Cancer-Associated Fibroblasts: Heterogeneity and Bimodality in Oncogenesis

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Malignant tumors are characterized by high cellular heterogeneity, including cancerous and non-malignant cells, as well as non-cellular components that are part of the tumor microenvironment. Cancer-associated fibroblasts often form a major component of the microenvironment, providing the very “soil” in which cancer cells thrive. Cancer-associated fibroblasts may contribute to tumor growth, invasion, metastasis, and resistance to therapy. However, clinical trials of treatment strategies targeting cancer-associated fibroblasts have largely failed. Moreover, there is evidence that cancer-associated fibroblasts are able to inhibit tumor development. In this review, we aimed to present the current understanding of the functional heterogeneity of cancer-associated fibroblasts, their bimodality in tumor development, and tumor progression. Understanding the tumor-promoting and tumor-inhibiting activities of cancer-associated fibroblasts may contribute to the development of new diagnostic and therapeutic approaches.

作者简介

N. Lunina

National Research Center “Kurchatov Institute”

编辑信件的主要联系方式.
Email: lunina-na.img@yandex.ru
Russia, 123182, Moscow

D. Safina

National Research Center “Kurchatov Institute”

Email: lunina-na.img@yandex.ru
Russia, 123182, Moscow

S. Kostrov

National Research Center “Kurchatov Institute”

Email: lunina-na.img@yandex.ru
Russia, 123182, Moscow

参考

  1. Kalluri R. (2016) The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 16(9), 582–598.
  2. Chen Y., McAndrews K.M., Kalluri R. (2021) Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18(12), 792–804.
  3. LeBleu V.S., Kalluri R. (2018) A peek into cancer-associated fibroblasts: origins, functions and translational impact. Dis. Model Mech. 11(4), dmm029447.
  4. Patel A.K., Singh S. (2020) Cancer associated fibroblasts: phenotypic and functional heterogeneity. Front. Biosci. 25(5), 961–978.
  5. Nissen N.I., Karsdal M., Willumsen N. (2019) Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J. Exp. Clin. Cancer Res. 38(1), 115.
  6. Liu T., Zhou L., Li D., Andl T., Zhang Y. (2019) Cancer-associated fibroblasts build and secure the tumor microenvironment. Front. Cell. Dev. Biol. 7, 60.
  7. Wang F.T., Sun W., Zhang J.T., Fan Y.Z. (2019) Cancer-associated fibroblast regulation of tumor neo-angiogenesis as a therapeutic target in cancer. Oncol. Lett. 17(3), 3055–3065.
  8. Gao P., Li C., Chang Z., Wang X., Xuan M. (2018) Carcinoma associated fibroblasts derived from oral squamous cell carcinoma promote lymphangiogenesis via c-Met/PI3K/AKT in vitro. Oncol. Lett. 15(1), 331–337.
  9. Yoshida G.J., Azuma A., Miura Y., Orimo A. (2019) Activated fibroblast program orchestrates tumor initiation and progression; molecular mechanisms and the associated therapeutic strategies. Int. J. Mol. Sci. 20(9), 2256.
  10. Monteran L., Erez N. (2019) The dark side of fibroblasts: cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front. Immunol. 10, 1835.
  11. Foster D.S., Jones R.E., Ransom R.C., Longaker M.T., Norton J.A. (2018) The evolving relationship of wound healing and tumor stroma. JCI Insight. 3(18), e99911.
  12. Dvorak H.F. (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315(26), 1650–1659.
  13. Öhlund D., Handly-Santana A., Biffi G., Elyada E., Almeida A.S., Ponz-Sarvise M., Corbo V., Oni T.E., Hearn S.A., Lee E.J., Chio I.I.C., Hwang C.-I., Tiriac H., Baker L.A., Engle D.D., Feig C., Kultti A., Egeblad M., Fearon D.T., Crawford J.M., Clevers H., Park Y., Tuveson D.A. (2017) Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214(3), 579–596.
  14. Sahai E., Astsaturov I., Cukierman E., DeNardo D.G., Egeblad M., Evans R.M., Fearon D., Greten F.R., Hingorani S.R., Hunter T., Hynes R.O., Jain R.K., Janowitz T., Jorgensen C., Kimmelman A.C., Kolonin M.G., Maki R.G., Powers R.S., Puré E., Ramirez D.C., Scherz-Shouval R., Sherman M.H., Stewart S., Tlsty T.D., Tuveson D.A., Watt F.M., Weaver V., Weeraratna A.T., Werb Z. (2020) A frame work for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer. 20(3), 174–186.
  15. Erez N., Truitt M., Olson P., Arron S. T., Hanahan D. (2010) Cancer associated fibroblasts are activated in incipient neoplasia to orchestrate tumor promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 17(2), 135–147.
  16. Rønnov-Jessen L., Petersen O.W., Koteliansky V.E., Bissell M.J. (1995) The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J. Clin. Investig. 95(2), 859–873.
  17. Zhang J., Liu J. (2013) Tumor stroma as targets for cancer therapy. Pharmacol. Ther. 137(2), 200–215.
  18. Tejada M.L., Yu L., Dong J., Jung K., Meng G., Peale F.V., Frantz G.D., Hall L., Liang X.H., Gerber H.P., Ferrara N. (2006) Tumor-driven paracrine platelet-derived growth factor receptor alpha signaling is a key determinant of stromal cell recruitment in a model of human lung carcinoma. Clin. Cancer Res. 12(9), 2676–2688.
  19. Boyd L.N.C., Andini K.D., Peters G.J., Kazemier G., Giovannetti E. (2022) Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment. Semin. Cancer Biol. 82, 184–196.
  20. Tian H., Callahan C.A., DuPree K.J., Darbonne W.C., Ahn C.P., Scales S.J., De Sauvage F.J. (2009) Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl. Acad. Sci. USA. 106(11), 4254–4259.
  21. Elenbaas B., Weinberg R.A. (2001) Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp. Cell Res. 264(1), 169–184.
  22. Strell C., Paulsson J., Jin S.B., Tobin N.P., Mezheyeuski A., Roswall P., Mutgan C., Mitsios N., Johansson H., Wickberg S.M., Svedlund J., Nilsson M., Hall P., Mulder J., Radisky D.C., Pietras K., Bergh J., Lendahl U., Wärnberg F., Östman A. (2019) Impact of epithelial-stromal interactions on peritumoral fibroblasts in ductal carcinoma in situ. J. Natl. Cancer Inst. 111(9), 983–995.
  23. Albrengues J., Bertero T., Grasset E., Bonan S., Maiel M., Bourget I., Philippe C., Herraiz Serrano C., Benamar S., Croce O., Sanz-Moreno V., Meneguzzi G., Feral C.C., Cristofari G., Gaggioli C. (2015) Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat. Commun. 6, 10204.
  24. Albrengues J., Bourget I., Pons C., Butet V., Hofman P., Tartare-Deckert S., Feral C.C., Meneguzzi G., Gaggioli C. (2014) LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep. 7(5), 1664–1678.
  25. Avery D., Govindaraju P., Jacob M., Todd L., Monslow J., Pure E. (2018) Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts. Matrix Biol. 67, 90–106.
  26. Calvo F., Ege N., Grande-Garcia A., Hooper S., Jenkins R.P., Chaudhry S.I., Harrington K., Williamson P., Moeendarbary E., Charras G., Sahai E. (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell. Biol. 15(6), 637–646.
  27. Amatangelo M.D., Bassi D.E., Klein-Szanto A.J., Cukierman E. (2005) Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. Am. J. Pathol. 167(2), 475–488.
  28. Ferrari N., Ranftl R., Chicherova I., Slaven N.D., Moeendarbary E., Farrugia A.J., Lam M., Semiannikova M., Westergaard M.C.W., Tchou J., Magnani L., Calvo F. (2019) Dickkopf-3 links HSF1 and YAP/TAZ signalling to control aggressive behaviours in cancer-associated fibroblasts. Nat. Commun. 10(1), 130.
  29. Fordyce C., Fessenden T., Pickering C., Jung J., Singla V., Berman H., Tlsty T. (2010) DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions. Cancer Prev. Res. (Phila) 3(2), 190–201.
  30. Costa A., Scholer-Dahirel A., Mechta-Grigoriou F. (2014) The role of reactive oxygen species and metabolism on cancer cells and their microenvironment. Semin. Cancer Biol. 25, 23–32.
  31. Zou B., Liu X., Zhang B., Gong Y., Cai C., Li P., Chen J., Xing S., Chen J., Peng S., Pokhrel B., Ding L., Zeng L., Li J. (2018) The expression of FAP in hepatocellular carcinoma cells is induced by hypoxia and correlates with poor clinical outcomes. J. Cancer. 9(18), 3278–3286.
  32. Radisky D.C., Levy D.D., Littlepage L.E., Liu H., Nelson C.M., Fata J.E., Leake D., Godden E.L., Albertson D.G., Nieto M.A., Werb Z., Bissell M.J. (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 436(7047), 123–127.
  33. Zheng X., Xu M., Yao B., Wang C., Jia Y., Liu Q. (2016) IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment. Cell. Signal. 28(9), 1314–1324.
  34. Liu T., Han C., Wang S., Fang P., Ma Z., Xu L., Yin R. (2019) Cancer-associated fibroblasts: an emerging target of anti-cancer immunotherapy. J. Hematol. Oncol. 12(1), 86.
  35. Shany S., Sigal-Batikoff I., Lamprecht S. (2016) Vitamin D and myofibroblasts in fibrosis and cancer: at cross-purposes with TGF-β/SMAD signaling. Anticancer Res. 36(12), 6225–6234.
  36. Sherman M.H., Yu R.T., Engle D.D., Ding N., Atkins A.R., Tiriac H., Collisson E.A., Connor F., Van Dyke T., Kozlov S., Martin P., Tseng T.W., Dawson D.W., Don-ahue T.R., Masamune A., Shimosegawa T., Apte M.V., Wilson J.S., Ng B., Lau S.L., Gunton J.E., Wahl G.M., Hunter T., Drebin J.A., O’Dwyer P.J., Liddle C., Tuveson D.A., Downes M., Evans R.M. (2014) Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 159(1), 80–93.
  37. Quante M., Tu S.P., Tomita H., Gonda T., Wang S.S.W., Takashi S., Baik G.H., Shibata W., Diprete B., Betz K.S., Friedman R., Varro A., Tycko B., Wang T.C. (2011) Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 19(2), 257–272.
  38. Kim W., Barron D.A., SanMartin R., Chan K.S., Tran L.L., Yang F., Ressler S.J., Rowley D.R. (2014) RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc. Natl. Acad. Sci. USA. 111(46), 16389–16394.
  39. Cho J.A., Park H., Lim E.H., Kim K.H., Choi J.S., Lee J.H., Shin J.W., Lee K.W. (2011) Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts. Gynecol. Oncol. 123(2), 379–386.
  40. Cho J.A., Park H., Lim E.H., Lee K.W. (2012) Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells in to myofibroblast-like cells. Int. J. Oncol. 40(1), 130–138.
  41. Kalluri R., Weinberg R.A. (2009) The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119(6), 1420–1428.
  42. Kahounová Z., Kurfürstová D., Bouchal J., Kharaishvili G., Navrátil J., Remšík J., Šimečková Š., Študent V., Kozubík A., Souček K. (2018) The fibroblast surface markers FAP, anti-fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial-to-mesenchymal transition. Cytometry A. 93(9), 941–951.
  43. Zeisberg E.M., Potenta S., Xie L., Zeisberg M., Kalluri R. (2007) Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67(21), 10123–10128.
  44. Hosaka K., Yang Y., Seki T., Fischer C., Dubey O., Fredlund E., Hartman J., Religa P., Morikawa H., Ishii Y., Sasahara M., Larsson O., Cossu G., Cao R., Lim S., Cao Y. (2016) Pericyte-fibroblast transition promotes tumor growth and metastasis. Proc. Natl. Acad. Sci. USA. 113(38), E5618–E5627.
  45. Abe R., Donnelly S.C., Peng T., Bucala R., Metz C.N. (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J. Immunol. 166(12), 7556–7562.
  46. Kidd S., Spaeth E., Watson K., Burks J., Lu H., Klopp A., Andreeff M., Marini F.C. (2012) Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One. 7(2), e30563.
  47. Jotzu C., Alt E., Welte G., Li J., Hennessy B.T., Devarajan E., Krishnappa S., Pinilla S., Droll L., Song Y.H. (2011) Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors. Cell. Oncol. 34(1), 55–67.
  48. Omary M.B., Lugea A., Lowe A.W., Pandol S.J. (2007) The pancreatic stellate cell: a star on the rise in pancreatic diseases. J. Clin. Investig. 117(1), 50–59.
  49. Yin C., Evason K.J., Asahina K., Stainier D.Y.R. (2013) Hepatic stellate cells in liver development, regeneration, and cancer. J. Clin. Investig. 123(5), 1902–1910.
  50. Haviv I., Polyak K., Qiu W., Hu M., Campbell I. (2009) Origin of carcinoma associated fibroblasts. Cell Cycle Georget. Tex. 8(4), 589–595.
  51. Nair N., Calle A.S., Zahra M.H., Prieto-Vila M., Oo A.K.K., Hurley L., Vaidyanath A., Seno A., Masuda J., Iwasaki Y., Tanaka H., Kasai T., Seno M. (2017) A cancer stem cell model as the point of origin of cancer-cssociated fibroblasts in tumor microenvironment. Sci. Rep. 7(1), 6838.
  52. Gascard P., Tlsty T. (2016) Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 30(9), 1002–1019.
  53. Liu Q., Liao Q., Zhao Y. (2017) Chemotherapy and tumor microenvironment of pancreatic cancer. Cancer Cell Int. 17, 68.
  54. Whittle M.C., Hingorani S.R. (2019) Fibroblasts in pancreatic ductal adenocarcinoma: biological mechanisms and the targets. Gastroenterology. 156(7), 2085–2096.
  55. Theiss A.L., Simmons J.G., Jobin C., Lund P.K. (2005) Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2. J. Biol. Chem. 280(43), 36099–36109.
  56. Zhang D., Wang Y., Shi Z., Liu J., Sun P., Hou X., Zhang J., Zhao S., Zhou B.P., Mi J. (2015) Metabolic reprogramming of cancer-associated fibroblasts by IDH3α downregulation. Cell. Rep. 10(8), 1335–1348.
  57. Nurmik M., Ullmann P., Rodriguez F., Haan S., Letellier E. (2020) In search of definitions: cancer-associated fibroblasts and their markers. Int. J. Cancer. 146(4), 895–905.
  58. Joshi R.S., Kanugula S.S., Sudhir S., Pereira M.P., Jain S., Aghi M.K. (2021) The role of cancer-associated fibroblasts in tumor progression. Cancers (Basel). 13(6), 1399.
  59. Kleinert R., Prenzel K., Stoecklein N., Alakus H., Bollschweiler E., Holscher A., Warnecke-Eberz U. (2015) Gene expression of Col11A1 is a marker not only for pancreas carcinoma but also for adenocarcinoma of the papilla of vater, discriminating between carcinoma and chronic pancreatitis. Anticancer Res. 35(11), 6153–6158.
  60. Öhlund D., Elyada E., Tuveson D. (2014) Fibroblast heterogeneity in the cancer wound. J. Exp. Med. 211(8), 1503–1523.
  61. Feig C., Jones J.O., Kraman M., Wells R.J., Deonarine A., Chan D.S., Connell C.M., Roberts E.W., Zhao Q., Caballero O.L., Teichmann S.A., Janowitz T., Jodrell D.I., Tuveson D.A., Fearon D.T. (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA. 110(50), 20212–20217.
  62. Lee H.O., Mullins S.R., Franco-Barraza J., Valianou M., Cukierman E., Cheng J.D. (2011) FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer. 11, 245.
  63. Strutz F., Okada H., Lo C.W., Danoff T., Carone R.L., Tomaszewski J.E., Neilson E.G. (1995) Identification and characterization of a fibroblast marker: FSP1. J. Cell. Biol. 130(2), 393–405.
  64. Osterreicher C.H., Penz-Osterreicher M., Grivennikov S.I., Guma M., Koltsova E.K., Datz C., Sasik R., Hardiman G., Karin M., Brenne D.A. (2011) Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl. Acad. Sci. USA. 108(1), 308–313.
  65. Garcia P.E., Adoumie M., Kim E.C., Zhang Y., Scales M.K., El-Tawil Y.S. Shaikh A.Z., Wen H.-J., Bednar F., Allen B.L., Wellik D.M., Crawford H.C., Pasca di Magliano M. (2020) Differential contribution of pancreatic fibroblast subsets to the pancreatic cancer stroma. Cell Mol. Gastroenterol. Hepatol. 10(3), 581–599.
  66. Dominguez C.X., Muller S., Keerthivasan S., Koeppen H., Hung J., Gierke S., Breart B., Foreman O., Bainbridge T.W., Castiglioni A., Senbabaoglu Y., Modrusan Z., Liang Y., Junttila M.R., Klijn C., Bourgon R., Turley S.J. (2020) Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 10(2), 232–253.
  67. Elyada E., Bolisetty M., Laise P., Flynn W.F., Courtois E.T., Burkhart R.A., Teinor J.A., Belleau P., Biffi G., Lucito M.S., Sivajothi S., Armstrong T.D., Engle D.D., Yu K.H., Hao Y., Wolfgang C.L., Park Y., Preall J., Jaffee E.M., Califano A., Robson P., Tuveson D.A. (2019) Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9(8), 1102–1123.
  68. Biffi G., Oni T.E., Spielman B., Hao Y., Elyada E., Park Y., Preall J., Tuveson D.A. (2019) IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9(2), 282–301.
  69. Maeda K., Enomoto A., Hara A., Asai N., Kobayashi T., Horinouchi A., Maruyama S., Ishikawa Y., Nishiyama T., Kiyoi H., Kato T., Ando K., Weng L., Mii S., Asai M., Mizutani Y., Watanabe O., Hirooka Y., Goto H., Takahashi M. (2016) Identification of meflin as a potential marker for mesenchymal stromal cells. Sci. Rep. 6, 22288.
  70. Mizutani Y., Kobayashi H., Iida T., Asai N., Masamune A., Hara A., Esaki N., Ushida K., Mii S., Shiraki Y., Ando K., Weng L., Ishihara S., Ponik S.M., Conklin M.W., Haga H., Nagasaka A., Miyata T., Matsuyama M., Kobayashi T., Fujii T., Yamada S., Yamaguchi J., Wang T., Woods S.L., Worthley D., Shimamura T., Fujishiro M., Hirooka Y., Enomoto A., Takahashi M. (2019) Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis. Cancer Res. 79(20), 5367–5381.
  71. Li S., Zhao W., Sun M. (2020) An analysis regarding the association between the ISLR gene and gastric carcinogenesis. Front. Genet. 11, 620.
  72. Yeung C.L.A., Co N.-N., Tsuruga T., Yeung T.-L., Kwan S.Y., Leung C.S., Li Y., Lu E.S., Kwan K., Wong K.-K., Schmandt R., Lu K.H., Mok S.C. (2016) Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat. Commun. 7, 11150.
  73. Funa K., Sasahara M. (2013) The roles of PDGF in development and during neurogenesis in the normal and diseased nervous system. J. Neuroimmune Pharmacol. 9(2), 168–181.
  74. Farahani R.M., Xaymardan M. (2015) Platelet-derived growth factor receptor alpha as a marker of mesenchymal stem cells in development and stem cell biology. Stem Cells Int. 2015, 362753.
  75. Hu G., Wang S., Xu F., Ding Q., Chen W., Zhong K., Huang L., Xu Q. (2018) Tumor-infiltrating Podoplanin+ fibroblasts predict worse outcome in solid tumors. Cell. Physiol. Biochem. 51(3), 1041–1050.
  76. Planche A., Bacac M., Provero P., Fusco C., Delorenzi M., Stehle J.-C., Stamenkovic I. (2011) Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. PLoS One. 6(5), e18640.
  77. Mezawa Y., Orimo A. (2016) The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res. 365(3), 675–689.
  78. Ozdemir B.C., Pentcheva-Hoang T., Carstens J.L., Zheng X., Wu C.C., Simpson T.R. Laklai H., Sugimoto H., Kahlert C., Novitskiy S.V., De Jesus-Acosta A., Sharma P., Heidari P., Mahmood U., Chin L., Moses H.L., Weaver V.M., Maitra A., Allison J.P., LeBleu V.S., Kalluri R. (2015) Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 28(6), 831–833.
  79. Costa A., Kieffer Y., Scholer-Dahirel A., Pelon F., Bourachot B., Cardon M., Sirven P., Magagna I., Fuhrmann L., Bernard C., Bonneau C., Kondratova M., Kuperstein I., Zinovyev A., Givel A.M., Parrini M.C., Soumelis V., Vincent-Salomon A., Mechta-Grigoriou F. (2018) Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 33(3), 463–479.
  80. Zhou J., Wang X.H., Zhao Y.X., Chen C., Xu X.Y., Sun Q., Wu H.-Y., Chen M., Sang J.-F., Su L., Tang X.-Q., Shi X.-B., Yin Zhang Y., Yu Q., Yao Y.-Z., Zhang W.-J. (2018) Cancer-associated fibroblasts correlate with tumor-associated macrophages infiltration and lymphatic metastasis in triple negative breast cancer patients. J. Cancer. 9(24), 4635–4641.
  81. Jiang M., Wang H., Chen H., Han Y. (2020) SMARCD3 is potential prognostic marker and therapeutic target in CAFs. Aging. 12(20), 20835–20861.
  82. Stock K., Estrada M., Vidic S., Gjerde K., Rudisch A., Santo V.E., Barbier M., Blom S., Arundkar S.C., Irwin Selvam I., Osswald A., Stein Y., Gruenewald S., Brito C., van Weerden W., Rotter V., Boghaert E., Oren M., Sommergruber W., Chong Y., de Hoogt R., Graeser R. (2016) Capturing tumor complexity in vitro: comparative analysis of 2D and 3D tumor models for drug discovery. Sci. Rep. 6, 28951.
  83. Micallef L., Vedrenne N., Billet F., Coulomb B., Darby I.A., Desmoulière A. (2012) The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair. 5(Suppl. 1), S5.
  84. Menezes S., Okail M.H., Jalil S.M.A., Kocher H.M., Cameron A.J.M. (2022) Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets. J. Pathol. 257(4), 526–544.
  85. Surowiak P., Murawa D., Materna V., Maciejczyk A., Pudelko M., Ciesla S., Breborowicz J., Murawa P., Zabel M., Dietel M., Lage H. (2007) Occurrence of stromal myofibroblasts in the invasive ductal breast cancer tissue is an unfavourable prognostic factor. Anticancer Res. 27(4C), 2917–2924.
  86. Tsujino T., Seshimo I., Yamamoto H., Ngan C.Y., Ezumi K., Takemasa I., Ikeda M., Sekimoto M., Matsuura N., Monden M. (2007) Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin. Cancer Res. 13(7), 2082–2090.
  87. Li H., Courtois E., Sengupta D., Tan Y., Chen K.H., Goh J.J.L., Kong S.L., Chua C., Hon L.K., Tan W.S., Wong M., Choi P.J., Wee L.J.K., Hillmer A.M., Tan I.B., Robson P., Prabhakar S. (2017) Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49(5), 708–718.
  88. Bergers G., Song S. (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol. 7(4), 452–464.
  89. Latif N., Sarathchandra P., Chester A., Yacoub M.H. (2014) Expression of smooth muscle cell markers and co-activators in calcified aortic valves. Eur. Heart J. 36(21), 1335–1345.
  90. Плешкан В.В., Алексеенко И.В., Тюлькина Д.В., Кузьмич А.И., Зиновьева М.В., Свердлов Е.Д. (2016) Белок активации фибробластов FAP как возможная мишень в противоопухолевой стратегии. Молекуляр. генетика, микробиология и вирусология. 34(3), 90–97.
  91. Brennen W., Isaacs J., Denmeade S. (2012) Rationale behind targeting fibroblast activation protein expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol. Cancer Ther. 11(2), 257–266.
  92. Moreno-Ruiz P., Corvigno S., te Grootenhuis N.C., La Fleur L., Backman M., Strell C., Mezheyeuski A., Hoelzlwimmer G., Klein C., Botling J., Micke P., Östman A. (2021) Stromal FAP is an independent poor prognosis marker in non-small cell lung adenocarcinoma and associated with p53 mutation. Lung Cancer. 155, 10–19.
  93. Narra K., Mullins S., Lee H., Strzemkowski-Brun B., Magalong K., Christiansen V.J., McKee P.A., Egleston B., Cohen S.J., Weiner L.M., Meropol N.J., Cheng J.D. (2007) Phase II trial of single agent Val-boroPro (Talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer. Cancer Biol. Ther. 6(11), 1691–1699.
  94. Hofheinz R., al-Batran S., Hartmann F. Hartung G., Jäger D., Renner C., Tanswell P., Kunz U., Amelsberg A., Kuthan H., Stehle G. (2003) Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Oncology. 26(1), 44–48.
  95. Heldin C. (2013) Targeting the PDGF signaling pathway in tumor treatment. Cell. Commun. Signal. 11, 97.
  96. Nallanthighal S., Heiserman J.P., Cheon D.-J. (2021) Collagen type XI alpha 1 (COL11A1): a novel biomarker and a key player in cancer. Cancers (Basel). 13(5), 935.
  97. Jia D.Y., Liu Z.Q., Deng N., Tan T.Z., Huang R.Y.J., Taylor-Harding B., Cheon D.J., Lawrenson K., Wiedemeyer W.R., Walts A.E., Karlan B.Y., Orsulic S. (2016) A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets. Cancer Lett. 382(2), 203–214.
  98. Louault K., Liand R.-R., DeClerck Y.A. (2020) Cancer-associated fibroblasts: understanding their heterogeneity. Cancers (Basel). 12(11), 3108.
  99. Bartoschek M., Oskolkov N., Bocci M., Lovrot J., Larsson C., Sommarin M., Madsen C.D., Lindgren D., Pekar G., Karlsson G., Ringnér M., Bergh J., Björklund Å., Pietras K. (2018). Spatially and functionally distinct subclasses of breast cancer associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 9(1), 5150.
  100. Walter S.G., Scheidt S., Nibler R., Gaisendrees C., Zarghooni K., Schildberg F.A. (2021) In-depth characterization of stromal cells within the tumor microenvironment yields novel therapeutic targets. Cancers (Basel). 13(6), 1466.
  101. Berglund E., Maaskola J., Schultz N., Friedrich S., Marklund M., Bergenstråhle J., Tarish F., Tanoglidi A., Vickovic S., Larsson L., Salmén F., Ogris C., Wallenborg K., Lagergren J., Ståhl P., Sonnhammer E., Helleday T., Lundeberg J. (2018) Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity. Nat. Commun. 9(1), 2419.
  102. Hosein A.N., Huang H., Wang Z., Parmar K., Du W., Huang J., Maitra A., Olson E., Verma U., Brekken R.A. (2019) Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution. JCI Insight. 5(16), e129212.
  103. Puram S.V., Tirosh I., Parikh A.S., Patel A.P., Yizhak K., Gillespie S., Rodman C., Luo C.L., Mroz E.A., Emerick K.S., Deschler D.G., Varvares M.A., Mylvaganam R., Rozenblatt-Rosen O., Rocco J.W., Faquin W.C., Lin D.T., Regev A., Bernstein B.E. (2017) Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell. 171(7), 1611–1624.
  104. Neuzillet C., Tijeras-Raballand A., Ragulan C., Cros J., Patil Y., Martinet M., Erkan M., Kleeff J., Wilson J., Apte M., Tosolini M., Wilson A.S., Delvecchio F.R., Bousquet C., Paradis V., Hammel P., Sadanandam A., Kocher H.M. (2019) Inter- and intra-tumoural heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J. Pathol. 248(1), 51–65.
  105. Олейникова Н.А., Данилова Н.В., Михайлов И.А., Семина Е.В., Мальков П.Г. (2020) Опухоль-ассоциированные фибробласты и их значение в прогрессии злокачественных новообразований. Архив патологии. 82(1), 68–77.
  106. Dang H., Harryvan T.J., Hawinkels L.J.A.C. (2021) Fibroblast subsets in intestinal homeostasis, carcinogenesis, tumor progression, and metastasis. Cancers (Basel). 13(2), 183.
  107. Karta J., Bossicard Y., Kotzamanis K., Dolznig H., Letellier E. (2021) Mapping the metabolic networks of tumor cells and cancer-associated fibroblasts. Cells. 10(2), 304.
  108. Steele N.G., Biffi G., Kemp S.B., Zhang Y., Drouillard D., Syu L.-J., Hao Y., Oni T.E., Brosnan E., Elyada E., Doshi A., Hansma C., Espinoza C., Abbas A., The S., Irizarry-Negron V., Halbrook C.J., Franks N.E., Hoffman M.T., Brown K., Carpenter E.S., Nwosu Z.C., Johnson C., Lima F., Anderson M. A., Park Y., Crawford H.C., Lyssiotis C.A., Frankel T.L., Rao A., Bednar F., Dlugosz A.A., Preall J.B., Tuveson D.A., Allen B.L., di Magliano M.P. (2021) Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer. Clin. Cancer Res. 27(7), 2023–2037.
  109. Hutton C., Heider F., Blanco-Gomez A., Banyard A., Kononov A., Zhang X., Karim S., Paulus-Hock V., Watt D., Steele N., Kemp S., Hogg E.K.J., Kelly J., Jackstadt R.-F., Lopes F., Menotti M., Chisholm L., Lamarca A., Valle J., Sansom O.J., Springer C., Malliri A., Marais R., di Magliano M.P., Zelenay S., Morton J.P., Jørgensen C. (2021) Single-cell analysis defines a pancreatic fibroblast lineage that supports antitumor immunity. Cancer Cell. 39(9), 1227–1244.e20.
  110. Miyai Y., Esaki N., Takahashi M., Enomoto A. (2020) Cancer-associated fibroblasts that restrain cancer progression: hypotheses and perspectives. Cancer Sci. 111(4), 1047–1057.
  111. Zhang L., Li Z., Skrzypczynska K.M., Fang Q., Zhang W., O’Brien S.A., He Y., Wang L., Zhang Q., Kim A., Gao R., Orf J., Wang T., Sawant D., Kang J., Bhatt D., Lu D., Li C.-M., Rapaport A.S., Perez K., Ye Y., Wang S., Hu X., Ren X., Ouyang W., Shen Z., Egen J.G., Zhang Z., Yu X. (2020) Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell. 181(2), 442–459.e29.
  112. Lambrechts D., Wauters E., Boeckx B., Aibar S., Nittner D., Burton O., Bassez A., Decaluwé H., Pircher A., Van den Eynde K., Weynand B., Verbeken E., De Leyn P., Liston A., Vansteenkiste J., Carmeliet P., Aerts S., Thienpont B. (2018) Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 24(8), 1277–1289.
  113. Davidson S., Fremova M., Riedel A., Mahata B., Pramanik J., Huuhtanen J., Kar G., Vento-Tormo R., Hagai T., Chen X., Haniffa M.A., Shields J.D., Teichmann S.A. (2020) Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth. Cell Rep. 31(7), 107628.
  114. Sebastian A., Hum N.R., Martin K.A., Gilmore S.F., Peran I., Byers S.W., Wheeler E.K., Coleman M.A., Loots G.G. (2020) Single-cell transcriptomic analysis of tumor-derived fibroblasts and normal tissue-resident fibroblasts reveals fibroblast heterogeneity in breast cancer. Cancers (Basel). 12(5), 1307.
  115. Grauel A.L., Nguyen B., Ruddy D., Laszewski T., Schwartz S., Chang J., Chen J., Piquet M., Pelletier M., Yan Z., Kirkpatrick N.D., Wu J., deWeck A., Riester M., Hims M., Geyer F.C., Wagner J., MacIsaac K., Deeds J., Diwanji R., Jayaraman P., Yu Y., Simmons Q., Weng S., Raza A., Minie B., Dostalek M., Chikkegowda P., Ruda V., Iartchouk O., Chen N., Thierry R., Zhou J., Pruteanu-Malinici I., Fabre C., Engelman J.A., Dranoff G., Cremasco V. (2020) TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts. Nat. Commun. 11(1), 6315.
  116. Wu S.Z., Roden D.L., Wang C., Holliday H., Harvey K., Cazet A.S., Murphy K.J., Pereira B., Al-Eryani G., Bartonicek N., Hou R., Torpy J.R., Junankar S., Chan C.-L., Lam C.E., Hui M.N. Gluch L., Beith J., Parker A., Robbins E., Segara D., Mak C., Cooper C., Warrier S., Forrest A., Powell J., O’Toole S., Cox T.R., Timpson P., Lim E., Liu X.S., Swarbrick A. (2020) Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J. 39(19), e104063.
  117. Kieffer Y., Hocine H.R., Gentric G., Pelon F., Bernard C., Bourachot B., Lameiras S., Albergante L., Bonneau C., Guyard A., Tarte K., Zinovyev A., Baulande S., Gerard Zalcman G., Vincent-Salomon A., Mechta-Grigoriou F. (2020) Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 10(9), 1330–1351.
  118. Givel A.M., Kieffer Y., Scholer-Dahirel A., Sirven P., Cardon M., Pelon F., Magagna I., Gentric G., Costa A., Bonneau C., Mieulet V., Vincent-Salomon A., Mechta-Grigoriou F. (2018) miR200-regulated C-XCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat. Commun. 9(1), 1056.
  119. Pelon F., Bourachot B., Kieffer Y., Magagna I., Mermet-Meillon F., Bonnet I., Costa A., Givel A.-M., Attieh Y., Barbazan J., Bonneau C., Fuhrmann L., Descroix S., Vignjevic D., Silberzan P., Parrini M.C., Vincent-Salomon A., Mechta-Grigoriou F. (2020) Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat. Commun. 11(1), 404.
  120. Affo S., Nair A., Brundu F., Ravichandra A., Bhattacharjee S., Matsuda M., Chin L., Filliol A., Wen W., Song X., Decker A., Worley J., Caviglia J.M., Yu L., Yin D., Saito Y., Savage T., Wells R.G., Mack M., Zender L., Arpaia N., Remotti H.E., Rabadan R., Sims P., Leblond A.L., Weber A., Riener M.O., Stockwell B.R., Gaublomme J., Llovet J.M., Kalluri. R, Michalopoulos G.K., Seki E., Sia D., Chen X., Califano A., Schwabe R.F. (2021) Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell. 39(6), 866–882.e11.
  121. Friedman G., Levi-Galibov J., David E., Bornstein C., Giladi A., Dadiani M., Mayo A., Halperin C., Pevsner-Fischer M., Lavon H., Mayer S., Nevo R., Stein Y., Balint-Lahat N., Barshack I., Ali H.R., Caldas C., Nili-Gal-Yam E., Alon U., Amit I., Scherz-Shouval R. (2020) Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer. 1(7), 692–708.
  122. Li X., Sun Z., Peng G., Xiao Y., Guo J., Wu B., Li X., Zhou W., Li J., Li Z., Bai C., Zhao L., Han Q., Zhao R.C., Xiaoyue Wang X. (2022) Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer. Theranostics. 12(2), 620–638.
  123. Chen Z., Zhou L., Liu L., Hou Y., Xiong M, Yang Y, Hu J., Chen K. (2020) Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 11(1), 5077.
  124. Chen S. Zhu G., Yang Y., Wang F., Xiao Y.-T., Zhang N., Bian X., Yasheng Zhu Y., Yu Y., Liu F., Dong K., Mariscal J., Liu Y., Soares F., Yau H.L., Zhang B., Chen W., Wang C., Chen D., Guo Q., Yi Z., Liu M., Fraser M., De Carvalho D.D., Boutros P.C., Di Vizio D., Jiang Z., Van der Kwast T., Berlin A., Wu S., Wang J., He H.H., Ren S. (2021) Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 23(1), 87–98.
  125. Qureshi-Baig K., Ullmann P., Haan S., Letellier E. (2017) Tumor-initiating cells: a criTICal review of isolation approaches and new challenges in targeting strategies. Mol. Cancer. 16(1), 40.
  126. Wang Z., Yang Q., Tan Y., Tang Y., Ye J., Yuan B., Yu W. (2021) Cancer-associated fibroblasts suppress cancer development: the other side of the coin. Front. Cell Dev. Biol. 9, 613534.
  127. Huang C., Wang X.-L., Qi F.-F., Pang Z.-L. (2020) Berberine inhibits epithelial-mesenchymal transition and promotes apoptosis of tumour-associated fibroblast-induced colonic epithelial cells through regulation of TGF-β signalling. J. Cell Commun. Signal. 14(1), 53–66.
  128. Wang S., Su X., Xu M., Xiao X., Li X., Li H., Keating A., Zhao R.C. (2019) Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem Cell Res. Ther. 10(1), 117.
  129. Ao M., Franco O.E., Park D., Raman D., Williams K., Hayward S.W. (2007) Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium. Cancer Res. 67(9), 4244–4253.
  130. Todaro M., Gaggianesi M., Catalano V., Benfante A., Iovino F., Biffoni M. Apuzzo T., Sperduti I., Volpe S., Cocorullo G., Gulotta G., Dieli F., De Maria R., Stass G. (2014) CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 14(3), 342–356.
  131. Han D., Wang M., Yu Z., Yin L., Liu C., Wang J., Liu Y., Jiang S., Ren Z., Yin J. (2019) FGF5 promotes osteosarcoma cells proliferation via activating MAPK signaling pathway. Cancer Manag. Res. 11, 6457–6466.
  132. Li H., Zhang Q., Wu Q., Cui Y., Zhu H., Fang M., Zhou X., Sun Z., Yu J. (2019) Interleukin-22 secreted by cancer-associated fibroblasts regulates the proliferation and metastasis of lung cancer cells via the PI3K-Akt-mTOR signaling pathway. Am. J. Transl. Res. 11(7), 4077–4088.
  133. Ma H., Wang J., Zhao X., Wu T., Huang Z., Chen D., Liu Y., Ouyang G. (2020) Periostin promotes colorectal tumorigenesis through integrin-FAK-Src pathway-mediated YAP/TAZ activation. Cell Rep. 30(3), 793–806.e6.
  134. Zhang M., Shi R., Guo Z., He J. (2020) Cancer-associated fibroblasts promote cell growth by activating ERK5/PD-L1 signaling axis in colorectal cancer. Pathol. Res. Pract. 216(4), 152884.
  135. Wang R., Sun Y.-Q., Yu W., Yan Y., Qiao M., Jiang R., Guan W., Wang L. (2019) Downregulation of miRNA-214 in cancer-associated fibroblasts contributes to migration and invasion of gastric cancer cells through targeting FGF9 and inducing EMT. J. Exp. Clin. Cancer Res. 38(1), 20.
  136. Shu C., Zha H., Long H., Wang X., Yang F., Gao J., Hu C., Zhou L., Guo B., Zhu B. (2020) C3a-C3aR signaling promotes breast cancer lung metastasis via modulating carcinoma associated fibroblasts. J. Exp. Clin. Cancer Res. 39(1), 11.
  137. Wen S., Hou Y., Fu L., Xi L., Yang D., Zhao M., Qin Y., Sun K., Teng Y., Liu M. (2019) Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling. Cancer Lett. 442, 320–332.
  138. Neri S., Miyashita T., Hashimoto H., Suda Y., Ishibashi M., Kii H., Watanabe H., Kuwata T., Tsuboi M., Goto K., Menju T., Sonobe M., Date H., Ochiai A., Ishii G. (2017) Fibroblast-led cancer cell invasion is activated by epithelial–mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma. Cancer Lett. 395, 20–30.
  139. Folkman J. (2002) Role of angiogenesis in tumor growth and metastasis. Semin. Oncol. 29(6, Suppl 16), 15–18.
  140. Kuriyama N., Yoshioka Y., Kikuchi S., Azuma N., Ochiya T. (2020) Extracellular vesicles are key regulators of tumor neovasculature. Front. Cell Dev. Biol. 8, 611039.
  141. Hlatky L., Tsionou C., Hahnfeldt P., Coleman C.N. (1994) Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 54(23), 6083–6086.
  142. Inoue K.-I., Kishimoto S., Akimoto K., Sakuma M., Toyoda S., Inoue T., Yoshida K.-I., Shimoda M., Suzuki S. (2019) Cancer-associated fibroblasts show heterogeneous gene expression and induce vascular endothelial growth factor A (VEGFA) in response to environmental stimuli. Ann. Gastroenterol. Surg. 3(4), 416–425.
  143. San Martin R., Barron D.A., Tuxhorn J.A., Ressler S.J., Hayward S.W., Shen X., Laucirica R., Wheeler T.M., Gutierrez C., Ayala G.E., Ittmann M., Rowley D.R. (2014) Recruitment of CD34(+) fibroblasts in tumor-associated reactive stroma: the reactive microvasculature hypothesis. Am. J. Pathol. 184(6), 1860–1870.
  144. Herrera A., Herrera M., Guerra-Perez N., Galindo-Pumariño C., Larriba M.J., García-Barberán V., Gil B., Giménez-Moyano S., Ferreiro-Monteagudo R., Veguillas P., Candia A., Peña R., Pinto J., García-Bermejo M.L., Muñoz A., García de Herreros A., Bonilla F., Carrato A., Peña C. (2018) Endothelial cell activation on 3D-matrices derived from PDGF-BB-stimulated fibroblasts is mediated by snail1. Oncogenesis. 7(9), 76.
  145. Unterleuthner D., Neuhold P., Schwarz K., Janker L., Neuditschko B., Nivarthi H., Crncec I., Kramer N., Unger C., Hengstschläger M., Eferl R., Moriggl R., Sommergruber W., Gerner C., Dolznig H. (2020) Cancer-associated fibroblast-derived WNT2 increases tumor angiogenesis in colon cancer. Angiogenesis. 23(2), 159–177.
  146. Sewell-Loftin M.K., Bayer S.V.H., Crist E., Hughes T., Joison S.M., Longmore G.D., George S.C. (2017) Cancer-associated fibroblasts support vascular growth through mechanical force. Sci. Rep. 7(1), 12574.
  147. Barrett R.L., Pure E. (2020) Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy. Elife. 9, e57243.
  148. Ziani L., Chouaib S., Thiery J. (2018) Alteration of the antitumor immune response by cancer-associated fibroblasts. Front. Immunol. 9, 414.
  149. Poltavets V., Kochetkova M., Pitson S.M., Samuel M.S. (2018) The role of the extracellular matrix and its molecular and cellular regulators in cancer cell plasticity. Front. Oncol. 8, 431.
  150. Zhao X., Ding L., Lu Z., Huang X., Jing Y., Yang Y., Chen S., Hu Q., Ni Y. (2020) Diminished CD68+ cancer-associated fibroblast subset induces regulatory T-cell (Treg) infiltration and predicts poor prognosis of oral squamous cell carcinoma patients. Am. J. Pathol. 190(4), 886–899.
  151. Bordignon P., Bottoni G., Xu X., Popescu A.S., Truan Z., Guenova E., Kofler L., Jafari P., Ostano P., Röcken M., Neel V., Dotto G.P. (2019) Dualism of FGF and TGF-β signaling in heterogeneous cancer-associated fibroblast activation with ETV1 as a critical determinant. Cell Rep. 28(9), 2358–2372.
  152. Vickman R.E., Broman M.M., Lanman N.A., Franco O.E., Sudyanti P.A.G., Ni Y., Ji Y., Helfand B.T., Petkewicz J., Paterakos M.C., Crawford S.E., Ratliff T.L., Hayward S.W. (2020) Heterogeneity of human prostate carcinoma-associated fibroblasts implicates a role for subpopulations in myeloid cell recruitment. Prostate. 80(2), 173–185.
  153. Robinson S.C., Scott K.A., Balkwill F.R. (2002) Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-α. Eur. J. Immunol. 32(2), 404–412.
  154. Sukkurwala A.Q., Martins I., Wang Y., Schlemmer F., Ruckenstuhl C., Durchschlag M. Michaud M., Senovilla L., Sistigu A., Ma Y., Vacchelli E., Sulpice E., Gidrol X., Zitvogel L., Madeo F., Galluzzi L., Kepp O., Kroemer G. (2013) Immunogeniccal reticulin exposure occurs through haphylo genetically conserved stress pathway involving the chemokine CXCL8. Cell Death Differ. 21(1), 59–68.
  155. Tessema M., Klinge D.M., Yingling C.M., Do K., Van Neste L., Belinsky S.A. (2010) Re-expression of CXCL14, a common target for epigenetic silencing in lung cancer, induces tumor necrosis. Oncogene. 29(37), 5159–5170.
  156. Raker V.K., Domogalla M.P., Steinbrink K. (2015) Tolerogenic dendritic cells for regulatory T cell induction in man. Front. Immunol. 6, 569.
  157. Flavell R.A., Sanjabi S., Wrzesinski S.H., Licona-Limón P. (2010) The polarization of immune cells in the tumour environment by TGFbeta. Nat. Rev. Immunol. 10(8), 554–567.
  158. Park Y.P., Choi S.-C., Kiesler P., Gil-Krzewska A., Borrego F., Weck J., Krzewski K., Coligan J.E. (2011) Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the c cytokines and TGF-1. Blood. 118(1), 3019–3027.
  159. Harper J., Sainson R.C.A. (2014) Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin. Cancer Biol. 25, 69–77.
  160. Mills L.D., Zhang Y., Marler R.J., Herreros-Villanueva M., Zhang L., Almada L.L., Couch F., Wetmore C., Pasca di Magliano M., Fernandez-Zapico M.E. (2013) Loss of the transcription factor GLI1 identifies a signaling network in the tumor microenvironment mediating KRAS oncogene-induced transformation. J. Biol. Chem. 288(17), 11786–11794.
  161. Sugimoto H., Mundel T.M., Kieran M.W., Kalluri R. (2006). Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 5(12), 1640–1646.
  162. Ichihara R., Shiraki Y., Mizutani Y., Iida T., Miyai Y., Esaki N., Kato A., Mii S., Ando R., Hayashi M., Takami H., Fujii T., Takahashi M., Enomoto A. (2022) Matrix remodeling-associated protein 8 is a marker of a subset of cancer-associated fibroblasts in pancreatic cancer. Pathol Int. 72(3), 161–175.
  163. Wang Y., Liang Y., Xu H., Zhang X., Mao T., Cui J., Yao J., Wang Y., Jiao F., Xiao X., Hu J., Xia Q., Zhang X., Wang X., Sun Y., Fu D., Shen L., Xu X., Xue J., Wang L. (2021) Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response. Cell Discov. 7(1), 36.
  164. Djurec M., Graña O., Lee A., Troulé K., Espinet E., Cabras L., Navas C., Blasco M.T., Martín-Díaz L., Burdiel M., Li J., Liu Z., Vallespinós M., Sanchez-Bueno F., Sprick M.R., Trumpp A., Sainz B.Jr., Al-Shahrour F., Rabadan R., Guerra C., Barbacid M. (2018) Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc. Natl. Acad. Sci. USA. 115(6), E1147–E1156.
  165. Wei L., Lin Q., Lu Y., Li G., Huang L., Fu Z., Chen R., Zhou Q. (2021) Cancer-associated fibroblasts-mediated ATF4 expression promotes malignancy and gemcitabine resistance in pancreatic cancer via the TGF-β1/SMAD2/3 pathway and ABCC1 transactivation. Cell Death Disease. 12(4), 334.
  166. Han S., Fu D., Tushoski G.W., Meng L., Herremans K.M., Riner A.N., Geoge T.J., Huo Z., Hughes S.J. (2022) Single-cell profiling of microenvironment components by spatial localization in pancreatic ductal adenocarcinoma. Theranostics. 12(11), 4980–4992.
  167. Zhao M., Zhuang A., Fang Y. (2022) Cancer-associated fibroblast-derived exosomal miRNA-320a promotes macrophage M2 polarization in vitro by regulating PTEN/PI3Kγ signaling in pancreatic cancer. J. Oncol. 2022, 9514697.
  168. Dai K., Tanaka M., Kamiyoshi A., Sakurai T., Ichikawa-Shindo Y., Kawate H., Cui N., Wei Y., Tanaka M., Kakihara S., Matsui S., Shindo T. (2020) Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts. Oncogene. 39(9), 1914–1930.
  169. Bhattacharjee S., Hamberger F., Ravichandra A., Miller M., Nair A., Affo S., Filliol A., Chin L., Savage T.M., Yin D., Wirsik N.M., Mehal A., Arpaia N., Seki E., Mack M., Zhu D., Sims P.A., Kalluri R., Stanger B.Z., Olive K.P., Schmidt T., Wells R.G., Mederacke I., Schwabe R.F. (2021) Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J. Clin. Invest. 131(11), e146987.
  170. Miyazaki Y., Mori N., Akagi Y., Oda T., Kida Y.S. (2022) Potential metabolite markers for pancreatic cancer identified by metabolomic analysis of induced cancer-associated fibroblasts. Cancers (Basel). 14(6), 1375.
  171. Lakins M.A., Ghorani E., Munir H., Martins C.P., Shields J.D. (2018) Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T cells to protect tumour cells. Nat. Commun. 9(1), 948.
  172. Shi L., Zhu W., Huang Y., Zhuo L., Wang S., Chen S., Zhang B., Ke B. (2022) Cancer-associated fibroblast-derived exosomal microRNA-20a suppresses the PTEN/PI3K-AKT pathway to promote the progression and chemoresistance of non-small cell lung cancer. Clin. Transl. Med. 12(7), e989.
  173. Kim D., Kim J.S., Cheon I., Kim S.R., Chun S.H., Kim J.J., Lee S., Yoon J.S., Hong S.A., Won H.S., Kang K., Ahn Y.H., Ko Y.H. (2022) Identification and characterization of cancer-associated fibroblast subpopulations in lung adenocarcinoma. Cancers (Basel). 14(14), 3486.
  174. Mathilakathu A., Wessolly M., Mairinger E., Uebner H., Kreidt D., Brcic L., Steinborn J., Greimelmaier K., Wohlschlaeger J., Schmid K.W., Mairinger F.D., Borchert S. (2022) Cancer-associated fibroblasts regulate kinase activity in mesothelioma cell lines via paracrine signaling and thereby dictate cell faith and behavior. Int. J. Mol. Sci. 23(6), 3278.
  175. Zhang G., Zheng H., Wang L. (2022) miR‑491‑3p functions as a tumor suppressor in non‑small cell lung cancer by targeting fibroblast growth factor 5. Oncol. Rep. 48(3), 164.
  176. Sugai M., Yanagawa N., Shikanai S., Hashimoto M., Saikawa H., Osakabe M., Saito H., Maemondo M., Sugai T. (2022) Correlation of tumor microenvironment-related markers with clinical outcomes in patients with squamous cell carcinoma of the lung. Transl. Lung Cancer Res. 11(6), 975–990.
  177. Wang Y., Lan W., Xu M., Song J., Mao J., Li C., Du X., Jiang Y., Li E., Zhang R., Wang Q. (2021) Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling. Cell Death Dis. 12(2), 214.
  178. Li H., Liu W., Zhang X., Wang Y. (2021) Cancer‑associated fibroblast‑secreted collagen triple helix repeat containing‑1 promotes breast cancer cell migration, invasiveness and epithelial‑mesenchymal transition by activating the Wnt/β‑catenin pathway. Oncol. Lett. 22(6), 814.
  179. O'Connell J.T., Sugimoto H., Cooke V.G., MacDonald B.A., Mehta A.I., LeBleu V.S., Dewar R., Rocha R.M., Brentani R.R., Resnick M.B., Neilson E.G., Zeisberg M., Kalluri R. (2011) VEGF-A and tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc. Natl. Acad. Sci. USA. 108(38), 16002–16007.
  180. Su S., Chen J., Yao H., Liu J., Yu S., Lao L., Wang M., Luo M., Xing Y., Chen F., Huang D., Zhao J., Yang L., Liao D., Su F., Li M., Liu Q., Song E. (2018) CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell. 172(4), 841–856.e16.
  181. Brechbuhl H.M., Finlay-Schultz J., Yamamoto T.M., Gillen A.E., Cittelly D.M., Tan A.C., Sams S.B., Pillai M.M., Elias A.D., Robinson W.A., Sartorius C.A., Kabos P. (2017) Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin. Cancer Res. 23(7), 1710–1721.
  182. Zheng S., Zou Y., Tang Y., Yang A., Liang J.Y., Wu L., Tian W., Xiao W., Xie X., Yang L., Xie J., Wei W., Xie X. (2022) Landscape of cancer-associated fibroblasts identifies the secreted biglycan as a protumor and immunosuppressive factor in triple-negative breast cancer. Oncoimmunology. 11(1), 2020984.
  183. Wang M., Feng R., Chen Z., Shi W., Li C., Liu H., Wu K., Li D., Li X. (2022) Identification of cancer-associated fibroblast subtype of triple-negative breast cancer. J. Oncol. 2022, 6452636.
  184. Wan X., Guan S., Hou Y., Qin Y., Zeng H., Yang L., Qiao Y., Liu S., Li Q., Jin T., Qiu Y., Liu M. (2021) FOSL2 promotes VEGF-independent angiogenesis by transcriptionally activating Wnt5a in breast cancer-associated fibroblasts. Theranostics. 11(10), 4975–4991.
  185. Li H., Liu W., Zhang X., Wang Y. (2021) Cancer-associated fibroblast-secreted collagen triple helix repeat containing-1 promotes breast cancer cell migration, invasiveness and epithelial-mesenchymal transition by activating the Wnt/β-catenin pathway. Oncol. Lett. 22(6), 814.
  186. Mir S., Golden B.D.O., Griess B.J., Vengoji R., Tom E., Kosmacek E.A., Oberley-Deegan R.E., Talmon G.A., Band V., Teoh-Fitzgerald M.L. (2022) Upregulation of Nox4 induces a pro-survival Nrf2 response in cancer-associated fibroblasts that promotes tumorigenesis and metastasis, in part via Birc5 induction. Breast Cancer Res. 24(1), 48.
  187. Itoh G., Takagane K., Fukushi Y., Kuriyama S., Umakoshi M., Goto A., Yanagihara K., Yashiro M., Tanaka M. (2022) Cancer-associated fibroblasts educate normal fibroblasts to facilitate cancer cell spreading and T-cell suppression. Mol. Oncol. 16(1), 166–187.
  188. Zhang J., Li S., Zhao Y., Ma P., Cao Y., Liu C., Zhang X., Wang W., Chen L., Li Y. (2020) Cancer-associated fibroblasts promote the migration and invasion of gastric cancer cells via activating IL-17a/JAK2/STAT3 signaling. Ann. Transl. Med. 8(14), 877.
  189. Zhang J., Ji C., Li W., Mao Z., Shi Y., Shi H., Ji R., Qian H., Xu W., Zhang X. (2020) Tumor-educated neutrophils activate mesenchymal stem cells to promote gastric cancer growth and metastasis. Front. Cell. Dev. Biol. 8, 788.
  190. Zhao Z., Li W., Zhu L., Xu B., Jiang Y., Ma N., Liu L., Qiu J., Zhang M. (2022) Construction and verification of a fibroblast-related prognostic signature model for colon cancer. Front. Genet. 13, 908957.
  191. Dai G., Yao X., Zhang Y., Gu J., Geng Y., Xue F., Zhang J. (2018) Colorectal cancer cell-derived exosomes containing mir-10b regulate fibroblast cells via the PI3K/Akt pathway. Bull. Cancer. 105(4), 336–349.
  192. Huang T.X., Tan X.Y., Huang H.S., Li Y.T., Liu B.L., Liu K.S., Chen X., Chen Z., Guan X.Y., Zou C., Fu L. (2022) Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity. Gut. 71(2), 333–344.
  193. Liu B., Liu T., Liu Y., Feng X., Jiang X., Long J., Ye S., Chen D., Wang J., Yang Z. (2022) TSG-6 promotes cancer cell aggressiveness in a CD44-dependent manner and reprograms normal fibroblasts to create a pro-metastatic microenvironment in colorectal cancer. Int. J. Biol. Sci. 18(4), 1677–1694.
  194. Yang M., Wei Z., Feng M., Zhu Y., Chen Y., Zhu D. (2021) Pharmacological inhibition and genetic knockdown of BCL9 modulate the cellular landscape of cancer-associated fibroblasts in the tumor-immune microenvironment of colorectal cancer. Front. Oncol. 11, 603556.
  195. Bonollo F., Thalmann G.N., Kruithof-de Julio M., Karkampouna S. (2020) The role of cancer-associated fibroblasts in prostate cancer tumorogenesis. Cancers. 12(7), 1887.
  196. Eiro N., Fernández-Gómez J.M., Gonzalez-Ruiz de León C., Fraile M., Gonzalez-Suarez J., Lobo-Rodríguez B., García-Rodríguez J., Escaf S., Vizoso F.J. (2022) Gene expression profile of stromal factors in cancer-associated fibroblasts from prostate cancer. Diagnostics (Basel). 12(7), 1605.
  197. Akinjiyan F.A., Dave R.M., Alpert E., Longmore G.D., Fuh K.C. (2022) DDR2 expression in cancer-associated fibroblasts promotes ovarian cancer tumor invasion and metastasis through periostin-ITGB1. Cancers (Basel). 14(14), 3482.
  198. Zeng L., Wang X., Wang F., Zhao X., Ding Y. (2022) Identification of a gene signature of cancer-associated fibroblasts to predict prognosis in ovarian cancer. Front. Genet. 13, 925231.
  199. Cheng J.T., Deng Y.N., Yi H.M., Wang G.Y., Fu B.S., Chen W.J., Liu W., Tai Y., Peng Y.W., Zhang Q. (2016) Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis. 5(2), e198.
  200. Jiao J., González Á., Stevenson H.L., Gagea M., Sugimoto H., Kalluri R., Beretta L. (2018) Depletion of S100A4+ stromal cells does not prevent HCC development but reduces the stem cell-like phenotype of the tumors. Exp. Mol. Med. 50(1), e422.
  201. Zhang J., Chen L., Liu X., Kammertoens T., Blankenstein T., Qin Z. (2013) Fibroblast-specific protein 1/S100A4-positive cells prevent carcinoma through collagen production and encapsulation of carcinogens. Cancer Res. 73(9), 2770–2781.
  202. Zhao X., Ding L., Lu Z., Huang X., Jing Y., Yang Y., Chen S., Hu Q., Ni Y. (2020) Diminished CD68+ cancer-associated fibroblast subset induces regulatory T-cell (Treg) infiltration and predicts poor prognosis of oral squamous cell carcinoma patients. Am. J. Pathol. 190(10), 886–899.
  203. Costea D.E., Hills A., Osman A.H., Thurlow J., Kalna G., Huang X., Murillo C.P., Parajuli H., Suliman S., Kulasekara K.K., Johannessen A.C., Partridge M. (2013) Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer Res. 73(13), 3888–3901.
  204. Hassona Y., Cirillo N., Heesom K.J., Parkinson E.K., Prime S.S. (2014) Senescent cancer-associated fibroblasts secrete active MMP-2 that promotes keratinocyte dis-cohesion and invasion. Br. J. Cancer. 111(6), 1230–1237.
  205. Rajthala S., Parajuli H., Dongre H.N., Ljøkjel B., Hoven K.M., Kvalheim A., Lybak S., Neppelberg E., Sapkota D., Johannessen A.C., Costea D.-E. (2022) MicroRNA-138 abates fibroblast motility with effect on invasion of adjacent cancer cells. Front. Oncol. 12, 833582.
  206. Haga K., Yamazaki M., Maruyama S., Kawaharada M., Suzuki A., Hoshikawa E., Chan N.N., Funayama A., Mikami T., Kobayashi T., Izumi K., Tanuma J.I. (2021) Crosstalk between oral squamous cell carcinoma cells and cancer-associated fibroblasts via the TGF-β/SOX9 axis in cancer progression. Transl. Oncol. 14(12), 101236.
  207. Heidary Z., Ghaisari J., Moein S., Javanmard S.H. (2020) The double-edged sword role of fibroblasts in the interaction with cancer cells; an agent-based modeling approach. PLoS One. 15(5), e0232965.
  208. Shi R., Tang Y.Q., Miao H. (2020) Metabolism in tumor microenvironment: implications for cancer immunotherapy. Med. Comm. 1(1), 47–68.
  209. Zhao H., Yang L., Baddour J., Achreja A., Bernard V., Moss T., Marini J.C., Tudawe T., Seviour E.G., San Lucas F.A., Alvarez H., Gupta S., Maiti S.N., Cooper L., Peehl D., Ram P.T., Maitra A., Nagrath D. (2016) Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife. 5, e10250.
  210. Sansone P., Savini C., Kurelac I., Chang Q., Amato L.B., Strillacci A., Stepanova A., Iommarini L., Mastroleo C., Daly L., Galkin A., Thakur B.K., Soplop N., Uryu K., Hoshino A., Norton L., Bonafé M., Cricca M., Gasparre G., Lyden D., Bromberg J. (2017) Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl. Acad. Sci. USA. 114(43), E9066–E9075.
  211. Gonda A., Kabagwira J., Senthil G.N., Wall N.R. (2019) Internalization of exosomes through receptor-mediated endocytosis. Mol. Cancer Res. 17(2), 337–347.
  212. Yan W., Wu X., Zhou W., Fong M.Y., Cao M., Liu J., Liu X., Chen C.-H., Fadare O., Pizzo D.P., Wu J., Liu L., Liu X., Chin A.R., Ren X., Chen Y., Locasale J.W., Wang S.E. (2018) Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells. Nat. Cell. Biol. 20(5), 597–609.
  213. Martinez-Outschoorn U.E., Whitaker-Menezes D., Lin Z., Flomenberg N., Howell A., Pestell R.G., Lisanti M.P., Sotgia F. (2011) Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle. 10(11), 1784–1793.
  214. Whitaker-Menezes D., Martinez-Outschoorn U.E., Lin Z., Ertel A., Flomenberg N., Witkiewicz A.K., Birbe R.C., Howell A., Pavlides S., Gandara R., Pestell R.G., Sotgia F., Philp N.J., Lisanti M.P. (2011) Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer associated fibroblasts. Cell Cycle. 10(11), 1772–1783.
  215. Sotgia F., Martinez-Outschoorn U.E., Pavlides S., Howell A., Pestell R.G., Lisanti M.P. (2011) Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Res. 13(4), 213.
  216. Ullah M.S., Davies A.J., Halestrap A.P. (2006). The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1 alpha-dependent mechanism. J. Biol. Chem. 281(14), 9030–9037.
  217. Giatromanolaki A., Koukourakis M.I., Koutsopoulos A., Mendrinos S., Sivridis E. (2012) The metabolic interactions between tumor cells and tumor-associated stroma (TAS) in prostatic cancer. Cancer Biol. Ther. 13(13), 1284–1289.
  218. Witkiewicz A.K., Whitaker-Menezes D., Dasgupta A., Philp N.J., Lin Z., Gandara R., Sneddon S., Martinez-Outschoorn U.E., Sotgia F., Lisanti M.P. (2012) Using the “reverse Warburg effect” to identify high risk breast cancer patients: stromal MCT4 predicts poor clinical outcome in triple-negative breast cancers. Cell Cycle. 11(6), 1108–1117.
  219. Curry J.M., Tuluc M., Whitaker-Menezes D., Ames J.A., Anantharaman A., Butera A., Leiby B., Cognetti D.M., Sotgia F., Lisanti M.P., Martinez-Outschoorn U.E. (2013). Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle. 12(9), 1371–1384.
  220. Martinez-Outschoorn U.E., Lisanti M.P., Sotgia F. (2014) Catabolic cancer associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. Semin. Cancer Biol. 25, 47–60.
  221. Yang L., Achreja A., Yeung T.L., Mangala L.S., Jiang D., Han C., Baddour J., Marini J.C., Ni J., Nakahara R., Wahlig S., Chiba L., Kim S.H., Morse J., Pradeep S., Nagaraja A.S., Haemmerle M., Kyunghee N., Derichsweiler M., Plackemeier T., Mercado-Uribe I., Lopez-Berestein G., Moss T., Ram P.T., Liu J., Lu X., Mok S.C., Sood A.K., Nagrath D. (2016) Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell. Metab. 24(5), 685–700.
  222. Monti D., Sotgia F., Whitaker-Menezes D., Tuluc M., Birbe R., Berger A., Lazar M., Cotzia P., Draganova-Tacheva R., Lin Z., Domingo-Vidal M., Newberg A., Lisanti M.P., Martinez-Outschoorn U. (2017) Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-acetylcysteine in breast cancer. Semin. Oncol. 44(3), 226–232.
  223. Zhang Y., Wei J., Xu J., Leong W.S., Liu G., Ji T., Cheng Z., Wang J., Lang J., Zhao Y., You L., Zhao X., Wei T., Anderson G.J., Qi S., Kong J., Nie G., Li S. (2018). Suppression of tumor energy supply by liposomal nanoparticle-mediated inhibition of aerobic glycolysis. ACS Appl. Mater. Interfaces. 10(3), 2347–2353.
  224. Huang W., Zhang L., Yang M., Wu X., Wang X., Huang W., Yuan L., Pan H., Wang Y., Wang Z., Wu Y., Huang J., Liang H., Li S., Liao L., Liu L., Guan J. (2021) Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway. J. Exp. Clin. Cancer Res. 40(1), 87.
  225. Chen X., Song E. (2019) Turning foes to friends: targeting cancer-associated fibroblasts. Nat. Rev. Drug Discov. 18(2), 99–115.
  226. Louault K., Bonneaud T.L., Séveno C., Gomez-Bougie P., Nguyen F., Gautier F., Bourgeois N., Loussouarn D., Kerdraon O., Barillé-Nion S., Jézéquel P., Campone M., Amiot M., Juin P.P., Souazé F. (2019) Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers. Oncogene. 38(17), 3261–3273.
  227. Zhang L., Yao J., Li W., Zhang C. (2018) Micro-RNA-21 regulates cancer-associated fibroblast-mediated drug resistance in pancreatic cancer. Oncol. Res. 26(6), 827–835.
  228. Lotti F., Jarrar A.M., Pai R.K., Hitomi M., Lathia J., Mace A., Gantt Jr G.A., Sukhdeo K., DeVecchio J., Vasanji A., Leahy P., Hjelmeland A.B., Kalady M.F., Rich J.N. (2013) Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J. Exp. Med. 210(13), 2851–2872.
  229. Kadel D., Zhang Y., Sun H.-R., Zhao Y., Dong Q.-Z., Qin L.X. (2019) Current perspectives of cancer-associated fibroblast in therapeutic resistance: potential mechanism and future strategy. Cell Biol. Toxicol. 35(5), 407–421.
  230. Mutgan A.C., Besikcioglu H.E., Wang S., Friess H., Ceyhan G.O., Demir I.E. (2018) Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. Mol. Cancer. 17(1), 66.
  231. Borriello L., Nakata R., Sheard M.A., Fernandez G.E., Sposto R., Malvar J., Blavier L., Shimada H., Asgharzadeh S., Seeger R.C., DeClerck Y.A. (2017) Cancer-associated fibroblasts share characteristics and protumorigenic activity with mesenchymal stromal cells. Cancer Res. 77(18), 5142–5157.
  232. Guo H., Ha C., Dong H., Yang Z., Ma Y., Ding Y. (2019) Cancer-associated fibroblast-derived exosomal microRNA-98-5p promotes cisplatin resistance in ovarian cancer by targeting CDKN1A. Cancer Cell Int. 19, 347.
  233. Zhang H., Deng T., Liu R., Ning T., Yang H., Liu D., Zhang Q., Lin D., Ge S., Bai M., Wang X., Zhang L., Li H., Yang Y., Ji Z., Wang H., Ying G., Ba Y. (2020) CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol. Cancer. 19(1), 43.
  234. Shiga K., Hara M., Nagasaki T., Sato T., Takahashi H., Takeyama H. (2015) Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel). 7(4), 2443–2458.
  235. Laklai H., Miroshnikova Y.A., Pickup M.W., Collisson E.A., Kim G.E., Barrett A.S., Hill R.C., Lakins J.N., Schlaepfer D.D., Mouw J.K., LeBleu V.S., Roy N., Novitskiy S.V., Johansen J.S., Poli V., Kalluri R., Iacobuzio-Donahue C.A., Wood L.D., Hebrok M., Hansen K., Moses H.L., Weaver V.M. (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22(5), 497–505.
  236. Busch S., Acar A., Magnusson Y., Gregersson P., Rydén L., Landberg G. (2015) TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer. Oncogene. 34(1), 27–38.
  237. Provenzano P.P., Cuevas C., Chang A.E., Goel V.K., Von Ho D.D., Hingorani S.R. (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 21(3), 418–429.
  238. Kobayashi H., Enomoto A., Woods S.L., Burt A.D., Takahashi M., Worthley D.L. (2019) Cancer-associated fibroblasts in gastrointestinal cancer. Nat. Rev. Gastroenterol. Hepatol. 16(5), 282–295.
  239. Luga V., Zhang L., Viloria-Petit A.M., Ogunjimi A.A., Inanlou M.R., Chiu E., Buchanan M., Hosein A.N., Basik M., Wrana J.L. (2012) Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 151(7), 1542–1556.
  240. Webber J.P., Spary L.K., Sanders A.J., Chowdhury R., Jiang W.G., Steadman R., Wymant J., Jones A.T., Kynaston H., Mason M.D., Tabi Z., Clayton A. (2015) Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene. 34(3), 290–302.
  241. Richards K.E., Zeleniak A.E., Fishel M.L., Wu J., Littlepage L.E., Hill R. (2017) Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 36(13), 1770–1778.
  242. Giusti I., DiFrancesco M., D’ascenzo S., Palmerini M.G., Macchiarelli G., Carta G., Dolo V. (2018) Ovarian cancer-derived extracellular vesicles affect normal human fibroblast behavior. Cancer Biol. Ther. 19(8), 722–734.
  243. Bellei B., Migliano E., Picardo M. (2020) A framework of major tumor-promoting signal transduction pathways implicated in melanoma-fibroblast dialogue. Cancers (Basel). 12(11), 3400.

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