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.

Turning foes to friends: targeting cancer-associated fibroblasts

Abstract

Current paradigms of cancer-centric therapeutics are usually not sufficient to eradicate the malignancy, as the cancer stroma may prompt tumour relapse and therapeutic resistance. Among all the stromal cells that populate the tumour microenvironment, cancer-associated fibroblasts (CAFs) are the most abundant and are critically involved in cancer progression. CAFs regulate the biology of tumour cells and other stromal cells via cell–cell contact, releasing numerous regulatory factors and synthesizing and remodelling the extracellular matrix, and thus these cells affect cancer initiation and development. The recent characterization of CAFs based on specific cell surface markers not only deepens our insight into their phenotypic heterogeneity and functional diversity but also brings CAF-targeting therapies for cancer treatment onto the agenda. In this Review, we discuss the current knowledge of biological hallmarks, cellular origins, phenotypical plasticity and functional heterogeneity of CAFs and underscore their contribution to cancer progression. Moreover, we highlight relevant translational advances and potential therapeutic strategies that target CAFs for cancer treatment.

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: Timeline of discoveries in normal fibroblasts and CAFs.
Fig. 2: Potential cellular sources of CAFs.
Fig. 3: Principal strategies for CAF-directed anticancer therapy.

References

  1. 1.

    Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    PubMed  Google Scholar 

  2. 2.

    Zhou, B.-B. S. et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat. Rev. Drug Discov. 8, 806 (2009).

    CAS  Google Scholar 

  3. 3.

    Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016). This is a systematic Review on the biology and function of fibroblasts in cancer.

    CAS  Google Scholar 

  4. 4.

    Maley, C. C. et al. Classifying the evolutionary and ecological features of neoplasms. Nat. Rev. Cancer 17, 605–619 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Paget, S. The distribution of secondary growths in cancer of the breast. Lancet 133, 571–573 (1889).

    Google Scholar 

  7. 7.

    van Maaren, M. C. et al. 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. Lancet. Oncol. 17, 1158–1170 (2016).

    Google Scholar 

  8. 8.

    Belletti, B. et al. Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding. Clin. Cancer Res. 14, 1325–1332 (2008).

    CAS  Google Scholar 

  9. 9.

    Strom, T. et al. Tumour radiosensitivity is associated with immune activation in solid tumours. Eur. J. Cancer 84, 304–314 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Su, S. et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856 (2018). This study provides the first evidence for different CAF subsets with diverse biological functions, defined by cell surface markers, and is the first time that a tumour-promoting CAF subset was selectively targeted in an animal tumour model.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    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). This is one of the two earliest back-to-back reports on the tumour-suppressive role of CAFs in cancer progression, along with reference 14.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Hwang, R. F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Rhim, A. D. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014). This is one of the two earliest back-to-back reports demonstrating the suppressive effects of tumour stroma on cancer progression, along with reference 12.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 6, 392–401 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    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  PubMed Central  Google Scholar 

  18. 18.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Virchow, R. Die Cellularpathologie in lhrer Begruendung auf Physiologische und Pathologische Gewebelehre (August Hirschwald, Berlin, 1858).

    Google Scholar 

  20. 20.

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

    CAS  Article  Google Scholar 

  21. 21.

    Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat. Med. 18, 1028–1040 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ohlund, D., Elyada, E. & Tuveson, D. Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211, 1503–1523 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    De Wever, O., Demetter, P., Mareel, M. & Bracke, M. Stromal myofibroblasts are drivers of invasive cancer growth. Int. J. Cancer 123, 2229–2238 (2008).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    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  Google Scholar 

  25. 25.

    Saadi, A. et al. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc. Natl Acad. Sci. USA 107, 2177–2182 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ma, X. J., Dahiya, S., Richardson, E., Erlander, M. & Sgroi, D. C. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res. 11, R7 (2009).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Tsujino, T. et al. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin. Cancer Res. 13, 2082–2090 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Laklai, H. et al. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22, 497–505 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15, 637–646 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C. & Brown, R. A. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell Biol. 3, 349–363 (2002).

    CAS  Google Scholar 

  31. 31.

    Rodemann, H. P. & Muller, G. A. Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am. J. Kidney Dis 17, 684–686 (1991).

    CAS  Google Scholar 

  32. 32.

    Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nat. Rev. Cancer 2, 161–174 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Dano, K. et al. Plasminogen activation and cancer. Thromb. Haemostasis 93, 676–681 (2005).

    CAS  Google Scholar 

  34. 34.

    Cukierman, E. & Bassi, D. E. Physico-mechanical aspects of extracellular matrix influences on tumorigenic behaviors. Semin. Cancer Biol. 20, 139–145 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Baeriswyl, V. & Christofori, G. The angiogenic switch in carcinogenesis. Semin. Cancer Biol. 19, 329–337 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Flavell, R. A., Sanjabi, S., Wrzesinski, S. H. & Licona-Limon, P. The polarization of immune cells in the tumour environment by TGFβ. Nat. Rev. Immunol. 10, 554–567 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Kim, J. H. et al. The role of myofibroblasts in upregulation of S100A8 and S100A9 and the differentiation of myeloid cells in the colorectal cancer microenvironment. Biochem. Biophys. Res. Commun. 423, 60–66 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    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  PubMed Central  Google Scholar 

  39. 39.

    Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017). This is the first report that provides precise characterization of CAF heterogeneity in cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Omary, M. B., Lugea, A., Lowe, A. W. & Pandol, S. J. The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Invest. 117, 50–59 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    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  Google Scholar 

  42. 42.

    Barth, P. J., Ebrahimsade, S., Ramaswamy, A. & Moll, R. CD34+ fibrocytes in invasive ductal carcinoma, ductal carcinoma in situ, and benign breast lesions. Virchows Arch. 440, 298–303 (2002).

    CAS  Google Scholar 

  43. 43.

    Jung, Y. et al. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat. Commun. 4, 1795 (2013).

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    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  Google Scholar 

  45. 45.

    Zhu, Q. et al. The IL-6-STAT3 axis mediates a reciprocal crosstalk between cancer-derived mesenchymal stem cells and neutrophils to synergistically prompt gastric cancer progression. Cell Death Dis. 5, e1295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Weber, C. E. et al. Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene 34, 4821–4833 (2015).

    CAS  Google Scholar 

  47. 47.

    Shi, Y., Du, L., Lin, L. & Wang, Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat. Rev. Drug Discov. 16, 35–52 (2017). This is a comprehensive Review of tumour-associated MSCs as cancer therapeutic targets.

    CAS  Google Scholar 

  48. 48.

    Iwano, M. et al. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J. Clin. Invest. 110, 341–350 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    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  Google Scholar 

  50. 50.

    Jotzu, C. et al. Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. Cell. Oncol. 34, 55–67 (2011).

    Google Scholar 

  51. 51.

    Dulauroy, S., Di Carlo, S. E., Langa, F., Eberl, G. & Peduto, L. Lineage tracing and genetic ablation of ADAM12+ perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat. Med. 18, 1262 (2012).

    CAS  Google Scholar 

  52. 52.

    Wikström, P., Marusic, J., Stattin, P. & Bergh, A. Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients. Prostate 69, 799–809 (2009).

    Google Scholar 

  53. 53.

    Huelsken, J. & Hanahan, D. A. Subset of cancer-associated fibroblasts determines therapy resistance. Cell 172, 643–644 (2018).

    CAS  Google Scholar 

  54. 54.

    Hosein, A. et al. Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations. Cancer Res. 70, 5770–5777 (2010).

    CAS  Google Scholar 

  55. 55.

    Allinen, M. et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004).

    CAS  Google Scholar 

  56. 56.

    Haviv, I., Polyak, K., Qiu, W., Hu, M. & Campbell, I. Origin of carcinoma associated fibroblasts. Cell Cycle 8, 589–595 (2009).

    CAS  Google Scholar 

  57. 57.

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

    CAS  Google Scholar 

  58. 58.

    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  Google Scholar 

  59. 59.

    Ayala, G. et al. Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. Clin. Cancer Res. 9, 4792–4801 (2003).

    CAS  Google Scholar 

  60. 60.

    Zhang, J. et al. Fibroblast-specific protein 1/S100A4–positive cells prevent carcinoma through collagen production and encapsulation of carcinogens. Cancer Res. 73, 2770–2781 (2013).

    CAS  Google Scholar 

  61. 61.

    Wang, X. M., Yu, D. M., McCaughan, G. W. & Gorrell, M. D. Fibroblast activation protein increases apoptosis, cell adhesion, and migration by the LX-2 human stellate cell line. Hepatology 42, 935–945 (2005).

    CAS  Google Scholar 

  62. 62.

    Pietras, K., Pahler, J., Bergers, G. & Hanahan, D. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLOS Med. 5, e19 (2008).

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Guido, C. et al. Metabolic reprogramming of cancer-associated fibroblasts by TGF-beta drives tumor growth: connecting TGF-beta signaling with “Warburg-like” cancer metabolism and L-lactate production. Cell Cycle 11, 3019–3035 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    LeBien, T. W. & McCormack, R. T. The common acute lymphoblastic leukemia antigen (CD10)—emancipation from a functional enigma. Blood 73, 625–635 (1989).

    CAS  Google Scholar 

  66. 66.

    Gerard, N. P. et al. An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. J. Biol. Chem. 280, 39677–39680 (2005).

    CAS  Google Scholar 

  67. 67.

    Stoker, M. G., Shearer, M. & O’Neill, C. Growth inhibition of polyoma-transformed cells by contact with static normal fibroblasts. J. Cell Sci. 1, 297–310 (1966).

    CAS  Google Scholar 

  68. 68.

    Alkasalias, T. et al. Inhibition of tumor cell proliferation and motility by fibroblasts is both contact and soluble factor dependent. Proc. Natl Acad. Sci. USA 111, 17188–17193 (2014).

    CAS  Google Scholar 

  69. 69.

    Trimboli, A. J. et al. Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461, 1084–1091 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    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  Google Scholar 

  71. 71.

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

    CAS  Google Scholar 

  72. 72.

    Erez, N., Truitt, M., Olson, P. & Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17, 135–147 (2010). This is the first evidence for the role of CAF-mediated inflammation in tumorigenesis.

    CAS  Google Scholar 

  73. 73.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Webber, J., Steadman, R., Mason, M. D., Tabi, Z. & Clayton, A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 70, 9621–9630 (2010).

    CAS  Google Scholar 

  75. 75.

    Fang, T. et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat. Commun. 9, 191 (2018).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Toullec, A. et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol. Med. 2, 211–230 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Albrengues, J. et al. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Kojima, Y. et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc. Natl Acad. Sci. USA 107, 20009–20014 (2010).

    CAS  Google Scholar 

  79. 79.

    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  Google Scholar 

  80. 80.

    Scherz-Shouval, R. et al. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158, 564–578 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Bruzzese, F. et al. Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. Cancer Res. 74, 3408–3417 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Lau, E. Y. et al. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep. 15, 1175–1189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Olumi, A. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  Google Scholar 

  84. 84.

    Kuperwasser, C. et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc. Natl Acad. Sci. USA 101, 4966–4971 (2004).

    CAS  Google Scholar 

  85. 85.

    Shekhar, M. P., Werdell, J., Santner, S. J., Pauley, R. J. & Tait, L. Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: implications for tumor development and progression. Cancer Res. 61, 1320–1326 (2001).

    CAS  Google Scholar 

  86. 86.

    Picard, O., Rolland, Y. & Poupon, M. F. Fibroblast-dependent tumorigenicity of cells in nude mice: implication for implantation of metastases. Cancer Res. 46, 3290–3294 (1986).

    CAS  Google Scholar 

  87. 87.

    Huang, M., Li, Y., Zhang, H. & Nan, F. Breast cancer stromal fibroblasts promote the generation of CD44+CD24- cells through SDF-1/CXCR4 interaction. J. Exp. Clin. Cancer Res. 29, 80 (2010).

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Seino, T. et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22, 454–467 (2018).

    CAS  Google Scholar 

  89. 89.

    Procopio, M. G. et al. Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat. Cell Biol. 17, 1193–1204 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Martens, J. W. et al. Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. Thromb. Haemost. 89, 393–404 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017). This is a systematic Review of the role of the TME in tumour angiogenesis.

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    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  Google Scholar 

  94. 94.

    Grum-Schwensen, B. et al. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res. 65, 3772–3780 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Zhang, X. H. et al. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154, 1060–1073 (2013). This study provides the first evidence for the role of CAFs in primary tumour stroma in determining specific organ-tropic metastasis of primary cancer cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Wu, M. H. et al. Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin. Cancer Res. 17, 1306–1316 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Pena, C. et al. STC1 expression by cancer-associated fibroblasts drives metastasis of colorectal cancer. Cancer Res. 73, 1287–1297 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kaur, A. et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Yu, Y. et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. Br. J. Cancer 110, 724–732 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Al-Ansari, M. M., Hendrayani, S. F., Shehata, A. I. & Aboussekhra, A. p16(INK4A) represses the paracrine tumor-promoting effects of breast stromal fibroblasts. Oncogene 32, 2356–2364 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Vellinga, T. T. et al. Collagen-rich stroma in aggressive colon tumors induces mesenchymal gene expression and tumor cell invasion. Oncogene 35, 5263–5271 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Provenzano, P. P. et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 6, 11–11 (2008).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Penet, M.-F. et al. Structure and function of a prostate cancer dissemination permissive extracellular matrix. Clin. Cancer Res. 23, 2245–2254 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Glentis, A. et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8, 924 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Labernadie, A. et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat. Cell Biol. 19, 224–237 (2017). This study presents the first demonstration that mechanical coupling between CAFs and cancer cells underlies collective cancer cell metastasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    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). This is the first report on the role of stromal cells in remodelling the pre-metastatic soil.

    PubMed  PubMed Central  Google Scholar 

  109. 109.

    Calon, A. et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell 22, 571–584 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Shintani, Y. et al. IL-6 secreted from cancer-associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial-mesenchymal transition signaling. J. Thorac. Oncol. 11, 1482–1492 (2016).

    Google Scholar 

  111. 111.

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

    CAS  Google Scholar 

  112. 112.

    Zheng, X. et al. EMT program is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Hessmann, E. et al. Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer. Gut 67, 497–507 (2018).

    CAS  Google Scholar 

  114. 114.

    Cheteh, E. H. et al. Human cancer-associated fibroblasts enhance glutathione levels and antagonize drug-induced prostate cancer cell death. Cell Death Dis. 8, e2848 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Straussman, R. et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487, 500–504 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).

    CAS  Google Scholar 

  117. 117.

    Sansone, P. et al. Evolution of cancer stem-like cells in endocrine-resistant metastatic breast cancers is mediated by stromal microvesicles. Cancer Res. 77, 1927–1941 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Brechbuhl, H. M. et al. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin. Cancer Res. 23, 1710–1721 (2017).

    CAS  Google Scholar 

  119. 119.

    Comito, G. et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene 33, 2423–2431 (2014).

    CAS  Google Scholar 

  120. 120.

    Augsten, M. et al. Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res. 74, 2999–3010 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Hashimoto, O. et al. Collaboration of cancer-associated fibroblasts and tumour-associated macrophages for neuroblastoma development. J. Pathol. 240, 211–223 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    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 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    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  Google Scholar 

  124. 124.

    Gutcher, I. et al. Autocrine transforming growth factor-beta1 promotes in vivo Th17 cell differentiation. Immunity 34, 396–408 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Ene-Obong, A. et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 145, 1121–1132 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Kraman, M. et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330, 827–830 (2010). This study provides the first evidence that CAFs suppress antitumour immunity.

    CAS  Google Scholar 

  128. 128.

    Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Armulik, A., Genove, G. & Betsholtz, C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev. Cell 21, 193–215 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Huber, M. A. et al. Fibroblast activation protein: differential expression and serine protease activity in reactive stromal fibroblasts of melanocytic skin tumors. J. Invest. Dermatol. 120, 182–188 (2003).

    CAS  Google Scholar 

  131. 131.

    Santos, A. M., Jung, J., Aziz, N., Kissil, J. L. & Pure, E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J. Clin. Invest. 119, 3613–3625 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Loeffler, M., Kruger, J. A., Niethammer, A. G. & Reisfeld, R. A. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 116, 1955–1962 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Ostermann, E. et al. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin. Cancer Res. 14, 4584–4592 (2008).

    CAS  Google Scholar 

  134. 134.

    Fang, J. et al. A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int. J. Cancer 138, 1013–1023 (2016).

    CAS  Google Scholar 

  135. 135.

    Welt, S. et al. Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts. J. Clin. Oncol. 12, 1193–1203 (1994).

    CAS  Google Scholar 

  136. 136.

    Scott, A. M. et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin. Cancer Res. 9, 1639–1647 (2003).

    CAS  Google Scholar 

  137. 137.

    Hofheinz, R. D. et al. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 26, 44–48 (2003).

    CAS  Google Scholar 

  138. 138.

    Duperret, E. K. et al. Alteration of the tumor stroma using a consensus DNA vaccine targeting fibroblast activation protein (FAP) synergizes with antitumor vaccine therapy in mice. Clin. Cancer Res. 24, 1190–1201 (2018).

    CAS  Google Scholar 

  139. 139.

    Kakarla, S. et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol. Ther. 21, 1611–1620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Wang, L.-C. S. et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014).

    CAS  Google Scholar 

  141. 141.

    Lo, A. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Roberts, E. W. et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 210, 1137–1151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Zalcman, G. et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387, 1405–1414 (2016).

    CAS  Google Scholar 

  144. 144.

    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). This is the first report demonstrating that metabolic reprograming of the tumour stroma inactivates CAFs and suppresses tumour progression.

    CAS  Google Scholar 

  145. 145.

    Carapuca, E. F. et al. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma. J. Pathol. 239, 286–296 (2016).

    CAS  PubMed  PubMed Central  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl Acad. Sci. USA 109, 9448–9453 (2012).

    CAS  Google Scholar 

  148. 148.

    Sanz-Moreno, V. et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20, 229–245 (2011).

    CAS  Google Scholar 

  149. 149.

    Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234 (2018).

    CAS  Google Scholar 

  150. 150.

    Patel, R. A. et al. RKI-1447 is a potent inhibitor of the Rho-associated ROCK kinases with anti-invasive and anti-tumor activities in breast cancer. Cancer Res. 72, 5025–5034 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Hong, D. et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci. Transl Med. 7, 314ra185 (2015).

    PubMed  PubMed Central  Google Scholar 

  152. 152.

    Duluc, C. et al. Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance. EMBO Mol. Med. 7, 735–753 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Moatassim-Billah, S. et al. Anti-metastatic potential of somatostatin analog SOM230: indirect pharmacological targeting of pancreatic cancer-associated fibroblasts. Oncotarget 7, 41584–41598 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. 154.

    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  Google Scholar 

  155. 155.

    Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Jacobetz, M. A. et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62, 112–120 (2013).

    CAS  Google Scholar 

  158. 158.

    Hingorani, S. R. et al. Phase Ib study of PEGylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin. Cancer Res. 22, 2848–2854 (2016).

    CAS  Google Scholar 

  159. 159.

    Ebbinghaus, C., Scheuermann, J., Neri, D. & Elia, G. Diagnostic and therapeutic applications of recombinant antibodies: targeting the extra-domain B of fibronectin, a marker of tumor angiogenesis. Curr. Pharm. Design 10, 1537–1549 (2004).

    CAS  Google Scholar 

  160. 160.

    Reardon, D. A. et al. Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results. J. Clin. Oncol. 24, 115–122 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Vandenbroucke, R. & Libert, C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat. Rev. Drug Discov. 13, 904–927 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Chiappori, A. A. et al. A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors. Clin. Cancer Res. 13, 2091–2099 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Athar, M., Li, C., Kim, A. L., Spiegelman, V. S. & Bickers, D. R. Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res. 74, 4967–4975 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Kim, D. J. et al. Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. J. Clin. Oncol. 32, 745–751 (2014).

    CAS  Google Scholar 

  166. 166.

    Rath, N. & Olson, M. F. Regulation of pancreatic cancer aggressiveness by stromal stiffening. Nat. Med. 22, 462–463 (2016).

    CAS  Google Scholar 

  167. 167.

    Miao, L. et al. Targeting tumor-associated fibroblasts for therapeutic delivery in desmoplastic tumors. Cancer Res. 77, 719–731 (2017).

    CAS  Google Scholar 

  168. 168.

    Niess, H. et al. Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial. BMC Cancer 15, 237 (2015).

    PubMed  PubMed Central  Google Scholar 

  169. 169.

    Younes, A. et al. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 17, 622–631 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Kirsner, R. et al. Spray-applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: a phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 380, 977–985 (2012).

    Google Scholar 

  171. 171.

    Su, S. et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell 25, 605–620 (2014).

    Google Scholar 

  172. 172.

    Chen, J. et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell 19, 541–555 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Su, S. et al. Blocking the recruitment of naive CD4(+) T cells reverses immunosuppression in breast cancer. Cell Res. 27, 461–482 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Simpkins, S. A., Hanby, A. M., Holliday, D. L. & Speirs, V. Clinical and functional significance of loss of caveolin-1 expression in breast cancer-associated fibroblasts. J. Pathol. 227, 490–498 (2012).

    CAS  Google Scholar 

  175. 175.

    Ferrer-Mayorga, G. et al. Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer. Gut 66, 1449–1462 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Zhao, L. et al. Long noncoding RNA LINC00092 acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer. Cancer Res. 77, 1369–1382 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Ma, L. J. et al. Telomere length variation in tumor cells and cancer-associated fibroblasts: potential biomarker for hepatocellular carcinoma. J. Pathol. 243, 407–417 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Paulsson, J. & Micke, P. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin. Cancer Biol. 25, 61–68 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Osterreicher, C. H. et al. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl Acad. Sci. USA 108, 308–313 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Vuoriluoto, K. et al. Vimentin regulates EMT induction by Slug and oncogenic H-Ras and migration by governing Axl expression in breast cancer. Oncogene 30, 1436–1448 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Eyden, B. The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J. Cell. Mol. Med. 12, 22–37 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Arnold, J. N., Magiera, L., Kraman, M. & Fearon, D. T. Tumoral immune suppression by macrophages expressing fibroblast activation protein-alpha and heme oxygenase-1. Cancer Immunol. Res. 2, 121–126 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Cohen, A. W., Hnasko, R., Schubert, W. & Lisanti, M. P. Role of caveolae and caveolins in health and disease. Physiol. Rev. 84, 1341–1379 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

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

    CAS  PubMed  Google Scholar 

  185. 185.

    Neesse, A. et al. CTGF antagonism with mAb FG-3019 enhances chemotherapy response without increasing drug delivery in murine ductal pancreas cancer. Proc. Natl Acad. Sci. USA 110, 12325–12330 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Hurwitz, H. I. et al. Randomized, double-blind, phase II study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J. Clin. Oncol. 33, 4039–4047 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank P. Cai and Q. Liu for proofreading the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Erwei Song.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Glossary

‘Seed and soil’ theory

A theory proposing that the pro-metastatic tumour cells (the ‘seeds’) and the supportive microenvironment in specific organ sites (the ‘soil’) are essential prerequisites for tumour metastasis.

Extracellular matrix

(ECM). A collection of fibrous proteins, such as collagens and fibronectins, that is secreted by mesenchymal cells and provides structural and biochemical support to the surrounding cells.

Fibrosis

A pathological deposition of extracellular matrix proteins that results in an exaggerated wound healing response that impairs the architecture and function of the normal organ or tissue.

Fibrillar ECM

A loosely assembled form of extracellular matrix (ECM), constituted by abundant fibronectin and type I collagen, which serves as a scaffold for other ECM components.

Desmoplastic reaction

The collective response of various stromal cells that is secondary to an initial tissue injury and usually causes dense fibrosis or scar tissue in malignant neoplasms.

Matrix metalloproteinases

(MMPs). Calcium-dependent zinc-containing endoproteases that belong to a larger family of proteases known as the metzincin superfamily and are able to degrade various matrix molecules such as collagens.

Stellate cells

Particular fibroblast-like cells in the pancreas and liver that are characterized by their vitamin A storage and can become activated fibroblasts.

Epithelial-to-mesenchymal transition

(EMT). A cellular programme wherein epithelial cells lose cell–cell contact and acquire mesenchymal-like characteristics.

Endothelial-to-mesenchymal transition

(EndMT). A cellular programme wherein endothelial cells lose some of their features and gain mesenchymal phenotypes.

Transdifferentiation

A process of lineage reprogramming whereby one mature somatic cell directly transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type.

Pericytes

Mesenchymal cells with contractility that wrap around endothelial cells to stabilize the capillaries and venules throughout the body.

M2 polarization

A process of macrophage polarization wherein macrophages are polarized and acquire a specific M2 (alternatively activated macrophage) phenotype.

T helper 17 (TH17) cells

TH cells that produce interleukin-17.

Regulatory T (Treg) cells

Suppressor T cells that maintain immune tolerance to self-antigens and restrain the expansion of effector T cells.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Song, E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov 18, 99–115 (2019). https://doi.org/10.1038/s41573-018-0004-1

Download citation

Further reading

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