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The top list of academic search engines

1. Google Scholar

4. science.gov, 5. semantic scholar, 6. baidu scholar, get the most out of academic search engines, frequently asked questions about academic search engines, related articles.

Academic search engines have become the number one resource to turn to in order to find research papers and other scholarly sources. While classic academic databases like Web of Science and Scopus are locked behind paywalls, Google Scholar and others can be accessed free of charge. In order to help you get your research done fast, we have compiled the top list of free academic search engines.

Google Scholar is the clear number one when it comes to academic search engines. It's the power of Google searches applied to research papers and patents. It not only lets you find research papers for all academic disciplines for free but also often provides links to full-text PDF files.

• Coverage: approx. 200 million articles
• Abstracts: only a snippet of the abstract is available
• Related articles: ✔
• References: ✔
• Cited by: ✔
• Links to full text: ✔
• Export formats: APA, MLA, Chicago, Harvard, Vancouver, RIS, BibTeX

BASE is hosted at Bielefeld University in Germany. That is also where its name stems from (Bielefeld Academic Search Engine).

• Coverage: approx. 136 million articles (contains duplicates)
• Abstracts: ✔
• Related articles: ✘
• References: ✘
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• Export formats: RIS, BibTeX

CORE is an academic search engine dedicated to open-access research papers. For each search result, a link to the full-text PDF or full-text web page is provided.

• Coverage: approx. 136 million articles
• Links to full text: ✔ (all articles in CORE are open access)
• Export formats: BibTeX

Science.gov is a fantastic resource as it bundles and offers free access to search results from more than 15 U.S. federal agencies. There is no need anymore to query all those resources separately!

• Coverage: approx. 200 million articles and reports
• Links to full text: ✔ (available for some databases)
• Export formats: APA, MLA, RIS, BibTeX (available for some databases)

Semantic Scholar is the new kid on the block. Its mission is to provide more relevant and impactful search results using AI-powered algorithms that find hidden connections and links between research topics.

• Coverage: approx. 40 million articles
• Export formats: APA, MLA, Chicago, BibTeX

Although Baidu Scholar's interface is in Chinese, its index contains research papers in English as well as Chinese.

• Coverage: no detailed statistics available, approx. 100 million articles
• Abstracts: only snippets of the abstract are available
• Export formats: APA, MLA, RIS, BibTeX

RefSeek searches more than one billion documents from academic and organizational websites. Its clean interface makes it especially easy to use for students and new researchers.

• Coverage: no detailed statistics available, approx. 1 billion documents
• Abstracts: only snippets of the article are available
• Export formats: not available

Consider using a reference manager like Paperpile to save, organize, and cite your references. Paperpile integrates with Google Scholar and many popular databases, so you can save references and PDFs directly to your library using the Paperpile buttons:

Google Scholar is an academic search engine, and it is the clear number one when it comes to academic search engines. It's the power of Google searches applied to research papers and patents. It not only let's you find research papers for all academic disciplines for free, but also often provides links to full text PDF file.

Semantic Scholar is a free, AI-powered research tool for scientific literature developed at the Allen Institute for AI. Sematic Scholar was publicly released in 2015 and uses advances in natural language processing to provide summaries for scholarly papers.

BASE , as its name suggest is an academic search engine. It is hosted at Bielefeld University in Germany and that's where it name stems from (Bielefeld Academic Search Engine).

CORE is an academic search engine dedicated to open access research papers. For each search result a link to the full text PDF or full text web page is provided.

Science.gov is a fantastic resource as it bundles and offers free access to search results from more than 15 U.S. federal agencies. There is no need any more to query all those resources separately!

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21 Legit Research Databases for Free Journal Articles in 2024

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Has this ever happened to you? While looking for websites for research, you come across a research paper site that claims to connect academics to a peer-reviewed article database for free.

Intrigued, you search for keywords related to your topic, only to discover that you must pay a hefty subscription fee to access the service. After the umpteenth time being duped, you begin to wonder if there's even such a thing as free journal articles.

Subscription fees and paywalls are often the bane of students and academics, especially those at small institutions who don't provide access to many free article directories and repositories.

Whether you're working on an undergraduate paper, a PhD dissertation, or a medical research study, we want to help you find tools to locate and access the information you need to produce well-researched, compelling, and innovative work.

Below, we discuss why peer-reviewed articles are superior and list out the best free article databases to use in 2024.

Download Our Free Research Database Roundup PDF

Why peer-reviewed scholarly journal articles are more authoritative.

Determining what sources are reliable can be challenging. Peer-reviewed scholarly journal articles are the gold standard in academic research. Reputable academic journals have a rigorous peer-review process.

The peer review process provides accountability to the academic community, as well as to the content of the article. The peer review process involves qualified experts in a specific (often very specific) field performing a review of an article's methods and findings to determine things like quality and credibility.

Peer-reviewed articles can be found in peer-reviewed article databases and research databases, and if you know that a database of journals is reliable, that can offer reassurances about the reliability of a free article. Peer review is often double blind, meaning that the author removes all identifying information and, likewise, does not know the identity of the reviewers. This helps reviewers maintain objectivity and impartiality so as to judge an article based on its merit.

Where to Find Peer-Reviewed Articles

Peer-reviewed articles can be found in a variety of research databases. Below is a list of some of the major databases you can use to find peer-reviewed articles and other sources in disciplines spanning the humanities, sciences, and social sciences.

What Are Open Access Journals?

An open access (OA) journal is a journal whose content can be accessed without payment. This provides scholars, students, and researchers with free journal articles. OA journals use alternate methods of funding to cover publication costs so that articles can be published without having to pass those publication costs on to the reader.

Some of these funding models include standard funding methods like advertising, public funding, and author payment models, where the author pays a fee in order to publish in the journal. There are OA journals that have non-peer-reviewed academic content, as well as journals that focus on dissertations, theses, and papers from conferences, but the main focus of OA is peer-reviewed scholarly journal articles.

The internet has certainly made it easier to access research articles and other scholarly publications without needing access to a university library, and OA takes another step in that direction by removing financial barriers to academic content.

Choosing Wisely

Features of legitimate oa journals.

 There are things to look out for when trying to decide if a free publication journal is legitimate:

Mission statement —The mission statement for an OA journal should be available on their website.

Publication history —Is the journal well established? How long has it been available?

Editorial board —Who are the members of the editorial board, and what are their credentials?

Indexing —Can the journal be found in a reliable database?

Peer review —What is the peer review process? Does the journal allow enough time in the process for a reliable assessment of quality?

Impact factor —What is the average number of times the journal is cited over a two-year period?

Features of Illegitimate OA Journals

There are predatory publications that take advantage of the OA format, and they are something to be wary of. Here are some things to look out for:

Contact information —Is contact information provided? Can it be verified?

Turnaround —If the journal makes dubious claims about the amount of time from submission to publication, it is likely unreliable.

Editorial board —Much like determining legitimacy, looking at the editorial board and their credentials can help determine illegitimacy.

Indexing —Can the journal be found in any scholarly databases?

Peer review —Is there a statement about the peer review process? Does it fit what you know about peer review?

How to Find Scholarly Articles

Identify keywords.

Keywords are included in an article by the author. Keywords are an excellent way to find content relevant to your research topic or area of interest. In academic searches, much like you would on a search engine, you can use keywords to navigate through what is available to find exactly what you're looking for.

Authors provide keywords that will help you easily find their article when researching a related topic, often including general terms to accommodate broader searches, as well as some more specific terms for those with a narrower scope. Keywords can be used individually or in combination to refine your scholarly article search.

Narrow Down Results

Sometimes, search results can be overwhelming, and searching for free articles on a journal database is no exception, but there are multiple ways to narrow down your results. A good place to start is discipline.

What category does your topic fall into (psychology, architecture, machine learning, etc.)? You can also narrow down your search with a year range if you're looking for articles that are more recent.

A Boolean search can be incredibly helpful. This entails including terms like AND between two keywords in your search if you need both keywords to be in your results (or, if you are looking to exclude certain keywords, to exclude these words from the results).

Consider Different Avenues

If you're not having luck using keywords in your search for free articles, you may still be able to find what you're looking for by changing your tactics. Casting a wider net sometimes yields positive results, so it may be helpful to try searching by subject if keywords aren't getting you anywhere.

You can search for a specific publisher to see if they have OA publications in the academic journal database. And, if you know more precisely what you're looking for, you can search for the title of the article or the author's name.

Determining the Credibility of Scholarly Sources

Ensuring that sources are both credible and reliable is crucial to academic research. Use these strategies to help evaluate the usefulness of scholarly sources:

• Peer Review : Look for articles that have undergone a rigorous peer-review process. Peer-reviewed articles are typically vetted by experts in the field, ensuring the accuracy of the research findings.

Tip: To determine whether an article has undergone rigorous peer review, review the journal's editorial policies, which are often available on the journal's website. Look for information about the peer-review process, including the criteria for selecting reviewers, the process for handling conflicts of interest, and any transparency measures in place.

• Publisher Reputation : Consider the reputation of the publisher. Established publishers, such as well-known academic journals, are more likely to adhere to high editorial standards and publishing ethics.
• Author Credentials : Evaluate the credentials and expertise of the authors. Check their affiliations, academic credentials, and past publications to assess their authority in the field.
• Citations and References : Examine the citations and references provided in the article. A well-researched article will cite credible sources to support its arguments and findings. Verify the accuracy of the cited sources and ensure they are from reputable sources.
• Publication Date : Consider the publication date of the article. While older articles may still be relevant, particularly in certain fields, it is best to prioritize recent publications for up-to-date research and findings.
• Journal Impact Factor : Assess the journal's impact factor or other metrics that indicate its influence and reputation within the academic community. Higher impact factor journals are generally considered more prestigious and reliable. 

Tip: Journal Citation Reports (JCR), produced by Clarivate Analytics, is a widely used source for impact factor data. You can access JCR through academic libraries or directly from the Clarivate Analytics website if you have a subscription.

• Peer Recommendations : Seek recommendations from peers, mentors, or professors in your field. They can provide valuable insights and guidance on reputable sources and journals within your area of study.
• Cross-Verification : Cross-verify the information presented in the article with other credible sources. Compare findings, methodologies, and conclusions with similar studies to ensure consistency and reliability.

By employing these strategies, researchers can confidently evaluate the credibility and reliability of scholarly sources, ensuring the integrity of their research contributions in an ever-evolving landscape.

The Top 21 Free Online Journal and Research Databases

Navigating OA journals, research article databases, and academic websites trying to find high-quality sources for your research can really make your head spin. What constitutes a reliable database? What is a useful resource for your discipline and research topic? How can you find and access full-text, peer-reviewed articles?

Fortunately, we're here to help. Having covered some of the ins and outs of peer review, OA journals, and how to search for articles, we have compiled a list of the top 21 free online journals and the best research databases. This list of databases is a great resource to help you navigate the wide world of academic research.

These databases provide a variety of free sources, from abstracts and citations to full-text, peer-reviewed OA journals. With databases covering specific areas of research and interdisciplinary databases that provide a variety of material, these are some of our favorite free databases, and they're totally legit!

CORE is a multidisciplinary aggregator of OA research. CORE has the largest collection of OA articles available. It allows users to search more than 219 million OA articles. While most of these link to the full-text article on the original publisher's site, or to a PDF available for download, five million records are hosted directly on CORE.

CORE's mission statement is a simple and straightforward commitment to offering OA articles to anyone, anywhere in the world. They also host communities that are available for researchers to join and an ambassador community to enhance their services globally. In addition to a straightforward keyword search, CORE offers advanced search options to filter results by publication type, year, language, journal, repository, and author.

CORE's user interface is easy to use and navigate. Search results can be sorted based on relevance or recency, and you can search for relevant content directly from the results screen.

Collection : 219,537,133 OA articles

Other Services : Additional services are available from CORE, with extras that are geared toward researchers, repositories, and businesses. There are tools for accessing raw data, including an API that provides direct access to data, datasets that are available for download, and FastSync for syncing data content from the CORE database.

CORE has a recommender plug-in that suggests relevant OA content in the database while conducting a search and a discovery feature that helps you discover OA versions of paywalled articles. Other features include tools for managing content, such as a dashboard for managing repository output and the Repository Edition service to enhance discoverability.

Good Source of Peer-Reviewed Articles : Yes

Advanced Search Options : Language, author, journal, publisher, repository, DOI, year

2. ScienceOpen

Functioning as a research and publishing network, ScienceOpen offers OA to more than 74 million articles in all areas of science. Although you do need to register to view the full text of articles, registration is free. The advanced search function is highly detailed, allowing you to find exactly the research you're looking for.

The Berlin- and Boston-based company was founded in 2013 to "facilitate open and public communications between academics and to allow ideas to be judged on their merit, regardless of where they come from." Search results can be exported for easy integration with reference management systems.

You can also bookmark articles for later research. There are extensive networking options, including your Science Open profile, a forum for interacting with other researchers, the ability to track your usage and citations, and an interactive bibliography. Users have the ability to review articles and provide their knowledge and insight within the community.

Collection : 74,560,631

Other Services : None

Advanced Search Options :   Content type, source, author, journal, discipline

3. Directory of Open Access Journals

A multidisciplinary, community-curated directory, the Directory of Open Access Journals (DOAJ) gives researchers access to high-quality peer-reviewed journals. It has archived more than two million articles from 17,193 journals, allowing you to either browse by subject or search by keyword.

The site was launched in 2003 with the aim of increasing the visibility of OA scholarly journals online. Content on the site covers subjects from science, to law, to fine arts, and everything in between. DOAJ has a commitment to "increase the visibility, accessibility, reputation, usage and impact of quality, peer-reviewed, OA scholarly research journals globally, regardless of discipline, geography or language."

Information about the journal is available with each search result. Abstracts are also available in a collapsible format directly from the search screen. The scholarly article website is somewhat simple, but it is easy to navigate. There are 16 principles of transparency and best practices in scholarly publishing that clearly outline DOAJ policies and standards.

Collection : 6,817,242

Advanced Search Options :   Subject, journal, year

4. Education Resources Information Center

The Education Resources Information Center (ERIC) of the Institution of Education Sciences allows you to search by topic for material related to the field of education. Links lead to other sites, where you may have to purchase the information, but you can search for full-text articles only. You can also search only peer-reviewed sources.

The service primarily indexes journals, gray literature (such as technical reports, white papers, and government documents), and books. All sources of material on ERIC go through a formal review process prior to being indexed. ERIC's selection policy is available as a PDF on their website.

The ERIC website has an extensive FAQ section to address user questions. This includes categories like general questions, peer review, and ERIC content. There are also tips for advanced searches, as well as general guidance on the best way to search the database. ERIC is an excellent database for content specific to education.

Collection : 1,292,897

Advanced Search Options : Boolean

5. arXiv e-Print Archive

The arXiv e-Print Archive is run by Cornell University Library and curated by volunteer moderators, and it now offers OA to more than one million e-prints.

There are advisory committees for all eight subjects available on the database. With a stated commitment to an "emphasis on openness, collaboration, and scholarship," the arXiv e-Print Archive is an excellent STEM resource.

The interface is not as user-friendly as some of the other databases available, and the website hosts a blog to provide news and updates, but it is otherwise a straightforward math and science resource. There are simple and advanced search options, and, in addition to conducting searches for specific topics and articles, users can browse content by subject. The arXiv e-Print Archive clearly states that they do not peer review the e-prints in the database.

Collection : 1,983,891

Good Source of Peer-Reviewed Articles : No

Advanced Search Options :   Subject, date, title, author, abstract, DOI

6. Social Science Research Network

The Social Science Research Network (SSRN) is a collection of papers from the social sciences community. It is a highly interdisciplinary platform used to search for scholarly articles related to 67 social science topics. SSRN has a variety of research networks for the various topics available through the free scholarly database.

The site offers more than 700,000 abstracts and more than 600,000 full-text papers. There is not yet a specific option to search for only full-text articles, but, because most of the papers on the site are free access, it's not often that you encounter a paywall. There is currently no option to search for only peer-reviewed articles.

You must become a member to use the services, but registration is free and enables you to interact with other scholars around the world. SSRN is "passionately committed to increasing inclusion, diversity and equity in scholarly research," and they encourage and discuss the use of inclusive language in scholarship whenever possible.

Collection : 1,058,739 abstracts; 915,452 articles

Advanced Search Options : Term, author, date, network

7. Public Library of Science

Public Library of Science (PLOS) is a big player in the world of OA science. Publishing 12 OA journals, the nonprofit organization is committed to facilitating openness in academic research. According to the site, "all PLOS content is at the highest possible level of OA, meaning that scientific articles are immediately and freely available to anyone, anywhere."

PLOS outlines four fundamental goals that guide the organization: break boundaries, empower researchers, redefine quality, and open science. All PLOS journals are peer-reviewed, and all 12 journals uphold rigorous ethical standards for research, publication, and scientific reporting.

PLOS does not offer advanced search options. Content is organized by topic into research communities that users can browse through, in addition to options to search for both articles and journals. The PLOS website also has resources for peer reviewers, including guidance on becoming a reviewer and on how to best participate in the peer review process.

Collection : 12 journals

Advanced Search Options : None

8. OpenDOAR

OpenDOAR, or the Directory of Open Access Repositories, is a comprehensive resource for finding free OA journals and articles. Using Google Custom Search, OpenDOAR combs through OA repositories around the world and returns relevant research in all disciplines.

The repositories it searches through are assessed and categorized by OpenDOAR staff to ensure they meet quality standards. Inclusion criteria for the database include requirements for OA content, global access, and categorically appropriate content, in addition to various other quality assurance measures. OpenDOAR has metadata, data, content, preservation, and submission policies for repositories, in addition to two OA policy statements regarding minimum and optimum recommendations.

This database allows users to browse and search repositories, which can then be selected, and articles and data can be accessed from the repository directly. As a repository database, much of the content on the site is geared toward the support of repositories and OA standards.

Collection : 5,768 repositories

Other Services : OpenDOAR offers a variety of additional services. Given the nature of the platform, services are primarily aimed at repositories and institutions, and there is a marked focus on OA in general. Sherpa services are OA archiving tools for authors and institutions.

They also offer various resources for OA support and compliance regarding standards and policies. The publication router matches publications and publishers with appropriate repositories.

There are also services and resources from JISC for repositories for cost management, discoverability, research impact, and interoperability, including ORCID consortium membership information. Additionally, a repository self-assessment tool is available for members.

Advanced Search Options :   Name, organization name, repository type, software name, content type, subject, country, region

9. Bielefeld Academic Search Engine

The Bielefeld Academic Search Engine (BASE) is operated by the Bielefeld University Library in Germany, and it offers more than 240 million documents from more than 8,000 sources. Sixty percent of its content is OA, and you can filter your search accordingly.

BASE has rigorous inclusion requirements for content providers regarding quality and relevance, and they maintain a list of content providers for the sake of transparency, which can be easily found on their website. BASE has a fairly elegant interface. Search results can be organized by author, title, or date.

From the search results, items can be selected and exported, added to favorites, emailed, and searched in Google Scholar. There are basic and advanced search features, with the advanced search offering numerous options for refining search criteria. There is also a feature on the website that saves recent searches without additional steps from the user.

Collection : 276,019,066 documents; 9,286 content providers

Advanced Search Options :   Author, subject, year, content provider, language, document type, access, terms of reuse

10. Digital Library of the Commons Repository

Run by Indiana University, the Digital Library of the Commons (DLC) Repository is a multidisciplinary journal repository that allows users to access thousands of free and OA articles from around the world. You can browse by document type, date, author, title, and more or search for keywords relevant to your topic.

DCL also offers the Comprehensive Bibliography of the Commons, an image database, and a keyword thesaurus for enhanced search parameters. The repository includes books, book chapters, conference papers, journal articles, surveys, theses and dissertations, and working papers. DCL advanced search features drop-down menus of search types with built-in Boolean search options.

Searches can be sorted by relevance, title, date, or submission date in ascending or descending order. Abstracts are included in selected search results, with access to full texts available, and citations can be exported from the same page. Additionally, the image database search includes tips for better search results.

Collection : 10,784

Advanced Search Options :   Author, date, title, subject, sector, region, conference

11. CIA World Factbook

The CIA World Factbook is a little different from the other resources on this list in that it is not an online journal directory or repository. It is, however, a useful free online research database for academics in a variety of disciplines.

All the information is free to access, and it provides facts about every country in the world, which are organized by category and include information about history, geography, transportation, and much more. The World Factbook can be searched by country or region, and there is also information about the world's oceans.

This site contains resources related to the CIA as an organization rather than being a scientific journal database specifically. The site has a user interface that is easy to navigate. The site also provides a section for updates regarding changes to what information is available and how it is organized, making it easier to interact with the information you are searching for.

Collection : 266 countries

12. Paperity

Paperity boasts its status as the "first multidisciplinary aggregator of OA journals and papers." Their focus is on helping you avoid paywalls while connecting you to authoritative research. In addition to providing readers with easy access to thousands of journals, Paperity seeks to help authors reach their audiences and help journals increase their exposure to boost readership.

Paperity has journal articles for every discipline, and the database offers more than a dozen advanced search options, including the length of the paper and the number of authors. There is even an option to include, exclude, or exclusively search gray papers.

Paperity is available for mobile, with both a mobile site and the Paperity Reader, an app that is available for both Android and Apple users. The database is also available on social media. You can interact with Paperity via Twitter and Facebook, and links to their social media are available on their homepage, including their Twitter feed.

Collection : 8,837,396

Advanced Search Options : Title, abstract, journal title, journal ISSN, publisher, year of publication, number of characters, number of authors, DOI, author, affiliation, language, country, region, continent, gray papers

13. dblp Computer Science Bibliography

The dblp Computer Science Bibliography is an online index of major computer science publications. dblp was founded in 1993, though until 2010 it was a university-specific database at the University of Trier in Germany. It is currently maintained by the Schloss Dagstuhl – Leibniz Center for Informatics.

Although it provides access to both OA articles and those behind a paywall, you can limit your search to only OA articles. The site indexes more than three million publications, making it an invaluable resource in the world of computer science. dblp entries are color-coded based on the type of item.

dblp has an extensive FAQ section, so questions that might arise about topics like the database itself, navigating the website, or the data on dblp, in addition to several other topics, are likely to be answered. The website also hosts a blog and has a section devoted to website statistics.

Collection : 5,884,702

14. EconBiz

EconBiz is a great resource for economic and business studies. A service of the Leibniz Information Centre for Economics, it offers access to full texts online, with the option of searching for OA material only. Their literature search is performed across multiple international databases.

EconBiz has an incredibly useful research skills section, with resources such as Guided Walk, a service to help students and researchers navigate searches, evaluate sources, and correctly cite references; the Research Guide EconDesk, a help desk to answer specific questions and provide advice to aid in literature searches; and the Academic Career Kit for what they refer to as Early Career Researchers.

Other helpful resources include personal literature lists, a calendar of events for relevant calls for papers, conferences, and workshops, and an economics terminology thesaurus to help in finding keywords for searches. To stay up-to-date with EconBiz, you can sign up for their newsletter.

Collection : 1,075,219

Advanced Search Options :   Title, subject, author, institution, ISBN/ISSN, journal, publisher, language, OA only

15. BioMed Central

BioMed Central provides OA research from more than 300 peer-reviewed journals. While originally focused on resources related to the physical sciences, math, and engineering, BioMed Central has branched out to include journals that cover a broader range of disciplines, with the aim of providing a single platform that provides OA articles for a variety of research needs. You can browse these journals by subject or title, or you can search all articles for your required keyword.

BioMed Central has a commitment to peer-reviewed sources and to the peer review process itself, continually seeking to help and improve the peer review process. They're "committed to maintaining high standards through full and stringent peer review."

Additionally, the website includes resources to assist and support editors as part of their commitment to providing high-quality, peer-reviewed OA articles.

Collection : 507,212

Other Services : BMC administers the International Standard Randomised Controlled Trial Number (ISRCTN) registry. While initially designed for registering clinical trials, since its creation in 2000, the registry has broadened its scope to include other health studies as well.

The registry is recognized by the International Committee of Medical Journal Editors, as well as the World Health Organization (WHO), and it meets the requirements established by the WHO International Clinical Trials Registry Platform.

The study records included in the registry are all searchable and free to access. The ISRCTN registry "supports transparency in clinical research, helps reduce selective reporting of results and ensures an unbiased and complete evidence base."

Advanced Search Options :   Author, title, journal, list

A multidisciplinary search engine, JURN provides links to various scholarly websites, articles, and journals that are free to access or OA. Covering the fields of the arts, humanities, business, law, nature, science, and medicine, JURN has indexed almost 5,000 repositories to help you find exactly what you're looking for.

Search features are enhanced by Google, but searches are filtered through their index of repositories. JURN seeks to reach a wide audience, with their search engine tailored to researchers from "university lecturers and students seeking a strong search tool for OA content" and "advanced and ambitious students, age 14-18" to "amateur historians and biographers" and "unemployed and retired lecturers."

That being said, JURN is very upfront about its limitations. They admit to not being a good resource for educational studies, social studies, or psychology, and conference archives are generally not included due to frequently unstable URLs.

Collection : 5,064 indexed journals

Other Services : JURN has a browser add-on called UserScript. This add-on allows users to integrate the JURN database directly into Google Search. When performing a search through Google, the add-on creates a link that sends the search directly to JURN CSE. JURN CSE is a search service that is hosted by Google.

Clicking the link from the Google Search bar will run your search through the JURN database from the Google homepage. There is also an interface for a DuckDuckGo search box; while this search engine has an emphasis on user privacy, for smaller sites that may be indexed by JURN, DuckDuckGo may not provide the same depth of results.

Advanced Search Options :   Google search modifiers

Dryad is a digital repository of curated, OA scientific research data. Launched in 2009, it is run by a not-for-profit membership organization, with a community of institutional and publisher members for whom their services have been designed. Members include institutions such as Stanford, UCLA, and Yale, as well as publishers like Oxford University Press and Wiley.

Dryad aims to "promote a world where research data is openly available, integrated with the scholarly literature, and routinely reused to create knowledge." It is free to access for the search and discovery of data. Their user experience is geared toward easy self-depositing, supports Creative Commons licensing, and provides DOIs for all their content.

Note that there is a publishing charge associated if you wish to publish your data in Dryad.  When searching datasets, they are accompanied by author information and abstracts for the associated studies, and citation information is provided for easy attribution.

Collection : 44,458

Advanced Search Options : No

Run by the British Library, the E-Theses Online Service (EThOS) allows you to search over 500,000 doctoral theses in a variety of disciplines. All of the doctoral theses available on EThOS have been awarded by higher education institutions in the United Kingdom.

Although some full texts are behind paywalls, you can limit your search to items available for immediate download, either directly through EThOS or through an institution's website. More than half of the records in the database provide access to full-text theses.

EThOS notes that they do not hold all records for all institutions, but they strive to index as many doctoral theses as possible, and the database is constantly expanding, with approximately 3,000 new records added and 2,000 new full-text theses available every month. The availability of full-text theses is dependent on multiple factors, including their availability in the institutional repository and the level of repository development.

Collection : 500,000+

Advanced Search Options : Abstract, author's first name, author's last name, awarding body, current institution, EThOS ID, year, language, qualifications, research supervisor, sponsor/funder, keyword, title

PubMed is a research platform well-known in the fields of science and medicine. It was created and developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM). It has been available since 1996 and offers access to "more than 33 million citations for biomedical literature from MEDLINE, life science journals, and online books."

While PubMed does not provide full-text articles directly, and many full-text articles may be behind paywalls or require subscriptions to access them, when articles are available from free sources, such as through PubMed Central (PMC), those links are provided with the citations and abstracts that PubMed does provide.

PMC, which was established in 2000 by the NLM, is a free full-text archive that includes more than 6,000,000 records. PubMed records link directly to corresponding PMC results. PMC content is provided by publishers and other content owners, digitization projects, and authors directly.

Collection : 33,000,000+

Advanced Search Options : Author's first name, author's last name, identifier, corporation, date completed, date created, date entered, date modified, date published, MeSH, book, conflict of interest statement, EC/RN number, editor, filter, grant number, page number, pharmacological action, volume, publication type, publisher, secondary source ID, text, title, abstract, transliterated title

20. Semantic Scholar

A unique and easy-to-use resource, Semantic Scholar defines itself not just as a research database but also as a "search and discovery tool." Semantic Scholar harnesses the power of artificial intelligence to efficiently sort through millions of science-related papers based on your search terms.

Through this singular application of machine learning, Semantic Scholar expands search results to include topic overviews based on your search terms, with the option to create an alert for or further explore the topic. It also provides links to related topics.

In addition, search results produce "TLDR" summaries in order to provide concise overviews of articles and enhance your research by helping you to navigate quickly and easily through the available literature to find the most relevant information. According to the site, although some articles are behind paywalls, "the data [they] have for those articles is limited," so you can expect to receive mostly full-text results.

Collection : 203,379,033

Other Services : Semantic Scholar supports multiple popular browsers. Content can be accessed through both mobile and desktop versions of Firefox, Microsoft Edge, Google Chrome, Apple Safari, and Opera.

Additionally, Semantic Scholar provides browser extensions for both Chrome and Firefox, so AI-powered scholarly search results are never more than a click away. The mobile interface includes an option for Semantic Swipe, a new way of interacting with your research results.

There are also beta features that can be accessed as part of the Beta Program, which will provide you with features that are being actively developed and require user feedback for further improvement.

Advanced Search Options : Field of study, date range, publication type, author, journal, conference, PDF

Zenodo, powered by the European Organization for Nuclear Research (CERN), was launched in 2013. Taking its name from Zenodotus, the first librarian of the ancient library of Alexandria, Zenodo is a tool "built and developed by researchers, to ensure that everyone can join in open science." Zenodo accepts all research from every discipline in any file format.

However, Zenodo also curates uploads and promotes peer-reviewed material that is available through OA. A DOI is assigned to everything that is uploaded to Zenodo, making research easily findable and citable. You can sort by keyword, title, journal, and more and download OA documents directly from the site.

While there are closed access and restricted access items in the database, the vast majority of research is OA material. Search results can be filtered by access type, making it easy to view the free articles available in the database.

Collection : 2,220,000+

Advanced Search Options : Access, file type, keywords

Check out our roundup of free research databases as a handy one-page PDF.

How to find peer-reviewed articles.

There are a lot of free scholarly articles available from various sources. The internet is a big place. So how do you go about finding peer-reviewed articles when conducting your research? It's important to make sure you are using reputable sources.

The first source of the article is the person or people who wrote it. Checking out the author can give you some initial insight into how much you can trust what you’re reading. Looking into the publication information of your sources can also indicate whether the article is reliable.

Aspects of the article, such as subject and audience, tone, and format, are other things you can look at when evaluating whether the article you're using is valid, reputable, peer-reviewed material. So, let's break that down into various components so you can assess your research to ensure that you're using quality articles and conducting solid research.

Check the Author

Peer-reviewed articles are written by experts or scholars with experience in the field or discipline they're writing about. The research in a peer-reviewed article has to pass a rigorous evaluation process, so it's a foregone conclusion that the author(s) of a peer-reviewed article should have experience or training related to that research.

When evaluating an article, take a look at the author's information. What credentials does the author have to indicate that their research has scholarly weight behind it? Finding out what type of degree the author has—and what that degree is in—can provide insight into what kind of authority the author is on the subject.

Something else that might lend credence to the author's scholarly role is their professional affiliation. A look at what organization or institution they are affiliated with can tell you a lot about their experience or expertise. Where were they trained, and who is verifying their research?

Identify Subject and Audience

The ultimate goal of a study is to answer a question. Scholarly articles are also written for scholarly audiences, especially articles that have gone through the peer review process. This means that the author is trying to reach experts, researchers, academics, and students in the field or topic the research is based on.

Think about the question the author is trying to answer by conducting this research, why, and for whom. What is the subject of the article? What question has it set out to answer? What is the purpose of finding the information? Is the purpose of the article of importance to other scholars? Is it original content?

Research should also be approached analytically. Is the methodology sound? Is the author using an analytical approach to evaluate the data that they have obtained? Are the conclusions they've reached substantiated by their data and analysis? Answering these questions can reveal a lot about the article's validity.

Format Matters

Reliable articles from peer-reviewed sources have certain format elements to be aware of. The first is an abstract. An abstract is a short summary or overview of the article. Does the article have an abstract? It's unlikely that you're reading a peer-reviewed article if it doesn't. Peer-reviewed journals will also have a word count range. If an article seems far too short or incredibly long, that may be reason to doubt it.

Another feature of reliable articles is the sections the information is divided into. Peer-reviewed research articles will have clear, concise sections that appropriately organize the information. This might include a literature review, methodology, results (in the case of research articles), and a conclusion.

One of the most important sections is the references or bibliography. This is where the researcher lists all the sources of their information. A peer-reviewed source will have a comprehensive reference section.

An article that has been written to reach an academic community will have an academic tone. The language that is used, and the way this language is used, is important to consider. If the article is riddled with grammatical errors, confusing syntax, and casual language, it almost definitely didn't make it through the peer review process.

Also consider the use of terminology. Every discipline is going to have standard terminology or jargon that can be used and understood by other academics in the discipline. The language in a peer-reviewed article is going to reflect that.

If the author is going out of their way to explain simple terms, or terms that are standard to the field or discipline, it's unlikely that the article has been peer reviewed, as this is something that the author would be asked to address during the review process.

Publication

The source of the article will be a very good indicator of the likelihood that it was peer reviewed. Where was the article published? Was it published alongside other academic articles in the same discipline? Is it a legitimate and reputable scholarly publication?

A trade publication or newspaper might be legitimate or reputable, but it is not a scholarly source, and it will not have been subject to the peer review process. Scholarly journals are the best resource for peer-reviewed articles, but it's important to remember that not all scholarly journals are peer reviewed.

It's helpful to look at a scholarly source's website, as peer-reviewed journals will have a clear indication of the peer review process. University libraries, institutional repositories, and reliable databases (and now you have a list of legit ones) can also help provide insight into whether an article comes from a peer-reviewed journal.

Common Research Mistakes to Avoid

Research is a lot of work. Even with high standards and good intentions, it's easy to make mistakes. Perhaps you searched for access to scientific journals for free and found the perfect peer-reviewed sources, but you forgot to document everything, and your references are a mess. Or, you only searched for free online articles and missed out on a ground-breaking study that was behind a paywall.

Whether your research is for a degree or to get published or to satisfy your own inquisitive nature, or all of the above, you want all that work to produce quality results. You want your research to be thorough and accurate.

To have any hope of contributing to the literature on your research topic, your results need to be high quality. You might not be able to avoid every potential mistake, but here are some that are both common and easy to avoid.

Sticking to One Source

One of the hallmarks of good research is a healthy reference section. Using a variety of sources gives you a better answer to your question. Even if all of the literature is in agreement, looking at various aspects of the topic may provide you with an entirely different picture than you would have if you looked at your research question from only one angle.

Not Documenting Every Fact

As you conduct your research, do yourself a favor and write everything down. Everything you include in your paper or article that you got from another source is going to need to be added to your references and cited.

It's important, especially if your aim is to conduct ethical, high-quality research, that all of your research has proper attribution. If you don't document as you go, you could end up making a lot of work for yourself if the information you don't write down is something that later, as you write your paper, you really need.

Using Outdated Materials

Academia is an ever-changing landscape. What was true in your academic discipline or area of research ten years ago may have since been disproven. If fifteen studies have come out since the article that you're using was published, it's more than a little likely that you're going to be basing your research on flawed or dated information.

If the information you're basing your research on isn't as up-to-date as possible, your research won't be of quality or able to stand up to any amount of scrutiny. You don't want all of your hard work to be for naught.

Relying Solely on Open Access Journals

OA is a great resource for conducting academic research. There are high-quality journal articles available through OA, and that can be very helpful for your research. But, just because you have access to free articles, that doesn't mean that there's nothing to be found behind a paywall.

Just as dismissing high-quality peer-reviewed articles because they are OA would be limiting, not exploring any paid content at all is equally short-sighted. If you're seeking to conduct thorough and comprehensive research, exploring all of your options for quality sources is going to be to your benefit.

Digging Too Deep or Not Deep Enough

Research is an art form, and it involves a delicate balance of information. If you conduct your research using only broad search terms, you won't be able to answer your research question well, or you'll find that your research provides information that is closely related to your topic but, ultimately, your findings are vague and unsubstantiated.

On the other hand, if you delve deeply into your research topic with specific searches and turn up too many sources, you might have a lot of information that is adjacent to your topic but without focus and perhaps not entirely relevant. It's important to answer your research question concisely but thoroughly.

Different Types of Scholarly Articles

Different types of scholarly articles have different purposes. An original research article, also called an empirical article, is the product of a study or an experiment. This type of article seeks to answer a question or fill a gap in the existing literature.

Research articles will have a methodology, results, and a discussion of the findings of the experiment or research and typically a conclusion.

Review articles overview the current literature and research and provide a summary of what the existing research indicates or has concluded. This type of study will have a section for the literature review, as well as a discussion of the findings of that review. Review articles will have a particularly extensive reference or bibliography section.

Theoretical articles draw on existing literature to create new theories or conclusions, or look at current theories from a different perspective, to contribute to the foundational knowledge of the field of study.

10 Tips for Navigating Journal Databases

Use the right academic journal database for your search, be that interdisciplinary or specific to your field. Or both!

If it's an option, set the search results to return only peer-reviewed sources.

Start by using search terms that are relevant to your topic without being overly specific.

Try synonyms, especially if your keywords aren't returning the desired results.

Even if you've found some good articles, try searching using different terms.

Explore the advanced search features of the database(s).

Learn to use Booleans (AND, OR, NOT) to expand or narrow your results.

Once you've gotten some good results from a more general search, try narrowing your search.

Read through abstracts when trying to find articles relevant to your research.

Keep track of your research and use citation tools. It'll make life easier when it comes time to compile your references.

7 Frequently Asked Questions

1. how do i get articles for free.

Free articles can be found through free online academic journals, OA databases, or other databases that include OA journals and articles. These resources allow you to access free papers online so you can conduct your research without getting stuck behind a paywall.

Academics don't receive payment for the articles they contribute to journals. There are often, in fact, publication fees that scholars pay in order to publish. This is one of the funding structures that allows OA journals to provide free content so that you don't have to pay fees or subscription costs to access journal articles.

2. How Do I Find Journal Articles?

Journal articles can be found in databases and institutional repositories that can be accessed at university libraries. However, online research databases that contain OA articles are the best resource for getting free access to journal articles that are available online.

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OA articles are articles that can be accessed for free. While some scholarly search engines and databases include articles that aren't peer reviewed, there are also some that provide only peer-reviewed articles, and databases that include non-peer-reviewed articles often have advanced search features that enable you to select "peer review only." The database will return results that are exclusively peer-reviewed content.

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Free scholarly article databases can provide access to abstracts, scholarly article websites, journal repositories, and high-quality peer-reviewed journal articles. The internet has a lot of information, and it's often challenging to figure out what information is reliable. 

Research databases and article directories are great resources to help you conduct your research. Our list of the best research paper websites is sure to provide you with sources that are totally legit.

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The presence of cancer-associated fibroblast in breast cavity side margins is in correlation with the expression of oncoproteins by adjacent epithelial cells: a new era in cancerous potential

• Open access
• Published: 17 September 2024
• Volume 150 , article number  421 , ( 2024 )

Cite this article

You have full access to this open access article

• Zohreh Sadat Miripour 1 , 2   na1 ,
• Mina Aminifar 1 ,
• Parisa Hoseinpour 1 , 3 ,
• Fereshteh Abbasvandi 4 , 5 ,
• Koosha Karimi 1   na2 ,
• Alireza Ghahremani 1   na2 ,
• Mohammad Parniani 4 ,
• Mohammadreza Ghaderinia 1 ,
• Faride Makiyan 1 ,
• Parisa Aghaee 1 ,
• Mohammad Esmaeil Akbari 5 &
• Mohammad Abdolahad 1 , 2 , 6   na1  

Cancer-associated fibroblasts (CAFs) are one of the most critical cells in the tumor environment, with crucial roles in cancer progression and metastasis. Due to Field-Effect phenomena (also called field cancerization), the adjacent cavity side area of the margin is histologically normal, but it has been entered into neoplastic transformation due to MCT4 and MCT1 pathways activated by H 2 O 2 /ROS oxidative stress agents secreted by CAF in adjacent tumor bed microenvironment. This paper specifically focused on the role of cancer-associated fibroblast in breast tumor beds and its correlation with the presence of scattered cancer cells or onco-protein-activated cells (may be high risk but not completely transformed cancer cells) in the cavity side margins.

In this study, the glycolytic behavior of non-tumoral cavity side margins was examined using carbon nanotube-based electrochemical biosensors integrated into a cancer diagnostic probe. This method enabled the detection of CAF accumulation sites in non-cancerous neighboring tissues of tumors, with a correlation to CAF concentration. Subsequently, RT-PCR, fluorescent, histopathological, and invasion assays were conducted on hyperglycolytic lesions to explore any correlation between the abundance of CAFs and the electrochemical responses of the non-cancerous tissues surrounding the tumor, as well as their neoplastic potential.

We observed overexpression of cancer-associated transcriptomes as well as the presence and hyperactivation of CAFs in cavity-side regions in which glycolytic metabolism was recorded, independent of the histopathological state of the lesion. At mean 70.4%, 66.7%, 70.4%, and 44.5% increments were observed in GLUT-1, MMP-2, N-cadherin, and MMP-9 transcriptomes by highly glycolytic but histologically cancer-free expression samples in comparison with negative controls (histologically non-cancer lesions with low glycolytic behavior).

The presence of CAFs is correlated with the presence of high glycolytic metabolism in the cavity margin lesion, high ROS level in the lesion, and finally aggressive cancer-associated proteins (such as MMP2, …) in the margin while these metabolomes, molecules, and proteins are absent in the margins with negatively scored CDP response and low ROS level. So, it seems that when we observe CAFs in glycolytic lesions with high ROS levels, some high-risk epithelial breast cells may exist while no histological trace of cancer cells was observed. Further research on CAFs could provide valuable insights into the local recurrence of malignant breast diseases. Hence, real-time sensors can be used to detect and investigate CAFs in the non-tumoral regions surrounding tumors in cancer patients, potentially aiding in the prevention of cancer recurrence.

Avoid common mistakes on your manuscript.

Introduction

Field cancerization is one of the hot subjects recently presented in cancer biology in which CAFs play a crucial role (Chan et al. 2018 ; Gascard and Tlsty 2016 ; Martinez-Outschoorn et al. 2010 ; Liao et al. 2018 ; Vanharanta and Massagué 2012 ; Gadaleta et al. 2022 ). The tumor stroma is no longer seen solely as physical support for mutated epithelial cells but as an essential modulator and even a driver of tumorigenicity. Within the tumor-stromal milieu, heterogeneous populations of fibroblast-like cells, collectively termed CAFs, are key players in the multicellular, stromal-dependent alterations that contribute to malignant initiation and progression (Gascard and Tlsty 2016 ; Giannoni et al. 2010 ).

High reputations of investigations are needed to reveal the correlation between the presence of CAFs in the far field from the tumor and their effect on cancer recurrences. In this phenomenon, the hydrogen peroxide and reactive oxygen species (ROS) were released by tumor-associated fibroblasts and the adjacent tumor microenvironment cells in the environment of normal stromal margins and cancerized them through “field effect” but revealed no pathological signs of cancerization (Lisanti et al. 2011 ).

Many methods were developed to find and indicate CAFs, such as fibroblast-cancer cell line co-cultures to investigate their markers (Martinez-Outschoorn et al. 2010 ; Louault et al. 2019 ; Erez et al. 2010 ) and invasive behavior of cancer cells in the presence of CAFs (Truong et al. 2019 ; Truong et al. 2016 ). Some research indicated that CAFs promoted aggressive phenotypes of breast cancer cells through epithelial-to-mesenchymal transition (EMT) induced by TGF-β1. This might be a common mechanism for acquiring metastatic potential in breast cancer cells with different biological characteristics (Yu et al. 2014 ). The distinct functions of CAFs in comparison with NFs are their glycolytic metabolism and over-expression of alpha-SMA transcriptomes (Chen et al. 2017 ).

Here we used a label-free and real-time method to find lesions with high glycolytic behavior in their live states for analysis and investigate their specifications. The technique (called a cancer diagnostic probe (CDP)) has been based on electrochemical tracking of ROS/H 2 O 2 released from the preneoplastic/neoplastic cells in the cavity side margins ((Miripour et al. 2022a , b ; Dabbagh et al. 2021 ), US 11,179,076 B2, US 10,786,188 B1, US 11,179,077 B2, US 11,181,499 B2). The indicated levels of released ROS/H 2 O 2 in pathologically free margins may correlate with CAF accumulations and the occurrence of field cancerization (Supplementary Section 1). This could be of significant impact to be further investigated. Finding and dissecting such CAFs may include valuable data about their phenotype and potential role in inducing neoplastic changes in epithelial cells, which were experimentally studied in this article.

We derived fibroblasts from the dissected specimens of 33 breast cancer mastectomy cases without inducing any perturbation or bias in the surgery and pathology trends. The specimen was dissected from the lesions, which weren’t important for pathological evaluation. The CDP score of each specimen was recorded, and a part of the specimen was used for H&E and PCR evaluation to find any correlation between the presence and activity of CAFs, levels of expressed cancer-associated transcriptomes, and the presence/absence of cancer cells in the specimen. Also, CAFs interacted with breast non-cancer (MCF10-A) and cancer (MCF-7) cell lines, and the co-effects of CAFs and breast cell lines on each other were evaluated. We aimed to find a relation between levels of ROS/H 2 O 2 released through the glycolysis metabolism of CAFs and the induced cancerous transformation transcriptomes in adjacent epithelial cells through molecular analysis.

We found that CAFs just could be actively found in adjacent cancer cells. Hence, we may not have active CAFs in the absence of cancer/pre-cancer cells except just adjacent to them (to promote their MCT4 pathway). This may be a new hallmark to understand better the hidden factors behind the local recurrence of breast cancer.

Material and methods

Cdp structure and protocols.

CDP is a cancer diagnostic probe that can diagnose the presence of pre-neoplastic/neoplastic cells in either cavity side margins of the patient's tumor during breast cancer surgery. It consists of an integrated automatic electrochemical readout board and a sensing disposable head probe as the main diagnostic part of the system. The sensing head probe was fabricated by the growth of Multi-Walled Carbon Nanotubes (MWCNTs) on the tip of steel needles in the conformation of three electrodes, named Working (WE), Counter (CE), and Reference (RE), with a triangular distance of 3mm from each other. The entered length of the needles into the breast margins is 4mm in the case of breast cancer surgery as the surgeons want to ensure the absence of any atypical/neoplastic or satellite lesions cells up to the depth of 4mm in the body side. The head probe is single-used and was sterilized under plasma sterilizer protocol (standard No: ISO/NP 22441) which didn’t induce any perturbations on the morphology and function of the nanostructures.

The system determines lively the trace of ROS/H 2 O 2 released from cancer or atypical cells, through reverse Warburg effect and hypoxia-assisted glycolysis pathways, in a quantitative electrochemical manner. A matched clinical diagnostic categorization between the pathological results of the tested tissues and response peaks of CDP was proposed based on pathological classification (ductal intraepithelial neoplasia (DIN), lobular intraepithelial neoplasia (LIN), and fibroepithelial lesion (FEL)) with the latest reported modifications. Still, no intra-operative technique has been reported for the detection of cavity side surgical margins with pathologically approved classification in breast cancer (as one of the most important one-surgeries required for accurate margin detection).

During the lumpectomy or mastectomy surgery, the CDP was used for checking both cavity side margins to observe any probable matching between the suggested pathological classification of CDP scores and the final diagnostics of the samples declared by pathologists. At first, Sterilized CDP (stored in ambient exposed to a formalin tablet for one day) was turned on and connected to the software. Then the head probe (sterilized by plasma standard protocol) was connected to the CDP and the body side margins of the patient undergone tumor dissection were checked by CDP. After tumor dissection, all of the regions in the body side margins were tested by CDP (Superior, inferior, medial, lateral, superficial, and deep). Depending on the size of the tumor and its proximity to one of the margins (not all of the margins), some margins must undergo further analysis. In this regard, the internal regions with more joint boundaries with the tumors would require further scans due to their larger formed internal margins. If a region is positively scored by CDP, its neighbors (with a width of 3mm) and under-existed margin should also be checked by CDP. As a result, surgeons could excise the involved region with safe neighbors. The gold standard is permanent H&E/IHC assay ((Miripour et al. 2022a , b ; Dabbagh et al. 2021 ), US 11,179,076 B2, US 10,786,188 B1, US 11,179,077 B2, US 11,181,499 B2).

Isolation of human breast fibroblasts and cell culture

Breast tissues with evaluated glycolytic behavior were obtained from the dissected specimens of 33 breast cancer mastectomy cases without inducing any perturbation or bias in the surgery trend. Also, a breast sample from mammoplasty surgery was used as a negative control for PCR analysis. Fibroblasts were isolated from these dissected breast regions. Tissues containing the CAFs were placed in collagenase type I (1 mg/mL; Boehringer Mannheim) and hyaluronidase (125 units/mL; Sigma-Aldrich) at 37 °C with agitation for 12–18 h. in Dulbecco’s modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS) and placed on a shaker within the cell culture incubator until tissues were dissociated. Following this, a cell strainer was used to isolate cells from the dissociated tissues and re-suspended in complete DMEM. Then it was centrifuged at 4000 rpm for 3 min, and the pellet was resuspended in DMEM with 10% FBS and then expanded into a cell culture plate with 48 wells and stored up to passage 3 to population doublings within the total of 8–10 days after tissue dissociation (Truong et al. 2019 ; Orimo et al. 2005 ).

ROS generation was analyzed with a CM-H2DCFDA assay. This probe is converted to DCF with a green fluorescent property by esterase enzymes in the cytosol of the cells. To do this experiment, after culturing the Fibroblast cultured cells overnight, the cells are washed twice with PBS, and then 500 µL of the CM-H2DCFDA solution with a concentration of 20 µM is added. After 30 min incubation at room temperature and dark, cells are washed and imaged with a fluorescent microscope. As a negative control, a sample of cells was incubated with 12 mg NAC (N-Acetyl Cysteine) as a ROS scavenger and then treated with CM-H2DCFDA. The samples were imaged with a fluorescent microscopy system (Miripour et al. 2022a ).

immunohistochemical staining procedure

The resected surgical tissue slides were deparaffinized in xylene, hydrated in dilutions of alcohol series, and immersed in 0.3% hydrogen peroxide in methanol to suppress endogenous peroxidase activity. TE buffer (10 mM Tris and 1 mM EDTA, pH 9.3) was used to treat sections at 98ºC for 30 min. Each section was blocked with 0.1% Tween 20 in PBS containing 4% bovine serum albumin for 30 min to reduce non-specific staining. The sections were incubated with anti-SMA (1:100, Millipore, Billerica, MA, USA) in PBST containing 3 mg/ml goat globulin (Sigma, St. Louis, MO, USA) for 60 min at room temperature, followed by three subsequent washes with buffer. Sections were then incubated with an anti-mouse/rabbit antibody (Envision plus, Dako) for 30 min. The chromogen used was 3,39-diaminobenzidine. Meyer’s hematoxylin was used to counterstain the sections. Negative controls for immunostaining were obtained by excluding the primary antibody (Ha et al. 2014 ).

Quantitative real-time polymerase chain reaction (qRT-PCR)

The total RNA of breast dissected samples was extracted using an RNX kit (Sinaclon, Iran) according to the manufacturer’s protocol. For each sample, 1 µg of RNA was reverse transcribed into complementary DNA (cDNA) using a cDNA synthesis Kit (Anacell, Iran) and analyzed with a StepOne real-time PCR system (Applied Biosystems) applying an SYBR Green PCR Master Mix (Anacell, Iran) to evaluate the gene expression of Glut-1, MMP-2, N-Cadherin, MMP-9. Sets of primers specific to each gene are provided in Supplementary Table 1. The human beta-actin (h-ACTB) gene was used to normalize the mRNA expression level of each gene. Also, data analysis was carried out based on the 2 −ΔΔCT method.

Twenty-eight samples with high glycolytic behavior and histologically negative were compared to the min value of the positive and max value of negative controls. Also, all samples were normalized to the mammoplasty sample.

Cell image analysis

ImageJ software and the OpenCV python library were used for cell detection and labeling through image processing tools. Each image was analyzed using various cell detection techniques to find the most applicable one. Shape, size, and circularity were considered parameters to distinguish between different cell lines in an identical image. Analysis was repeated separately for each different cell line present in an image and based on its particular parameters. Then, the results were shown simultaneously in the original image.

Statistical analysis

Data on bar graphs are expressed as means ± SD or ± SEM (as indicated). Statistical analysis was performed using one-way ANOVA, followed by Tukey’s multiple comparisons test for repeated measurements, with the significance assessed at the 5% significance level (P < 0.05).

CAFs are activated fibroblasts with heterogeneous shapes and metabolism within the tumor microenvironment and adjacent to the tumor boundaries (Ping et al. 2021 ). They secret various factors that play key roles in tumor development, metastasis, and resistance to therapy (Gadaleta et al. 2022 ; Orimo et al. 2005 ; Ping et al. 2021 ) (Fig.  1 ).

The schematic of field cancerization procedure in the tumor microenvironment. Hydrogen peroxide released by tumor cells promotes oxidative stress to surrounding stromal cells, such as fibroblasts. Additionally, oxidative stress in fibroblasts leads to ROS production in the tumor stroma, allowing cancer cells to mutate further, eventually resulting in stromal lactate production and metastasis. Furthermore, hydrogen peroxide and ROS production can also mutagenize adjacent normal epithelial cells, promoting the growth of new cancerous cells (Lisanti et al. 2011 )

We investigated the hypoxia glycolysis behavior of tumor central and margin sides of breast cancer patients who had undergone mastectomy by CDP as a known glycolysis probing system by presenting the level of ROS-associated electrochemical peaks (Miripour et al. 2022a , b ; Dabbagh, et al. 2021 ). Our gold standard for the pathological state of the specimen was H&E staining and diagnosis by pathologists.

Fibroblasts from the dissected specimens of 33 breast cancer mastectomy cases (which weren’t important for pathological evaluation) were investigated. The CDP score for the ROS level of each lesion was recorded before dissection. We pathologically and biologically analyzed these fibroblasts to understand if they are CAFs or NFs. A part of the specimen was used for H&E and PCR evaluation to find any correlation between the presence and activity of CAFs, levels of expressed cancer-associated transcriptomes, electrochemical levels of released ROS from the lesion, and the presence or absence of cancer cells in the specimen. Also, extracted fibroblast cells were exposed individually near breast non-cancer and cancer cell lines to investigate their effects on the invasion behavior of breast cells. The gold standard in this study was permanent pathology. Samples with high glycolytic behavior (due to CDP results) and positive for cancer in histology diagnosis were selected as positive controls (ID 3–5). These samples were IDC grade 2, High/Intermediate grade Ductal Carcinoma Insitu (DIN3,2). Samples with low glycolytic behavior and non-cancerous histology diagnosis (Non-proliferating FCC, Fatty breast tissue) were used as negative controls ID 1, 2, and mammoplasty operation samples. The other margin samples were histologically negative while showing high glycolytic behavior (based on CDP results). Through this investigation, we aimed to find a relation between levels of ROS/H 2 O 2 released by the glycolytic cells (recorded by CDP) and the potential for cancerous transformation in these cells by evaluating their RT-PCR/IHC and fibroblast activity.

CAFs enhanced the aggressive behavior of cancer cells

First, 33 samples from individual patients underwent a mastectomy, excised, and driven by the protocol discussed in the method section to separate fibroblasts from other cells (immune, epithelial cells, endothelial cells, and so on) and recultured individually. The protocol for investigating the behavior of extracted fibroblasts from dissected tissues is presented in Fig.  2 .

The protocol for investigating CAFs in dissected tissues from breast cancer patients. The specimen was dissected from the lesions, which were not essential for pathological evaluation. In order to find a correlation between the presence and activity of CAFs, the levels of expressed cancer-associated transcriptomes, and the presence or absence of cancer cells in the specimen, the CDP score of each specimen was recorded, and a portion of each specimen was used for H&E and PCR evaluation. Moreover, CAFs interacted with breast non-cancer (MCF10-A) and cancer (MCF-7) cell lines, and their interactions were evaluated. Molecular analysis was performed to discover a relation between ROS/H2O2 levels released by CAFs through glycolysis metabolism and transcriptomes of adjacent epithelial cells that undergo cancerous transformation

Alpha-SMA is a specific IHC marker for distinguishing CAFs from NFs (Ha et al. 2014 ). The tissue sample with ID 4, which had high glycolytic behavior and positive histological diagnosis (High-grade Ductal Carcinoma (DIN 3)), showed a positive expression of alpha-SMA IHC (Fig.  3 a). Also, fibroblast cells excised and cultured from this sample showed positive staining for alpha SMA ICC (Fig.  3 b) and negative staining for the epithelial marker E-cadherin (Fig.  3 e). However, fibroblast cells driven from non-cancer breast tissue (ID 2: fatty breast tissue) with low glycolytic behavior showed negative staining for IHC and ICC of alpha SMA (Fig.  3 b,d).

H&E staining and SMA IHC marker expression of paraffin-embedded of a sample ID 4, which had high glycolytic behavior and positive histological diagnosis (high-grade ductal carcinoma (DIN 3), and b sample ID 2 with low glycolytic behavior and negative histological diagnosis (fatty breast tissue), H&E staining and SMA marker of isolated CAFs from samples c ID 4, and d ID 2, e Epithelial marker E-cadherin of CAF. All the primary cultured CAFs expressed SMA highly (Ha et al. 2014 ) but did not express E-cadherin, presenting characteristics of CAFs (Yu et al. 2014 ). f Schematic of CAF behavior in adjacent tumoral and non-tumoral cells. g Evaluating fibroblast cells behavior extracted from the samples ID 4, 2 tissues and cultured in interaction with non-cancerous (MCF-10A) and cancerous (MCF-7) breast cells, tumor environment (TE)-CAF, tumor-adjacent (TA)-CAF. h Cell invasion ability was measured in three groups. The invasion ability of the MCF-7 cell lines cultured with tumor environment and adjacent CAF was significantly greater than MCF-10A non-cancer cells (P < 0.0001). i The exact invasion number of cells to the channel for each group. Each bar is equal to 100 μm

To evaluate the effect of CAF interactions with cancer and non-cancer cells in the tumor microenvironment, fibroblast cells extracted from breast margin tissues with high glycolytic behaviors were exposed to them. IHC and ICC analyses showed expression of alpha SMA and non-expression of E-Cadherin on these cells (Fig.  3 a, c, e), which indicates the CAF nature of these cells. Some of these cells were extracted from breast lesions that were histologically negative for cancer, and others were extracted from histologically positive lesions (Fig.  3 a, b). The similar specification of these cells is high glycolytic levels of their primary lesion and IHC/ICC expressing in favor of being CAFs. The mentioned fibroblasts were individually exposed to breast cancer (MCF-7) and non-cancerous (MCF-10A) cell lines. It was observed that MCF-7 cells showed a significant increase in their proliferation after being exposed to CAFs, (either to tumor environment (TE)-CAF (Fig.  3 g (I)) or tumor adjacent (TA)-CAF (Fig.  3 g (II)). About 948 and 833 MCF-7 cells invade the joint channel (between CAFs and breast cells culturing well (Fig.  3 h, i)) after exposure to tumor environment (TE)-CAF and tumor-adjacent (TA)-CAF, respectively. But just 357 MCF-7 cells come to the channel in the control group (without exposure to the CAF). Also, the CAFs showed hyperactivated proliferation and extension in interaction with breast cancer cells (Fig.  3 g–i).

On the other hand, it was observed that CAF's hyperactive behavior regressed when they were exposed to non-cancerous breast cells (MCF-10A) (Fig.  3 g (IV)). Also, no hyperproliferation behavior was observed in the non-cancer breast cells after being interacted with CAFs (tumor adjacent (TA)-CAF, which was extracted from histologically non-cancer lesions with high glycolytic behavior (Fig.  3 g (IV)).

So it seems that CAFs and MCF-7 show synergic proliferative behavior in their co-interactions. While CAFs and MCF-10A not only showed no synergic proliferation but also CAFs showed regressed activity in interaction with MCF10A cells (Fig.  3 g–i).

CAFs promote ROS expression of cancer cells

NAC (( N -acetyl- l -cysteine) is a ROS Inhibitor (ab143032)) agent used in cellular investigations (Halasi et al. 2013 ; Zhang et al. 2011 ), and medical purposes (Shi and Puyo 2020 ; Sengupta and Dutta 2022 ). Here, it was used to evaluate ROS/hypoxic functions of fibroblasts before and after exposure near the breast cancer cell line (MCF-7). We also evaluated the electrochemical level of ROS/H 2 O 2 in those cell cultures. In this regard, 1 µL (12 mg) of NAC was individually added to the CAFs cultured samples, and their ROS electrochemical peak was recorded in time intervals of two hours up to 8 h. The fluorescent microscope images of negative control (without NAC) after 8 h of adding NAC and positive control (100µM of H 2 O 2 ) to breast cancer cell line (MCF-7), tumor environment CAF, tumor-adjacent CAF, and co-culture of MCF-7 + tumor environment CAF/tumor adjacent CAF were presented in Fig.  4 a. ROS fluorescent assay (see method section) showed a drastic reduction in the expression of green fluorescent protein by samples including CAFs, MCF-7, and their co-interaction after treatment with 1µl of NAC (Fig.  4 a). Similarly, a sharp reduction in ROS electrochemical peaks was observed in all mentioned samples (Fig.  4 b).

a The fluorescent microscope images of negative control (without NAC) after 8 h of adding NAC and positive control (100µM of H 2 O 2 ) to breast cancer cell line (MCF-7), tumor environment CAF, tumor-adjacent CAF, and co-culture of MCF-7 + tumor environment CAF/tumor adjacent CAF, b electrochemical current peaks of control (without NAC), and the cells treated with NAC after 2, 4, 6, and 8 h. Each bar is equal to 100 μm

RT-PCR and immunohistochemistry analysis of glycolytic breast cells

It is believed that high-level expression of glucose transporter-1 (GLUT1) transcriptome, as the main indication of glycolysis metabolism, is found in several types of cancer, including breast cancer, and is associated with poor survival rates (Kunkel et al. 2003 ; Kang et al. 2002 ). Glut1 facilitates glycolytic phenotypes such as glucose uptake, cellular ATP, and lactate production levels for cancer cells (Oh et al. 2017 ). The matrix metalloproteinases (MMPs) transcriptomes are a family of zinc-dependent proteases. MMP-2 and MMP-9 are critical representatives of the MMP family and have been demonstrated to be important factors in promoting tumor invasion and metastasis by degrading extracellular matrices (Iochmann et al. 2009 ; Safranek et al. 2009 ). According to many studies, MMP-2 and MMP-9 are highly expressed in breast cancer tissues and are closely associated with lymph node metastasis and tumor staging.

Moreover, N-cadherin-1 is another significant transcriptome activated during cancer. N-cadherin is a member of classical cadherins' calcium-dependent adhesion molecule family, directly mediating homotypic and heterotypic cell–cell adhesion (Mrozik et al. 2018 ). N-cadherin expression is aberrant in many solid tumors, indicating epithelial-to-mesenchymal transition, leading to the development of aggressive tumors (Cao et al. 2019 ). Several mechanisms have been identified in which N-cadherin promotes tumor cell migration: enhancing Fibroblast growth factor receptor-1 (FGFR-1) signaling, modulating canonical Wnt signaling, and facilitating collective cell migration (Mrozik et al. 2018 ).

RT-PCR results of the GLUT-1, MMP 2, MMP-9, and N-cadherin expression in breast tissues of the studied cases are presented in Fig.  5 . It shows meaningful oncogenic changes of about 18.5% (MMP 2, MMP-9, and N-cadherin) in tissues with non-cancerous histology but high glycolytic behavior (ID 8–10, 28, 30–33) with respect to negative controls (ID 1,2). The number of samples with cancer-associated transcriptomic expression (GLUT-1, MMP 2, MMP-9, and N-cadherin) which have more than the mean value expression of positive control samples (histologically cancerous samples; ID 3–5) were about 40.7%, 18.5%, 18.5%, and 18.5%. At mean 70.4%, 66.7%, 70.4%, and 44.5% increments were observed in GLUT-1, MMP-2, N-cadherin, and MMP-9 transcriptomes by highly glycolytic but histologically cancer-free expression samples in comparison with negative controls (histologically non-cancer lesions with low glycolytic behavior).

a Clinical and pathologic characteristics of patients and adjacent tumor margins samples randomly assigned to this study, b CDP ROS/H 2 O 2 current peaks and declaration and pathological diagnosis of samples, c RT-PCR of oncogenic associated transcriptomes adjacent tumor margins samples, all samples expression were normalized to mammoplasty expression value (Green and red color indicated negative and positive controls diagnosed by CDP and confirmed by pathology, and the blue ones are margin samples with high glycolytic behavior but histologically negative), d Heat maps representing four transcripts were investigated on 33 cavity margins of breast cancer patients, e The comparative outcomes of the adjacent cavity margins RNA sequencing results to the control samples, f IHC of four transcripts VEGF, MMP-2,9, and N-cadherin were investigated on assayed samples. Intensity Score (Score 0: no or weak staining, Score 1: mild staining, Score 2: moderate staining, Score 3: strong staining), Proportion score (Score 0: no or weak intensity, Score 1: < 10% of tumor with strong intensity (SI), Score 2: = 10% ≤ strong intensity < 1/3 of tumor, Score 3: 1/3 ≤ strong staining < 2/3 of tumor), f IHC analysis for cancer-associated markers (VEGF, MMP-2, N-cadherin, and MMP-9) on the samples, g IHC VEGF, MMP-2, N-cadherin, and MMP-9 in negative control samples (CDP negative and H&E negative), positive control samples (CDP positive and H&E positive), and CDP positive and H&E negative samples. Each bar is equal to 100 μm

Moreover, IHC analysis for cancer-associated markers (VEGF, MMP-2, N-Cadherin, and MMP-9) (Kim et al. 2016 ) was conducted on the samples. None of them was expressed in negative controls. In positive control samples, there was a considerable expression of VEGF, MMP-2, N-Cadherin, and MMP-9. In samples with positive scores of CDP and negative diagnosis of histology, such expressions were 83%, 39%, 0%, and 61% of samples have proportion and intensity ≥ 1, respectively.

We investigated the cancer-associated behaviors of the lesions adjacent to tumor margins and found two critical factors about biologically high-risk while histologically benign representations in some of such lesions, which was a strong correlation with their glycolytic metabolism; first: the expression of cancer transcriptomes such as GLUT-1, MMP-2, MMP-9, and N-cadherin in those lesions. Second the presence of active CAFs among epithelium which, due to our ex vivo observation, just become activated in the presence of cancer cells. Our main distinct factor in finding these lesions was the real-time electrochemical measuring of their released ROS levels with the assistance of a newly presented CDP system (Miripour et al. 2022a , b ; Dabbagh et al. 2021 ). Also, florescent-based ROS detection was applied to confirm the increased released ROS from those lesions to normal negative controls. It is known that preneoplastic and neoplastic breast cells (in adjacent margins) and their surrounding CAFs can increase their metabolism by switching to aerobic glycolysis [through Warburg, reverse Warburg and field cancerization effects (Potter et al. 2016 ; Chai and Brown 2009 )], which results in the release of ROS by the cells in the intercoastal fluid. So, due to the correlation between ROS electrochemical expressed responses and florescent ROS release assay, the presence of CAFs could be a hallmark of oncogenic changes due to glycolytic-based ROS expression.

As shown in Figs.  3 a–e, CAF (All the primary cultured CAFs express high levels of alpha SMA (Ha et al. 2014 ) while they do not express E-cadherin [as a molecular characteristic of CAFs) (Yu et al. 2014 )] interaction by the non-cancer and cancer breast cells (Fig.  3 g) demonstrates that the activation of the CAFs just could be happened in the presence of neoplastic cells. It was interesting that MCF-10A cells in the proximity of CAFs do not show any change in their growth, but the behavior of CAFs regresses. We observed that if there is a high ROS signal in a cavity margin with no observable cancer cells except CAFs (due to conventional histopathological assay), this margin should be further investigated because some single cancer or high risk precancer cells maybe existed in the vicinity of CAF (Fig.  3 g–i), which causes oncogenic changes in cavity margin’s fibroblasts. Presence of these CAFs may be due to he presence of such single cells. It means that CAFs without the presence of neoplastic cells in their neighbor area might not keep their function. So, if a distribution of CAFs were found in breast lesions, there may be a hallmark about presence of scattered single preneoplastic or cancer cells in that lesion even if they were observed in histological slide. Activated cancer-associated proteins observed in those lesions (Fig. 5 f–g) were in accordance to this hypothesis.

RT-PCR of those lesions also showed meaningful increased expression of cancer-associated transcriptomes (MMP-2, MMP-9, N-cadherin) and glycolytic metabolism (GLUT-1) in those cells with respect to histologically benign and metabolically non-glycolytic cells (negative controls) (Fig.  5 ). Also, oncogenic changes in GLUT-1 were higher in about 40.7% of samples with non-cancerous histology but high glycolytic behavior, like positive controls. As it was predictable, the expression of the transcriptomes was much higher in positive control samples (Fig.  5 c–e). Beta-actin transcriptome (conventionally applied as Housekeeping) also showed increased expression in malignant samples, which indicates the test's reliability because we observe an increase in beta-actin transcriptome in malignant breast cancer cells.

Co-culturing these CAFs with non-neoplastic (MCF-10A) and neoplastic (MCF-7) cells of the same patients and monitoring the ROS/Hypoxic changes in the co-culture near evaluating metabolic changes of the cells are our future trends in this investigation .

No expression of important breast cancer-associated proteins (evaluated by IHC) such as VEGF, MMP-2, N-Cadherin, and MMP-9 were observed in negative control samples (CDP negative and H&E negative). The strong and somehow perfect expression of these proteins was observed in positive control samples (CDP positive and H&E positive). We observed meaningful expression of these proteins in CDP samples (CDP positive and H&E negative) (Fig.  5 f). In 71% (20/28) of the samples, there was a mild expression of VEGF, while 11% (3/28) of the samples had a moderate expression of VEGF. 39% (11/28) of those samples had mildly expressed MMP-2 as a protease enzyme produced by progressive cancer cells (Yaqoob et al. 2020 ). Moreover, 29% (8/28), 25% (7/28), and 7% (2/28) of the mentioned samples had mild, moderate, and strong expression of MMP-9 as a protease indicator of primary cancer cells (Huang 2018 ). So, it can be deduced that the expression of cancerous functional proteins in the histologically normal/benign cells with glycolysis metabolism (detected by CDP) was meaningfully further than in normal/benign cells without any glycolytic metabolism (negatively scored by CDP).

The main findings of this paper are that the presence of CAFs in the cavity side margins indicates the existence of cancerous, precancerous, or oncologically activated epithelial cells around CAFs. If these cells didn’t exist in the margin lesions, CAFs would be downregulated, reducing their aggressive behaviors to normal fibroblasts. Hence, the presence of CAFs is correlated with the presence of high glycolytic metabolism in the lesion, high ROS level in the lesion, and finally aggressive cancer-associated proteins (such as MMP2, …) in the margin lesion while these metabolomes, molecules, and proteins are absent in the margins with negatively scored CDP response and low ROS level (Fig.  5 ). Other papers didn’t report this result that CAFs could be down-functioned into behaviors similar to normal FBs if no cancer/precancer cells were in their adjacent, while this evidence was observed, discussed, and reported in our paper (Fig.  3 ). In summary, we concluded that: (1) High levels of ROS in the cavity side margins are correlated with the presence of cancer-associated fibroblasts (CAFs) near cancer or precancerous cells, or potentially activated to become cancer cells. (2) If none of these high-risk cells existed in the media, the CAFs would reduce their aggressive functions turned into normal FBs. (3) Similar to other papers we also observed the synergic effect of CAFs and breast cancer cells to each other due to secreting the by-products of glycolysis metabolism to the media. (4) CDP positively scored responses are important to be considered because even if no cancer cells were histologically found in the margin, high-risk epithelial cells in that margin express cancer-associated proteins and metabolomes, which is one of the hallmarks that stimulate the fibroblast to become CAF. So, metabolic probing could be a good indicator to distinguish these cells.

In summary, we showed the hyperactivation of fibroblasts derived from cavity-side breast margins with glycolytic metabolism, even in the absence of neoplastic breast cells. These fibroblasts expressed CAF markers and RT-PCR of cancer-free margins with positive glycolytic metabolism and these CAFs, showed over-expression of cancer-associated transcriptomes, while the fibroblasts derived from cancer-free cavity side margins and absence of CAFs showed normal RT-PCR profile. At mean 70.4%, 66.7%, 70.4%, and 44.5% increments were observed in GLUT-1, MMP-2, N-Cadherin, and MMP-9 transcriptomes by highly glycolytic but histologically cancer-free expression samples in comparison with negative controls (histologically non-cancer lesions with low glycolytic behavior). Also, immunohistochemical analysis of important cancer-related proteins such as MMP-2, MMP-9, and VEGF revealed a significant presence of these proteins in glycolytic margins (with histology of non-cancerous lesions), while no expression of N-Cadherin was observed. Furthermore, cancer-free glycolytic margins contained CAFs capable of activating cancer cells in vitro. However, these CAFs were downregulated when interacting with normal breast cells. These pieces of evidence may present a hidden hallmark factor; the presence of CAFs in histologically cancer-free breast margins may warn about the presence of pre-cancer or cancer cells in a hidden state because CAFs could not be activated, and glycolytic function may not be traced in a cavity margin without any neoplastic/pre-neoplastic cells. Metabolic probing can provide valuable insights for more effective investigation of tumor margins in order to detect any oncogenic or oncoproteomic changes. This information can be crucial for improving the management of organ-conserving tumor surgery. The study results highlight the need for further research on non-histologically tumoral margins with glycolytic behavior and CAF content. This research may help in understanding the increased risk of cancerous changes in marginal cells.

Availability of data and materials

The authors declare that all the other data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. Also, the authors declare that all codes supporting the findings of this study are available from the corresponding author upon reasonable request. No datasets were generated or analysed during the current study.

Cao Z-Q, Wang Z, Leng P (2019) Aberrant N-cadherin expression in cancer. Biomed Pharmacother 118:109320

Article   CAS   PubMed   Google Scholar  

Chai H, Brown RE (2009) Field effect in cancer-an update. Ann Clin Lab Sci 39(4):331–337

CAS   PubMed   Google Scholar  

Chan JSK et al (2018) Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress. Cell Death Dis 8(1):e2562–e2562

Article   Google Scholar  

Chen J et al (2017) Overexpression of α-sma-positive fibroblasts (CAFs) in nasopharyngeal carcinoma predicts poor prognosis. J Cancer 8(18):3897

Article   PubMed   PubMed Central   Google Scholar  

Dabbagh N et al (2021) Accuracy of cancer diagnostic probe (CDP) for intra-surgical checking of cavity side margins in neoadjuvant breast cancer cases; a human model study. Int J Med Robot Comput Assist Surg 18:e2335

Erez N, Truitt M, Olson P, Hanahan D (2010) Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17(2):135–147

Gadaleta E, Thorn GJ, Ross-Adams H, Jones LJ, Chelala C (2022) Field cancerization in breast cancer. J Pathol 257:561–574

Gascard P, Tlsty TD (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev 30(9):1002–1019

Article   CAS   PubMed   PubMed Central   Google Scholar  

Giannoni E et al (2010) Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res 70(17):6945–6956

Ha SY, Yeo S-Y, Xuan Y, Kim S-H (2014) The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma. PLoS ONE 9(6):e99955

Halasi M, Wang M, Chavan TS, Gaponenko V, Hay N, Gartel AL (2013) ROS inhibitor N -acetyl- l -cysteine antagonizes the activity of proteasome inhibitors. Biochemical Journal 454(2):201–208

Huang H (2018) Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP-9 biosensors: recent advances. Sensors 18(10):3249

Iochmann S et al (2009) Transient RNA silencing of tissue factor pathway inhibitor-2 modulates lung cancer cell invasion. Clin Exp Metastasis 26(5):457–467

Kang SS et al (2002) Clinical significance of glucose transporter 1 (GLUT1) expression in human breast carcinoma. Jpn J Cancer Res 93(10):1123–1128

Kim S-W, Roh J, Park C-S (2016) Immunohistochemistry for pathologists: protocols, pitfalls, and tips. J Pathol Transl Med 50(6):411

Kunkel M et al (2003) Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer Interdiscip Int J Am Cancer Soc 97(4):1015–1024

CAS   Google Scholar  

Liao Z, Tan ZW, Zhu P, Tan NS (2018) Cancer-associated fibroblasts in tumor microenvironment–Accomplices in tumor malignancy. Cell Immunol 343:103729

Article   PubMed   Google Scholar  

Lisanti MP et al (2011) Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs “fertilizer.” Cell Cycle 10(15):2440–2449

Louault K et al (2019) Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers. Oncogene 38(17):3261

Martinez-Outschoorn UE et al (2010) Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: a new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 9(16):3276–3296

Miripour ZS et al (2022a) Electrochemical tracing of hypoxia glycolysis by carbon nanotube sensors, a new hallmark for intra-operative detection of suspicious margins to breast neoplasia. Bioeng Transl Med 7:e10236

Miripour ZS et al (2022b) Human study on cancer diagnostic probe (CDP) for real-time excising of breast positive cavity side margins based on tracing hypoxia glycolysis; checking diagnostic accuracy in non-neoadjuvant cases. Cancer Med 11(7):1630–1645

Mrozik KM, Blaschuk OW, Cheong CM, Zannettino ACW, Vandyke K (2018) N-cadherin in cancer metastasis, its emerging role in haematological malignancies and potential as a therapeutic target in cancer. BMC Cancer 18(1):1–16

Oh S, Kim H, Nam K, Shin I (2017) Glut1 promotes cell proliferation, migration and invasion by regulating epidermal growth factor receptor and integrin signaling in triple-negative breast cancer cells. BMB Rep 50(3):132

Orimo A et al (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121(3):335–348

Ping Q et al (2021) Cancer-associated fibroblasts: overview, progress, challenges, and directions. Cancer Gene Ther 28(9):984–999

Potter M, Newport E, Morten KJ (2016) The Warburg effect: 80 years on. Biochem Soc Trans 44(5):1499–1505

Safranek J et al (2009) Expression of MMP-7, MMP-9, TIMP-1 and TIMP-2 mRNA in lung tissue of patients with non-small cell lung cancer (NSCLC) and benign pulmonary disease. Anticancer Res 29(7):2513–2517

Sengupta P, Dutta S (2022) N -Acetyl cysteine as a potential regulator of SARS-CoV-2-induced male reproductive disruptions. Middle East Fertil Soc J 27(1):1–6

Shi Z, Puyo CA (2020) N -Acetylcysteine to combat COVID-19: an evidence review. Ther Clin Risk Manag 16:1047

Truong D, Puleo J, Llave A, Mouneimne G, Kamm RD, Nikkhah M (2016) Breast cancer cell invasion into a three dimensional tumor-stroma microenvironment. Sci Rep 6:34094

Truong DD et al (2019) A human organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast cancer cells. Cancer Res 79(12):3139–3151

Vanharanta S, Massagué J (2012) Field cancerization: something new under the sun. Cell 149(6):1179–1181

Yaqoob I, Saeed M, Azhar A (2020) MMP-2 levels evaluation and their relationship with breast cancer progression. Prof Med J 27(02):424–430

Google Scholar  

Yu Y, Xiao CH, Tan L, Wang QS, Li XQ, Feng YM (2014) Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br J Cancer 110(3):724–732

Zhang F, Lau SS, Monks TJ (2011) The cytoprotective effect of N -acetyl- l -cysteine against ROS-induced cytotoxicity is independent of its ability to enhance glutathione synthesis. Toxicol Sci 120(1):87–97

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Acknowledgements

We thank Professors Saeed Sarkar, Habib Mahmoudzadeh and S.R. Miri for their great scientific supports of this project.

This research was supported by the Iran Nano Fund institution, P.O. Box 1533984611, Tehran, Iran.

Author information

Zohreh Sadat Miripour and Mohammad Abdolahad contributed equally.

Koosha Karimi and Alireza Ghahremani contributed equally.

Authors and Affiliations

Nano Bio Electronic Devices Lab, Cancer Electronics Research Group, School of Electrical and Computer Engineering, College of Engineering, University of Tehran, P.O. Box 14395/515, Tehran, Iran

Zohreh Sadat Miripour, Mina Aminifar, Parisa Hoseinpour, Koosha Karimi, Alireza Ghahremani, Mohammadreza Ghaderinia, Faride Makiyan, Parisa Aghaee & Mohammad Abdolahad

UT&TUMS Cancer Electronics Research Center, University of Tehran, P.O. Box 14395/515, Tehran, Iran

Zohreh Sadat Miripour & Mohammad Abdolahad

SEPAS Pathology Lab, P. O. Box 1991945391, Tehran, Iran

Parisa Hoseinpour

ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, P.O. Box 15179/64311, Tehran, Iran

Fereshteh Abbasvandi & Mohammad Parniani

Cancer Research Center, Shahid Beheshti University of Medical Sciences, P.O. Box 15179/64311, Tehran, Iran

Fereshteh Abbasvandi & Mohammad Esmaeil Akbari

Cancer Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, P.O. Box 1419733141, Tehran, Iran

Mohammad Abdolahad

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Contributions

Zohreh Sadat Miripour manufactured the electrodes, designed a test setup for CDP clinical studies, performed most of the experiments, categorized the tabled data. Mina Aminifar, Farideh Makian, and Parisa Aghaee assisted in the isolation of human breast fibroblasts and cell culture preparation and also assisted in the experiment. Parisa Hoseinpour and Mohammad Parniani did the pathological experiments and declared the diagnosis. Fereshteh Abbasvandi and Mohammad Esmaeil Akbari supervised the clinical and surgical procedures and follow-ups. Koosha Karimi and Alireza Ghahremani performed material preparation, data collection, and assistance in the experiment. Mohammadreza Ghaderinia assisted in statistical analysis. Mohammad Abdolahad  proposed the hypothesis of the paper, designed and coordinated the idea and all steps of the research, did the  analysis and also wrote the manuscript. All authors commented on previous versions of the manuscript and approved the final manuscript for submission.

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Miripour, Z.S., Aminifar, M., Hoseinpour, P. et al. The presence of cancer-associated fibroblast in breast cavity side margins is in correlation with the expression of oncoproteins by adjacent epithelial cells: a new era in cancerous potential. J Cancer Res Clin Oncol 150 , 421 (2024). https://doi.org/10.1007/s00432-024-05943-8

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Beginner’s Guide on How Create a Research Survey

• Author Survey Point Team
• Published September 16, 2024

Research survey is a good tool, If you’re new to creating surveys, you might wonder where to start. Research survey is a great tool to collect valuable information, whether you’re looking for customer feedback, market research, or data for a school project. A well-made survey can give you clear answers and helpful insights.

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Table of Contents

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People are more likely to finish your survey if it’s short and to the point . Long surveys can cause people to lose interest and quit halfway through.

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Once your survey is ready, it’s time to share it with your audience. The method you choose depends on who you’re targeting.

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7. Analyze Your Data

Once you have your survey responses, it’s time to analyze the results. This will help you find patterns, trends, and answers to your research questions.

How to Analyze:

• For Yes/No and Multiple Choice Questions : Look at the percentages of people who chose each answer.
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• Use Charts and Graphs : Visualize your data using tools like Google Sheets or Excel. This makes it easier to understand the results.

8. Present Your Findings

After analyzing the data, create a report or presentation to show what you’ve learned. Use this information to make decisions or improvements based on the survey results.

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Conclusion: Start Small and Build Your Skills

Creating a research survey doesn’t have to be difficult. By following these steps—knowing your purpose, writing clear questions, keeping it short, and analyzing the results—you can collect useful data that helps you make better decisions. With practice, you’ll get better at creating surveys that provide even deeper insights.

Whether you’re doing a school project, market research, or customer feedback, these tips will guide you through the process with confidence. For more information checkout – surveypoint.ai

Survey Point Team

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