Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical and therapeutic relevance of cancer-associated fibroblasts

Abstract

Cancer-associated fibroblasts (CAFs) found in primary and metastatic tumours are highly versatile, plastic and resilient cells that are actively involved in cancer progression through complex interactions with other cell types in the tumour microenvironment. As well as generating extracellular matrix components that contribute to the structure and function of the tumour stroma, CAFs undergo epigenetic changes to produce secreted factors, exosomes and metabolites that influence tumour angiogenesis, immunology and metabolism. Because of their putative pro-oncogenic functions, CAFs have long been considered an attractive therapeutic target; however, clinical trials of treatment strategies targeting CAFs have mostly ended in failure and, in some cases, accelerated cancer progression and resulted in inferior survival outcomes. Importantly, CAFs are heterogeneous cells and their characteristics and interactions with other cell types might change dynamically as cancers evolve. Studies involving single-cell RNA sequencing and novel mouse models have increased our understanding of CAF diversity, although the context-dependent roles of different CAF populations and their interchangeable plasticity remain largely unknown. Comprehensive characterization of the tumour-promoting and tumour-restraining activities of CAF subtypes, including how these complex bimodal functions evolve and are subjugated by neoplastic cells during cancer progression, might facilitate the development of novel diagnostic and therapeutic approaches. In this Review, the clinical relevance of CAFs is summarized with an emphasis on their value as prognosis factors and therapeutic targets.

Key points

  • Cancer-associated fibroblasts (CAFs) are found in both primary and metastatic tumours; studies using modern cell sorting and sequencing technologies have provided exciting new insights into the potential therapeutic and prognostic value of CAFs.

  • In particular, studies using single-cell RNA sequencing and genetically engineered mouse models have begun to reveal the heterogeneity and functional roles of CAFs, which are dynamic and context dependent.

  • The precise functional roles of various CAF subtypes remain largely undefined, which requires future investigations integrating functional studies using multiple model systems with transcriptomic and/or proteomic data at single-cell resolution.

  • The identification and precise characterization of the tumour-promoting and tumour-restraining functions of different CAF populations might provide opportunities to develop novel diagnostic and therapeutic approaches.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Activation of CAFs.
Fig. 2: The heterogeneity and plasticity of CAFs with both tumour-restraining and tumour-promoting functions.
Fig. 3: Proposed models explaining the diverse functions and phenotypes of CAFs in cancer.
Fig. 4: Interactions between CAFs and other cell types in the tumour microenvironment.

References

  1. 1.

    Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  Article  Google Scholar 

  3. 3.

    Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat. Rev. Cancer 3, 422–433 (2003).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Madhavan, S. & Nagarajan, S. GRP78 and next generation cancer hallmarks: an underexplored molecular target in cancer chemoprevention research. Biochimie 175, 69–76 (2020).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Pietras, K. & Ostman, A. Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316, 1324–1331 (2010).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Ronnov-Jessen, L., Petersen, O. W. & Bissell, M. J. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol. Rev. 76, 69–125 (1996).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Schulz, M., Salamero-Boix, A., Niesel, K., Alekseeva, T. & Sevenich, L. Microenvironmental regulation of tumor progression and therapeutic response in brain metastasis. Front. Immunol. 10, 1713 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Vong, S. & Kalluri, R. The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis. Genes Cancer 2, 1139–1145 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002). A comprehensive review on the connection between inflammation and cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014). A comprehensive review on CAFs and their putative heterogeneity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020). Article providing a consensus framework of CAF biology.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Bernard, V. et al. Single-cell transcriptomics of pancreatic cancer precursors demonstrates epithelial and microenvironmental heterogeneity as an early event in neoplastic progression. Clin. Cancer Res. 25, 2194–2205 (2019).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Hosein, A. N. et al. Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight 5, e129212 (2019).

    Article  Google Scholar 

  17. 17.

    Peng, J. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 29, 725–738 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Dominguez, C. X. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10, 232–253 (2020).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Li, H. et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49, 708–718 (2017).

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Zhang, L. et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 181, 442–459.e29 (2020).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Puram, S. V. et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 171, 1611–1624.e24 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Bartoschek, M. et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9, 5150 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Friedman, G. et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer 1, 692–708 (2020).

    Article  Google Scholar 

  24. 24.

    Kieffer, Y. et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10, 1330–1351 (2020).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479.e10 (2018).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Lambrechts, D. et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24, 1277–1289 (2018).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Davidson, S. et al. Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth. Cell Rep. 31, 107628 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Chen, Z. et al. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 11, 5077 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Virchow, R. Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. Zwanzig vorlesungen gehalten während der monate februar, märz und april 1858 im Pathologischen institute zu Berlin 440 (A. Hirschwald, 1858).

  30. 30.

    Tarin, D. & Croft, C. B. Ultrastructural features of wound healing in mouse skin. J. Anat. 105, 189–190 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Arina, A. et al. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc. Natl Acad. Sci. USA 113, 7551–7556 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Ronnov-Jessen, L. & Petersen, O. W. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab. Invest. 68, 696–707 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Driskell, R. R. et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504, 277–281 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Bachem, M. G. et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115, 421–432 (1998).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Apte, M. V. et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut 44, 534–541 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Yin, C., Evason, K. J., Asahina, K. & Stainier, D. Y. Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Invest. 123, 1902–1910 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Mishra, P. J. et al. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 68, 4331–4339 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Quante, M. et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19, 257–272 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Raz, Y. et al. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J. Exp. Med. 215, 3075–3093 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Zeisberg, E. M., Potenta, S., Xie, L., Zeisberg, M. & Kalluri, R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67, 10123–10128 (2007).

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952–961 (2007).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Bochet, L. et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 73, 5657–5668 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986). A comprehensive review on the connection between cancer and wound healing.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Ueba, T. et al. Transcriptional regulation of basic fibroblast growth factor gene by p53 in human glioblastoma and hepatocellular carcinoma cells. Proc. Natl Acad. Sci. USA 91, 9009–9013 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Mills, L. D. et al. Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J. Biol. Chem. 288, 11786–11794 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Cox, T. R. & Erler, J. T. Fibrosis and cancer: partners in crime or opposing forces? Trends Cancer 2, 279–282 (2016).

    PubMed  Article  PubMed Central  Google Scholar 

  49. 49.

    Schafer, M. & Werner, S. Cancer as an overhealing wound: an old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9, 628–638 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Sugimoto, H., Mundel, T. M., Kieran, M. W. & Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5, 1640–1646 (2006). Early study revealing the putative heterogeneity of CAFs.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Kanzaki, R. & Pietras, K. Heterogeneity of cancer-associated fibroblasts: opportunities for precision medicine. Cancer Sci. 111, 2708–2717 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Biffi, G. & Tuveson, D. A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 101, 147–176 (2021).

    PubMed  Article  Google Scholar 

  53. 53.

    Chen, S. et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 23, 87–98 (2021).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Affo, S. et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 39, 866–882.e11 (2021).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Zhou, Y. et al. Single-cell multiomics sequencing reveals prevalent genomic alterations in tumor stromal cells of human colorectal cancer. Cancer Cell 38, 818–828.e5 (2020).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Chen, Y. et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 39, 548–565.e6 (2021). Study showing that deletion of type I collagen in αSMA-expressing stromal cells exacerbates pancreatic cancer.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Wu, S. Z. et al. Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J. 39, e104063 (2020).

    CAS  PubMed  Google Scholar 

  58. 58.

    Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017). Study revealing that two distinct populations of CAFs exist in pancreatic cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Monteran, L. & Erez, N. The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front. Immunol. 10, 1835 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Umetsu, D. T., Katzen, D., Jabara, H. H. & Geha, R. S. Antigen presentation by human dermal fibroblasts: activation of resting T lymphocytes. J. Immunol. 136, 440–445 (1986).

    CAS  PubMed  Google Scholar 

  62. 62.

    Kundig, T. M. et al. Fibroblasts as efficient antigen-presenting cells in lymphoid organs. Science 268, 1343–1347 (1995).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Lakins, M. A., Ghorani, E., Munir, H., Martins, C. P. & Shields, J. D. Cancer-associated fibroblasts induce antigen-specific deletion of CD8+ T cells to protect tumour cells. Nat. Commun. 9, 948 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Nitta, T. et al. Fibroblasts as a source of self-antigens for central immune tolerance. Nat. Immunol. 21, 1172–1180 (2020).

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Givel, A. M. et al. miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat. Commun. 9, 1056 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. 66.

    Pelon, F. et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat. Commun. 11, 404 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Su, S. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856.e16 (2018).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Ligorio, M. et al. Stromal microenvironment shapes the intratumoral architecture of pancreatic cancer. Cell 178, 160–175.e27 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Zhang, Z. et al. Tumor microenvironment-derived nrg1 promotes antiandrogen resistance in prostate cancer. Cancer Cell 38, 279–296.e9 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Francescone, R. et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov. 11, 446–479 (2021).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Korc, M. Pancreatic cancer-associated stroma production. Am. J. Surg. 194, S84–S86 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Mahadevan, D. & Von Hoff, D. D. Tumor-stroma interactions in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 6, 1186–1197 (2007).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Feig, C. et al. The pancreas cancer microenvironment. Clin. Cancer Res. 18, 4266–4276 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Whittle, M. C. & Hingorani, S. R. Fibroblasts in pancreatic ductal adenocarcinoma: biological mechanisms and therapeutic targets. Gastroenterology 156, 2085–2096 (2019).

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    Biffi, G. et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).

    PubMed  Article  Google Scholar 

  76. 76.

    Shi, Y. et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569, 131–135 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Cortot, A. B. et al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors through a multistep mechanism involving the IGF1R pathway. Cancer Res. 73, 834–843 (2013).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Pein, M. et al. Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nat. Commun. 11, 1494 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Ershaid, N. et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat. Commun. 10, 4375 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Thomas, D. A. & Massague, J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Mariathasan, S. et al. TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    O’Connell, J. T. et al. VEGF-A and Tenascin-C produced by S100A4+stromal cells are important for metastatic colonization. Proc. Natl Acad. Sci. USA 108, 16002–16007 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 1818 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Bhowmick, N. A. et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303, 848–851 (2004).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Boire, A. et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313 (2005).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Sternlicht, M. D. et al. The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98, 137–146 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Kumar, V. et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 32, 654–668.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Mhaidly, R. & Mechta-Grigoriou, F. Fibroblast heterogeneity in tumor micro-environment: role in immunosuppression and new therapies. Semin. Immunol. 48, 101417 (2020).

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Fidler, I. J. et al. Modulation of tumor cell response to chemotherapy by the organ environment. Cancer Metastasis Rev. 13, 209–222 (1994).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Farmer, P. et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat. Med. 15, 68–74 (2009).

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Meads, M. B., Gatenby, R. A. & Dalton, W. S. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat. Rev. Cancer 9, 665–674 (2009).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Vennin, C. et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan. Nat. Commun. 10, 3637 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Heldin, C. H., Rubin, K., Pietras, K. & Ostman, A. High interstitial fluid pressure - an obstacle in cancer therapy. Nat. Rev. Cancer 4, 806–813 (2004).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Shimoda, M. et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat. Cell Biol. 16, 889–901 (2014).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Chauhan, V. P. et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc. Natl Acad. Sci. USA 116, 10674–10680 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827–830 (2010). Study showing that depletion of FAP-expressing stromal cells restores antitumour immunity.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013). Study reporting the immune-evasive functions of FAP-expressing CAFs mediated through CXCL12.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Yang, X. et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res. 76, 4124–4135 (2016).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Parker, S. J. et al. Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer. Cancer Discov. 10, 1018–1037 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Dalin, S. et al. Deoxycytidine release from pancreatic stellate cells promotes gemcitabine resistance. Cancer Res. 79, 5723–5733 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Helms, E., Onate, M. K. & Sherman, M. H. Fibroblast heterogeneity in the pancreatic tumor microenvironment. Cancer Discov. 10, 648–656 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Bertero, T. et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab. 29, 124–140.e10 (2019).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Auciello, F. R. et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov. 9, 617–627 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. 108.

    Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under nutrient limited conditions. Nat. Commun. 8, 16031 (2017). References 101–108 report studies showing the regulatory functions of CAFs on cancer metabolism.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Kahlert, C. & Kalluri, R. Exosomes in tumor microenvironment influence cancer progression and metastasis. J. Mol. Med. 91, 431–437 (2013).

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Luga, V. & Wrana, J. L. Tumor-stroma interaction: revealing fibroblast-secreted exosomes as potent regulators of Wnt-planar cell polarity signaling in cancer metastasis. Cancer Res. 73, 6843–6847 (2013).

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Hu, Y. et al. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One 10, e0125625 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Richards, K. E. et al. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 36, 1770–1778 (2017).

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Zhao, H. et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife 5, e10250 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Mueller, M. M. & Fusenig, N. E. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Neesse, A., Algul, H., Tuveson, D. A. & Gress, T. M. Stromal biology and therapy in pancreatic cancer: a changing paradigm. Gut 64, 1476–1484 (2015).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016). Study demonstrating that pancreatic cancer genotypes can influence stromal extracellular matrix content, architecture and stiffness.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012). References 117 and 118 report that cancer cell-derived Hedgehog proteins act on stromal cells and αSMA-expressing stromal cells to restrain pancreatic cancer progression.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009). Study indicating that targeting of the tumour stroma through Hedgehog signalling in pancreatic cancer might improve the delivery of chemotherapeutics.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Lee, J. J. et al. Stromal response to Hedgehog signaling restrains pancreatic cancer progression. Proc. Natl Acad. Sci. USA 111, E3091–E3100 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Torphy, R. J. et al. Stromal content is correlated with tissue site, contrast retention, and survival in pancreatic adenocarcinoma. JCO Precis. Oncol. https://doi.org/10.1200/PO.17.00121 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Shin, K. et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26, 521–533 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Bhattacharjee, S. et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J. Clin. Invest. 131, e146987 (2021).

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  124. 124.

    Jiang, H. et al. Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. J. Clin. Invest. 130, 4704–4709 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Armstrong, T. et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 10, 7427–7437 (2004).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Bachem, M. G. et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology 128, 907–921 (2005).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Egeblad, M., Rasch, M. G. & Weaver, V. M. Dynamic interplay between the collagen scaffold and tumor evolution. Curr. Opin. Cell Biol. 22, 697–706 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Catenacci, D. V. et al. Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. J. Clin. Oncol. 33, 4284–4292 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Ko, A. H. et al. A phase I study of FOLFIRINOX Plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma. Pancreas 45, 370–375 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Benson, A. B. III et al. A phase II randomized, double-blind, placebo-controlled study of simtuzumab or placebo in combination with gemcitabine for the first-line treatment of pancreatic adenocarcinoma. Oncologist 22, 241–e15 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Hecht, J. R. et al. A phase II, randomized, double-blind, placebo-controlled study of simtuzumab in combination with FOLFIRI for the second-line treatment of metastatic KRAS mutant colorectal adenocarcinoma. Oncologist 22, 243–e23 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Ramanathan, R. K. et al. Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313. J. Clin. Oncol. 37, 1062–1069 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Van Cutsem, E. et al. Randomized phase III trial of pegvorhyaluronidase Alfa with Nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma. J. Clin. Oncol. 38, 3185–3194 (2020).

    PubMed  Article  Google Scholar 

  135. 135.

    Uhlen, M. et al. A pathology atlas of the human cancer transcriptome. Science 357, eaan2507 (2017).

    PubMed  Article  CAS  Google Scholar 

  136. 136.

    Moinfar, F. et al. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 60, 2562–2566 (2000).

    CAS  PubMed  Google Scholar 

  137. 137.

    Kurose, K. et al. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat. Genet. 32, 355–357 (2002).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Patocs, A. et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N. Engl. J. Med. 357, 2543–2551 (2007).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    McAndrews, K. M., Chen, Y. & Kalluri, R. Stromal cells exhibit prevalent genetic aberrations in colorectal cancer. Cancer Cell 38, 774–775 (2020).

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Bassez, A. et al. A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer. Nat. Med. 27, 820–832 (2021).

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Zafar, H., Wang, Y., Nakhleh, L., Navin, N. & Chen, K. Monovar: single-nucleotide variant detection in single cells. Nat. Methods 13, 505–507 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Nam, A. S. et al. Somatic mutations and cell identity linked by Genotyping of Transcriptomes. Nature 571, 355–360 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Zhang, L. et al. Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc. Natl Acad. Sci. USA 116, 9014–9019 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Froeling, F. E. et al. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-beta-catenin signaling to slow tumor progression. Gastroenterology 141, 1486–1497 (2011).

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014). Study demonstrating that treatment with vitamin D can reprogramme CAFs to a quiescent state and enhance response to chemotherapy in models of pancreatic cancer.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Kiselev, V. Y., Andrews, T. S. & Hemberg, M. Challenges in unsupervised clustering of single-cell RNA-seq data. Nat. Rev. Genet. 20, 273–282 (2019). A comprehensive review on the challenges and caveats of single-cell RNA-sequencing data analysis.

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Schonhuber, N. et al. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat. Med. 20, 1340–1347 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. 150.

    Chen, Y. et al. Dual reporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol. Med. 10, e9085 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151.

    Han, X. et al. A suite of new Dre recombinase drivers markedly expands the ability to perform intersectional genetic targeting. Cell Stem Cell 28, 1160–1176.e7 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  152. 152.

    Chen, Y. et al. Podoplanin+tumor lymphatics are rate limiting for breast cancer metastasis. PLoS Biol. 16, e2005907 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153.

    Hoshino, A. et al. Podoplanin-positive fibroblasts enhance lung adenocarcinoma tumor formation: podoplanin in fibroblast functions for tumor progression. Cancer Res. 71, 4769–4779 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  154. 154.

    LeBleu, V. S. et al. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 19, 1047–1053 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Wendling, O., Bornert, J. M., Chambon, P. & Metzger, D. Efficient temporally-controlled targeted mutagenesis in smooth muscle cells of the adult mouse. Genesis 47, 14–18 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  156. 156.

    Garcia, P. E. et al. Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma. Cell Mol. Gastroenterol. Hepatol. 10, 581–599 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Kobayashi, H. et al. The balance of stromal BMP signaling mediated by GREM1 and ISLR drives colorectal carcinogenesis. Gastroenterology 160, 1224–1239.e30 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  158. 158.

    Mizutani, Y. et al. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Res. 79, 5367–5381 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  159. 159.

    LeBleu, V. S. et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat. Med. 19, 227–231 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Becker, L. M. et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 31, 107701 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Mascharak, S. et al. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science 372, eaba2374 (2021).

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Hirata, E. et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell 27, 574–588 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Lazard, D. et al. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc. Natl Acad. Sci. USA 90, 999–1003 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The CAF-related work of the authors is supported by MD Anderson Cancer Center, and was supported by the Cancer Prevention and Research Institute of Texas (CPRIT) award RP150231. The NIH National Cancer Institute grant P01CA117969 supports ECM-related research in the Kalluri laboratory.

Author information

Affiliations

Authors

Contributions

All authors contributed to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Raghu Kalluri.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks Michael Karin, Kenneth Valkenburg and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., McAndrews, K.M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol (2021). https://doi.org/10.1038/s41571-021-00546-5

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing