 2016;17(11):1158–67.

Sakamoto A, Kato K, Hasegawa T, Ikeda S. An agonistic antibody to EPHA2 exhibits Antitumor effects on Human Melanoma cells. Anticancer Res. 2018;38(6):3273–82.

Dobrzanski P, Hunter K, Jones-Bolin S, Chang H, Robinson C, Pritchard S, et al. Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res. 2004;64(3):910–9.

Giorgio C, Hassan Mohamed I, Flammini L, Barocelli E, Incerti M, Lodola A, et al. Lithocholic acid is an eph-ephrin ligand interfering with eph-kinase activation. PLoS ONE. 2011;6(3):e18128.

Tognolini M, Incerti M, Hassan-Mohamed I, Giorgio C, Russo S, Bruni R, et al. Structure-activity relationships and mechanism of action of eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor. ChemMedChem. 2012;7(6):1071–83.

Giorgio C, Russo S, Incerti M, Bugatti A, Vacondio F, Barocelli E, et al. Biochemical characterization of EphA2 antagonists with improved physico-chemical properties by cell-based assays and surface plasmon resonance analysis. Biochem Pharmacol. 2016;99:18–30.

Tognolini M, Incerti M, Pala D, Russo S, Castelli R, Hassan-Mohamed I, et al. Target hopping as a useful tool for the identification of novel EphA2 protein-protein antagonists. ChemMedChem. 2014;9(1):67–72.

Incerti M, Tognolini M, Russo S, Pala D, Giorgio C, Hassan-Mohamed I, et al. Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. J Med Chem. 2013;56(7):2936–47.

Hassan-Mohamed I, Giorgio C, Incerti M, Russo S, Pala D, Pasquale EB, et al. UniPR129 is a competitive small molecule eph-ephrin antagonist blocking in vitro angiogenesis at low micromolar concentrations. Br J Pharmacol. 2014;171(23):5195–208.

Festuccia C, Gravina GL, Giorgio C, Mancini A, Pellegrini C, Colapietro A, et al. UniPR1331, a small molecule targeting Eph/ephrin interaction, prolongs survival in glioblastoma and potentiates the effect of antiangiogenic therapy in mice. Oncotarget. 2018;9(36):24347–63.

Ferrari FR, Giorgio C, Zappia A, Ballabeni V, Bertoni S, Barocelli E, et al. Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: a successful application of target hopping approach. Biochem Pharmacol. 2023;209:115452.

Buettner R, Mesa T, Vultur A, Lee F, Jove R. Inhibition of src family kinases with dasatinib blocks migration and invasion of human melanoma cells. Mol Cancer Res. 2008;6(11):1766–74.

Huang F, Reeves K, Han X, Fairchild C, Platero S, Wong TW, et al. Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection. Cancer Res. 2007;67(5):2226–38.

Chang Q, Jorgensen C, Pawson T, Hedley DW. Effects of dasatinib on EphA2 receptor tyrosine kinase activity and downstream signalling in pancreatic cancer. Br J Cancer. 2008;99(7):1074–82.

Miller AA, Pang H, Hodgson L, Ramnath N, Otterson GA, Kelley MJ, et al. A phase II study of dasatinib in patients with chemosensitive relapsed small cell lung cancer (Cancer and Leukemia Group B 30602). J Thorac Oncol. 2010;5(3):380–4.

Duckett DR, Cameron MD. Metabolism considerations for kinase inhibitors in cancer treatment. Expert Opin Drug Metab Toxicol. 2010;6(10):1175–93.

Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32.

Heinzlmeir S, Lohse J, Treiber T, Kudlinzki D, Linhard V, Gande SL, et al. Chemoproteomics-aided Medicinal Chemistry for the Discovery of EPHA2 inhibitors. ChemMedChem. 2017;12(12):999–1011.

Ho HK, Chua BT, Wong W, Lim KS, Teo V, Ong HT, et al. Benzylidene-indolinones are effective as multi-targeted kinase inhibitor therapeutics against hepatocellular carcinoma. Mol Oncol. 2014;8(7):1266–77.

Dolan M, Mastri M, Tracz A, Christensen JG, Chatta G, Ebos JML. Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance. PLoS ONE. 2019;14(8):e0220101.

Patwardhan PP, Ivy KS, Musi E, de Stanchina E, Schwartz GK. Significant blockade of multiple receptor tyrosine kinases by MGCD516 (Sitravatinib), a novel small molecule inhibitor, shows potent anti-tumor activity in preclinical models of sarcoma. Oncotarget. 2016;7(4):4093–109.

Bauer T, Cho BC, Heist R, Bazhenova L, Werner T, Goel S, et al. First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors. Invest New Drugs. 2022;40(5):990–1000.

Amato KR, Wang S, Tan L, Hastings AK, Song W, Lovly CM, et al. EPHA2 blockade overcomes Acquired Resistance to EGFR kinase inhibitors in Lung Cancer. Cancer Res. 2016;76(2):305–18.

Xiang YP, Xiao T, Li QG, Lu SS, Zhu W, Liu YY, et al. Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway. Cell Death Dis. 2020;11(8):709.

Li X, Li D, Ma R. ALW-II-41-27, an EphA2 inhibitor, inhibits proliferation, migration and invasion of cervical cancer cells via inhibition of the RhoA/ROCK pathway. Oncol Lett. 2022;23(4):129.

Wang H, Hou W, Perera A, Bettler C, Beach JR, Ding X, et al. Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling. Cell Rep. 2021;34(8):108765.

Rezaie E, Amani J, Bidmeshki Pour A, Mahmoodzadeh Hosseini H. A new scfv-based recombinant immunotoxin against EPHA2-overexpressing breast cancer cells; high in vitro anti-cancer potency. Eur J Pharmacol. 2020;870:172912.

Wykosky J, Gibo DM, Debinski W. A novel, potent, and specific ephrinA1-based cytotoxin against EphA2 receptor expressing tumor cells. Mol Cancer Ther. 2007;6(12 Pt 1):3208–18.

Lee JW, Stone RL, Lee SJ, Nam EJ, Roh JW, Nick AM, et al. EphA2 targeted chemotherapy using an antibody drug conjugate in endometrial carcinoma. Clin Cancer Res. 2010;16(9):2562–70.

Lee JW, Han HD, Shahzad MM, Kim SW, Mangala LS, Nick AM, et al. EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma. J Natl Cancer Inst. 2009;101(17):1193–205.

Annunziata CM, Kohn EC, LoRusso P, Houston ND, Coleman RL, Buzoianu M, et al. Phase 1, open-label study of MEDI-547 in patients with relapsed or refractory solid tumors. Invest New Drugs. 2013;31(1):77–84.

Mudd GE, Brown A, Chen L, van Rietschoten K, Watcham S, Teufel DP, et al. Identification and optimization of EphA2-Selective bicycles for the delivery of cytotoxic payloads. J Med Chem. 2020;63(8):4107–16.

Bicyclic Peptide Makes Targeting EphA2 Possible. Cancer Discov. 2021;11(12):2951–2.

Google Scholar

Wang S, Placzek WJ, Stebbins JL, Mitra S, Noberini R, Koolpe M, et al. Novel targeted system to deliver chemotherapeutic drugs to EphA2-expressing cancer cells. J Med Chem. 2012;55(5):2427–36.

Wang S, Noberini R, Stebbins JL, Das S, Zhang Z, Wu B, et al. Targeted delivery of paclitaxel to EphA2-expressing cancer cells. Clin Cancer Res. 2013;19(1):128–37.

Barile E, Wang S, Das SK, Noberini R, Dahl R, Stebbins JL, et al. Design, synthesis and bioevaluation of an EphA2 receptor-based targeted delivery system. ChemMedChem. 2014;9(7):1403–12.

Wu B, Wang S, De SK, Barile E, Quinn BA, Zharkikh I, et al. Design and characterization of Novel EphA2 agonists for targeted delivery of chemotherapy to Cancer cells. Chem Biol. 2015;22(7):876–87.

Salem AF, Wang S, Billet S, Chen JF, Udompholkul P, Gambini L, et al. Reduction of circulating Cancer cells and metastases in breast-Cancer models by a potent EphA2-Agonistic peptide-drug Conjugate. J Med Chem. 2018;61(5):2052–61.

Quinn BA, Wang S, Barile E, Das SK, Emdad L, Sarkar D, et al. Therapy of pancreatic cancer via an EphA2 receptor-targeted delivery of gemcitabine. Oncotarget. 2016;7(13):17103–10.

Baggio C, Udompholkul P, Gambini L, Pellecchia M, Targefrin. A potent Agent targeting the ligand binding domain of EphA2. J Med Chem. 2022;65(22):15443–56.

Fu Y, Rathod D, Abo-Ali EM, Dukhande VV, Patel K. EphA2-Receptor targeted PEGylated nanoliposomes for the treatment of BRAF(V600E) mutated parent- and Vemurafenib-Resistant Melanoma. Pharmaceutics. 2019;11(10).

Haghiralsadat F, Amoabediny G, Sheikhha MH, Zandieh-Doulabi B, Naderinezhad S, Helder MN, et al. New liposomal doxorubicin nanoformulation for osteosarcoma: drug release kinetic study based on thermo and pH sensitivity. Chem Biol Drug Des. 2017;90(3):368–79.

Haghiralsadat F, Amoabediny G, Naderinezhad S, Zandieh-Doulabi B, Forouzanfar T, Helder MN. Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted PEGylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance. Int J Nanomed. 2018;13:3853–66.

Carofiglio M, Mesiano G, Rosso G, Conte M, Zuccheri M, Pignochino Y, et al. Targeted lipid-coated ZnO nanoparticles coupled with ultrasound: a sonodynamic approach for the treatment of osteosarcoma as 3D spheroid models. Mater Today Commun. 2024;40:109826.

Kamoun W, Swindell E, Pien C, Luus L, Cain J, Pham M et al. Targeting EphA2 in bladder Cancer using a novel antibody-Directed Nanotherapeutic. Pharmaceutics. 2020;12(10).

Kamoun WS, Dugast AS, Suchy JJ, Grabow S, Fulton RB, Sampson JF, et al. Synergy between EphA2-ILs-DTXp, a Novel EphA2-Targeted nanoliposomal taxane, and PD-1 inhibitors in preclinical Tumor models. Mol Cancer Ther. 2020;19(1):270–81.

Marc S, Ernstoff WWM, Tsai FY-C, Munster PN, Zhang T, Kamoun W, Pipas JM, Chen S. Sergio Santillana, and Vasileios Askoxylakis. A phase 1 study 1325 evaluating the safety, pharmacology and preliminary activity of MM-310 in patients with solid 1326 tumors. J Clin Oncol. 2018;36.

Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133(1):38–52.

Neuber C, Belter B, Mamat C, Pietzsch J. Radiopharmacologist’s and Radiochemist’s view on targeting the Eph/Ephrin receptor tyrosine kinase system. ACS Omega. 2020;5(27):16318–31.

Cai W, Ebrahimnejad A, Chen K, Cao Q, Li ZB, Tice DA, et al. Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice. Eur J Nucl Med Mol Imaging. 2007;34(12):2024–36.

Puttick S, Stringer BW, Day BW, Bruce ZC, Ensbey KS, Mardon K, et al. EphA2 as a diagnostic imaging target in Glioblastoma: a Positron Emission Tomography/Magnetic resonance imaging study. Mol Imaging. 2015;14:385–99.

Pyo A, You SH, Sik Kim H, Young Kim J, Min JJ, Kim DY, et al. Production of (64)Cu-labeled monobody for imaging of human EphA2-expressing tumors. Bioorg Med Chem Lett. 2020;30(14):127262.

Burvenich IJ, Parakh S, Gan HK, Lee FT, Guo N, Rigopoulos A, et al. Molecular imaging and quantitation of EphA2 expression in Xenograft models with 89Zr-DS-8895a. J Nucl Med. 2016;57(6):974–80.

Shitara K, Satoh T, Iwasa S, Yamaguchi K, Muro K, Komatsu Y, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the afucosylated, humanized anti-EPHA2 antibody DS-8895a: a first-in-human phase I dose escalation and dose expansion study in patients with advanced solid tumors. J Immunother Cancer. 2019;7(1):219.

Gan HK, Parakh S, Lee FT, Tebbutt NC, Ameratunga M, Lee ST, et al. A phase 1 safety and bioimaging trial of antibody DS-8895a against EphA2 in patients with advanced or metastatic EphA2 positive cancers. Invest New Drugs. 2022;40(4):747–55.

Furukawa T, Kimura H, Sasaki M, Yamada T, Iwasawa T, Yagi Y, et al. Novel [ (111) in]In-BnDTPA-EphA2-230-1 antibody for single-Photon Emission computed Tomography Imaging Tracer Targeting of EphA2. ACS Omega. 2023;8(7):7030–5.

Pretze M, Mosch B, Bergmann R, Steinbach J, Pietzsch J, Mamat C. Radiofluorination and first radiopharmacological characterization of a SWLAY peptide-based ligand targeting EphA2. J Label Comp Radiopharm. 2014;57(11):660–5.

Liu Y, Lan X, Wu T, Lang J, Jin X, Sun X, et al. (99m)Tc-labeled SWL specific peptide for targeting EphA2 receptor. Nucl Med Biol. 2014;41(6):450–6.

Furukawa T, Kimura H, Torimoto H, Yagi Y, Kawashima H, Arimitsu K, et al. A putative single-Photon Emission CT Imaging Tracer for Erythropoietin-Producing Hepatocellular A2 receptor. ACS Med Chem Lett. 2021;12(8):1238–44.

Yang Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest. 2015;125(9):3335–7.

Dotti G, Gottschalk S, Savoldo B, Brenner MK. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol Rev. 2014;257(1):107–26.

Li N, Liu S, Sun M, Chen W, Xu X, Zeng Z, et al. Chimeric Antigen Receptor-Modified T Cells Redirected to EphA2 for the Immunotherapy of Non-small Cell Lung Cancer. Transl Oncol. 2018;11(1):11–7.

Shi H, Yu F, Mao Y, Ju Q, Wu Y, Bai W, et al. EphA2 chimeric antigen receptor-modified T cells for the immunotherapy of esophageal squamous cell carcinoma. J Thorac Dis. 2018;10(5):2779–88.

Chow KK, Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z, et al. T cells redirected to EphA2 for the immunotherapy of glioblastoma. Mol Ther. 2013;21(3):629–37.

Hsu K, Middlemiss S, Saletta F, Gottschalk S, McCowage GB, Kramer B. Chimeric Antigen receptor-modified T cells targeting EphA2 for the immunotherapy of paediatric bone tumours. Cancer Gene Ther. 2021;28(3–4):321–34.

Yi Z, Prinzing BL, Cao F, Gottschalk S, Krenciute G. Optimizing EphA2-CAR T cells for the Adoptive Immunotherapy of Glioma. Mol Ther Methods Clin Dev. 2018;9:70–80.

Lange S, Sand LGL, Bell M, Patil SL, Langfitt D, Gottschalk S. A chimeric GM-CSF/IL18 receptor to sustain CAR T-cell function. Cancer Discov. 2021;11(7):1661–71.

Muhammad N, Wang R, Li W, Zhang Z, Chang Y, Hu Y, et al. A novel TanCAR targeting IL13Rα2 and EphA2 for enhanced glioblastoma therapy. Mol Ther Oncolytics. 2022;24:729–41.

Lin Q, Ba T, Ho J, Chen D, Cheng Y, Wang L et al. First-in-human trial of EphA2-Redirected CAR T-Cells in patients with recurrent glioblastoma: a preliminary Report of three cases at the starting dose. Front Oncol. 2021;11.

Fu C, Zhou L, Mi QS, Jiang A. DC-Based vaccines for Cancer Immunotherapy. Vaccines (Basel). 2020;8(4).

Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human dendritic cells: their heterogeneity and clinical application potential in Cancer Immunotherapy. Front Immunol. 2018;9:3176.

Huber A, Dammeijer F, Aerts J, Vroman H. Current state of dendritic cell-based immunotherapy: opportunities for in vitro Antigen Loading of different DC subsets? Front Immunol. 2018;9:2804.

Hatano M, Kuwashima N, Tatsumi T, Dusak JE, Nishimura F, Reilly KM, et al. Vaccination with EphA2-derived T cell-epitopes promotes immunity against both EphA2-expressing and EphA2-negative tumors. J Transl Med. 2004;2(1):40.

Hatano M, Eguchi J, Tatsumi T, Kuwashima N, Dusak JE, Kinch MS, et al. EphA2 as a glioma-associated antigen: a novel target for glioma vaccines. Neoplasia. 2005;7(8):717–22.

Chen H, Yuan B, Zheng Z, Liu Z, Wang S, Liu Y. A novel vaccine containing EphA2 epitope and LIGHT plasmid induces robust cellular immunity against glioma U251 cells. Cell Immunol. 2011;272(1):102–6.

Yeung JT, Hamilton RL, Okada H, Jakacki RI, Pollack IF. Increased expression of tumor-associated antigens in pediatric and adult ependymomas: implication for vaccine therapy. J Neurooncol. 2013;111(2):103–11.

Pollack IF, Jakacki RI, Butterfield LH, Hamilton RL, Panigrahy A, Potter DM, et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J Clin Oncol. 2014;32(19):2050–8.

Yamaguchi S, Tatsumi T, Takehara T, Sakamori R, Uemura A, Mizushima T, et al. Immunotherapy of murine colon cancer using receptor tyrosine kinase EphA2-derived peptide-pulsed dendritic cell vaccines. Cancer. 2007;110(7):1469–77.

Yamaguchi S, Tatsumi T, Takehara T, Sasakawa A, Hikita H, Kohga K, et al. Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity. Cancer Immunol Immunother. 2008;57(12):1861–9.

Yamaguchi S, Tatsumi T, Takehara T, Sasakawa A, Yamamoto M, Kohga K, et al. EphA2-derived peptide vaccine with amphiphilic poly(gamma-glutamic acid) nanoparticles elicits an anti-tumor effect against mouse liver tumor. Cancer Immunol Immunother. 2010;59(5):759–67.

Storkus WJ, Maurer D, Lin Y, Ding F, Bose A, Lowe D et al. Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma. J Immunother Cancer. 2021;9(11).

Upadhyaya P, Lahdenranta J, Hurov K, Battula S, Dods R, Haines E et al. Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist. J Immunother Cancer. 2021;9(1).

Download references

Acknowledgements

The authors are grateful to Prof. Michele De Bortoli and Dr. Giovanni Grignani for their helpful discussion and continuous support.

This work was supported by Italian Ministry of Health, Ricerca Corrente 2024 and Ministero della Salute- Ricerca Finalizzata- Giovani Ricercatori GR-2016-02362726 to YP (UO2). Biorender.com license was provided by the Department of Clinical and Biological Sciences (grant RILO 2021_01) to Y.P.

Author information

Authors and affiliations.

Sarcoma Unit, Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy

Giorgia Giordano, Cristina Tucciarello & Ymera Pignochino

Department of Oncology, University of Turin, 10043, Orbassano, TO, Italy

Giorgia Giordano & Alessandra Merlini

Department of Clinical and Biological Sciences, University of Turin, 10043, Orbassano, TO, Italy

Cristina Tucciarello, Santina Cutrupi & Ymera Pignochino

You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: G.G. and Y.P.; original draft and figure preparation: G.G.; writing-review and editing, C.T., A.M, S.C., and Y.P.; supervision and funding acquisition: Y.P. All authors have read and approved the final version of the manuscript.

Corresponding author

Correspondence to Ymera Pignochino .

Ethics declarations

Ethical approval.

Not applicable.

Consent for publication

Competing interests.

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Giordano, G., Tucciarello, C., Merlini, A. et al. Targeting the EphA2 pathway: could it be the way for bone sarcomas?. Cell Commun Signal 22 , 433 (2024). https://doi.org/10.1186/s12964-024-01811-7

Download citation

Received : 09 April 2024

Accepted : 30 August 2024

Published : 09 September 2024

DOI : https://doi.org/10.1186/s12964-024-01811-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

Bone sarcomas
Targeted therapy
Immunotherapy
Drug delivery

Cell Communication and Signaling

ISSN: 1478-811X

General enquiries: [email protected]

COMMENTS

7 easy steps to do a literature review
Joseph shared 7 steps to do a literature review in a stress-free manner: 1. Define your research scope. Establish the research area, topics and questions you want to address. Make a list of keywords (including synonyms) and main concepts linked to your research topic, and establish the connections between these concepts and your research ...
Seven Steps to a Comprehensive Literature Review
Teaches the CORE of the literature review - Critical thinking, Organization, Reflections and Evaluation - and provides a guide for reflexivity at the end of each of the seven steps. Visualizes the steps with roadmaps so you can track progress and self-evaluate as you learn the steps. This book is the essential best practices guide for ...
Seven Steps to a Comprehensive Literature Review
This book is the essential best practices guide for students and researchers, providing the understanding and tools to approach both the 'how' and 'why' of a rigorous, comprehensive, literature review. Available formats. Chapter 6: Step 3: Storing and Organizing Information. Chapter 7: Step 4: Selecting/Deselecting Information.
How to Write a Literature Review
Examples of literature reviews. Step 1 - Search for relevant literature. Step 2 - Evaluate and select sources. Step 3 - Identify themes, debates, and gaps. Step 4 - Outline your literature review's structure. Step 5 - Write your literature review.
A Comprehensive Review of Seven Steps to a Comprehensive Literature Review
method: acting (using p oetry, music, or d ance), visualizing (using paintings, drawings, or. photography), oral (oral presentation), and writing (producing a written account). Applying the 7-Step ...
Seven Steps to a Comprehensive Literature Review
This dynamic guide to doing literature reviews demystifies the process in seven steps to show researchers how to produce a comprehensive literature review. Teaching techniques to bring systematic thoroughness and reflexivity to research, the authors show how to achieve a rich, ethical and reflexive review. What makes this book unique: Focuses on multimodal texts and settings such as ...
Seven Steps to Writing a Literature Review
Seven Steps to Writing a Literature Review. 1. Narrow your topic and select papers accordingly; 2. Search for literature; 3. Read the selected articles thoroughly and evaluate them; 4. Organize the selected papers by looking for patterns and by developing subtopics; 5. Develop a thesis or purpose statement; 6. Write the paper; 7. Review your work
How To Write A Literature Review (+ Free Template)
As mentioned above, writing your literature review is a process, which I'll break down into three steps: Finding the most suitable literature. Understanding, distilling and organising the literature. Planning and writing up your literature review chapter. Importantly, you must complete steps one and two before you start writing up your chapter.
Seven Steps to a Comprehensive Literature Review
Teaches the CORE of the literature review - Critical thinking, Organization, Reflections and Evaluation - and provides a guide for reflexivity at the end of each of the seven steps. Visualizes the steps with roadmaps so you can track progress and self-evaluate as you learn the steps. This book is the essential best practices guide for ...
Literature Review: The What, Why and How-to Guide
Example: Predictors and Outcomes of U.S. Quality Maternity Leave: A Review and Conceptual Framework: 10.1177/08948453211037398 ; Systematic review: "The authors of a systematic review use a specific procedure to search the research literature, select the studies to include in their review, and critically evaluate the studies they find." (p. 139).
Steps to Write a Literature Review
What is a Literature Review? Steps to Write a Literature Review. Step 1: Choosing a Topic ; Step 2: Finding Information ; Step 3: Evaluating Content ; Step 4: Taking Notes ; Step 5: Synthesizing Content ; Step 6: Writing the Review ; Step 7: Citing Your Sources ; Library Services Toggle Dropdown. Meet the Library Team ; Off-Campus & Mobile Access
Steps in Conducting a Literature Review
A literature review is an integrated analysis-- not just a summary-- of scholarly writings and other relevant evidence related directly to your research question.That is, it represents a synthesis of the evidence that provides background information on your topic and shows a association between the evidence and your research question.
Steps in the Literature Review Process
Systematic Approaches to a Successful Literature Review by Andrew Booth; Anthea Sutton; Diana Papaioannou Showing you how to take a structured and organized approach to a wide range of literature review types, this book helps you to choose which approach is right for your research. Packed with constructive tools, examples, case studies and hands-on exercises, the book covers the full range of ...
How to Write a Literature Review: Six Steps to Get You from ...
Step One: Decide on your areas of research: Before you begin to search for articles or books, decide beforehand what areas you are going to research. Make sure that you only get articles and books in those areas, even if you come across fascinating books in other areas. A literature review I am currently working on, for example, explores ...
Book Review: Seven Steps to a Comprehensive Literature Review: A
In Seven Steps to a Comprehensive Literature Review: A Multimodal and Cultural Approach, Anthony J. Onwuegbuzie and Rebecca Frels offer a new guide on how to produce a comprehensive literature review through seven key steps that incorporate rigour, validity and reliability.Ana Raquel Nunes recommends this helpful, well-informed and well-organised book to those undertaking literature reviews as ...
Seven Steps to a Comprehensive Literature Review
Lecturers/instructors - request a free digital inspection copy here This dynamic guide to doing literature reviews demystifies the process in seven steps to show researchers how to produce a comprehensive literature review. Teaching techniques to bring systematic thoroughness and reflexivity to research, the authors show how to achieve a rich, ethical and reflexive review.
Steps for Conducting a Lit Review
Steps for Conducting a Lit Review. 1. Choose a topic. Define your research question. 2. Decide on the scope of your review. 3. Select the databases you will use to conduct your searches. 4. Conduct your searches and find the literature. Keep track of your searches! 5. Review the literature. Finding "The Literature" Organizing/Writing
Seven Steps to a Comprehensive Literature Review
In so doing, the authors innovate and advance our understandings of the processes and products involved in a comprehensive literature review and provide practical guidance for each of the steps. I have been seeking such a book and plan to make this required reading for the graduate students I instruct, mentor, and supervise.
A Comprehensive Review of Seven Steps to a Comprehensive Literature Review
A Comprehensive Review of Seven Steps to a Comprehensive Literature Review. Jan Kirksey Williams 8272621. Lone Star College, [email protected]. Follow this and additional works at: https://nsuworks.nova.edu/tqr. Part of the Online and Distance Education Commons, Quantitative, Qualitative, Comparative, and Historical Methodologies Commons ...
How to Write a Literature Review: 5 Steps for Clear and Meaningful
Since the literature review forms the backbone of your research, writing a clear and thorough review is essential. The steps below will help you do so: 1. Search for relevant information and findings. In research, information published on a given subject is called "literature" or "background literature.".
Literature Review Steps
When seeking information for a literature review or for any purpose, it helps to understand information-seeking as a process that you can follow. 5 Each of the six (6) steps has its own section in this web page with more detail. Do (and re-do) the following six steps: 1. Define your topic.
Steps in the Literature Review Process
Systematic Approaches to a Successful Literature Review by Andrew Booth; Anthea Sutton; Diana Papaioannou Showing you how to take a structured and organized approach to a wide range of literature review types, this book helps you to choose which approach is right for your research. Packed with constructive tools, examples, case studies and hands-on exercises, the book covers the full range of ...
Seven Steps To Producing A Literature Review
The document outlines a seven step process for producing a high-quality literature review: 1) define scope, 2) conduct thorough research, 3) organize sources, 4) analyze and synthesize information, 5) structure the review, 6) write clearly and concisely, and 7) revise and edit. It emphasizes comprehensively researching the topic, critically analyzing sources, and synthesizing information to ...
How to Use AI for Literature Review (2024): Complete 7 Step Guide for
3. Generate a Literature Review. With Elephas' Smart Write feature, you can create a well-structured literature review in just a few prompts. It pulls in the key themes and drafts a coherent review, ensuring that all relevant abstracts are referenced accurately. 4. Organise with Super Brain
Targeting the EphA2 pathway: could it be the way for bone sarcomas
Bone sarcomas are malignant tumors of mesenchymal origin. Complete surgical resection is the cornerstone of multidisciplinary treatment. However, advanced, unresectable forms remain incurable. A crucial step towards addressing this challenge involves comprehending the molecular mechanisms underpinning tumor progression and metastasis, laying the groundwork for innovative precision medicine ...

7 easy steps to do a literature review

You might also like:

You are here

Seven Steps to a Comprehensive Literature Review A Multimodal and Cultural Approach

Preview this book

For instructors

Related Products

Seven Steps to a Comprehensive Literature Review

Available formats

Session Timeout

Have a language expert improve your writing

How to Write a Literature Review | Guide, Examples, & Templates

Instantly correct all language mistakes in your text

Table of contents

Don't submit your assignments before you do this

Make a list of keywords

Search for relevant sources

Take notes and cite your sources

Chronological

Methodological

Theoretical

Cite this Scribbr article

Is this article helpful?

Shona McCombes

Write a Literature Review

Ask Us: Chat, email, visit or call

Get Assistance

How To Write An A-Grade Literature Review

Overview: The Literature Review Process

But first, the “why”…

Step 1: Find the relevant literature

Method 1 – Google Scholar Scrubbing

Method 2 – University Database Scrounging

Method 3 – Journal Article Snowballing

Method 4 – Dissertation Scavenging

Need a helping hand?

Step 2: Log, catalogue and synthesise

2.1 – Log the reference information

2.2 – Build an organised catalogue

2.3 – Digest and synthesise

Step 3: Outline and write it up!

3.1 – Draw up your outline

3.2 – Get writing

Literature Review Example

Let’s Recap

Psst… there’s more!

38 Comments

Submit a Comment Cancel reply

You are here

Seven Steps to a Comprehensive Literature Review A Multimodal and Cultural Approach

Preview this book

Rebecca Frels

Order from:

Related Products

Literature Review: The What, Why and How-to Guide — Introduction

What are Literature Reviews?

Goals of Literature Reviews

Types of Literature Reviews

Literature Reviews in the Health Sciences

Writing a Literature Review

Library Hours

Steps To Write a Literature Review

Harvey Cushing/John Hay Whitney Medical Library

YSN Doctoral Programs: Steps in Conducting a Literature Review

What is a literature review?

APA7 Style resources

1. Choose a topic. Define your research question.

2. Decide on the scope of your review

3. Select the databases you will use to conduct your searches.

4. Conduct your searches to find the evidence. Keep track of your searches.

Review the literature

How to Write a Literature Review: Six Steps to Get You from Start to Finish

How to Write a Literature Review

Watch our Webinar to help you get published

Leveraging user research to improve author guidelines at the Council of Science Editors Annual Meeting

How research content supports academic integrity

Finding time to publish as a medical student: 6 tips for Success

Software to Improve Reliability of Research Image Data: Wiley, Lumina, and Researchers at Harvard Medical School Work Together on Solutions

Driving Research Outcomes: Wiley Partners with CiteAb

ISBN, ISSN, DOI: what they are and how to find them