Diversity and biology of cancer-associated fibroblasts
Open accessAbstract
Efforts to develop anti-cancer therapies have largely focused on targeting the epithelial compartment, despite the presence of non-neoplastic stromal components that substantially contribute to the progression of the tumor. Indeed, cancer cell survival, growth, migration, and even dormancy are influenced by the surrounding tumor microenvironment (TME). Within the TME, cancer-associated fibroblasts (CAFs) have been shown to play several roles in the development of a tumor. They secrete growth factors, inflammatory ligands, and extracellular matrix proteins that promote cancer cell proliferation, therapy resistance, and immune exclusion. However, recent work indicates that CAFs may also restrain tumor progression in some circumstances. In this review, we summarize the body of work on CAFs, with a particular focus on the most recent discoveries about fibroblast heterogeneity, plasticity, and functions. We also highlight the commonalities of fibroblasts present across different cancer types, and in normal and inflammatory states. Finally, we present the latest advances regarding therapeutic strategies targeting CAFs that are undergoing preclinical and clinical evaluation.
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Fibroblasts constitute the dominant cellular mass among stromal cells within the tumor microenvironment.
“Among the various stromal cells within the TME, fibroblasts constitute the dominant cellular mass [27,28,29,30].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [29]
The prevalent stromal contingent in CMS4 colorectal cancer is likely to contribute to resistance mechanisms.
“In terms of TME contexture, the prevalent stromal contingent is likely to contribute to resistance mechanisms, for instance through ECM deposition and cancer cells insulation (54), co-migration with cancer cells to metastatic sites (70), chemotherapy-induced secretome fostering metastasis, angiogenesis, immune evasion and/or drug resistance (71), or even drug retention, as demonstrated in the case”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [54]
Stromal contribution to resistance in CMS4 colorectal cancer occurs through ECM deposition and cancer cell insulation.
“through ECM deposition and cancer cells insulation (54)”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [54]
The enrichment of CMS4 tumors in CAFs is a shared outstanding characteristic.
“Whatever their intrinsic subtype correspondence, the enrichment of CMS4 tumors in CAFs is a shared outstanding characteristic.”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [54]
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Self-citation
Flagged first, then by citations
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“In normal physiology, fibroblasts are essential for maintaining tissue integrity and play pivotal roles in inflammation, wound healing, and fibrosis [29].”
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- Authors
- Biffi, G., & Tuveson, D. A.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Biffi, Giulia
- Tuveson, David A.
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2021-01-01
- Volume
- 101
- Issue
- 1
- Pages
- 147-176
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- PMC
- PMC7864232
- OpenAlex
- W3031767666
- Cited by
- 1,265
- References
- 345
- Citations by year
- 2026: 227 · 2025: 241 · 2024: 274 · 2023: 258 · 2022: 188 · 2021: 71 · 2020: 5
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Physiological Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- HHS | National Institutes of Health (5P30CA045508)
- Lustgarten Foundation
- CSHL and Northwell Health Affiliation
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- cancer-associated fibroblasts, tumor microenvironment, fibroblast heterogeneity, fibroblast plasticity, extracellular matrix, treatment resistance, immune exclusion, tumor progression, CAF-targeted therapy
- MeSH terms
- Cancer-Associated Fibroblasts, Animals, Antineoplastic Agents, Humans, Neoplasms, Cell Proliferation, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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