journal article
Feb 28, 2022
Cancer-associated fibroblasts and their role in tumor progression
Vavilov Journal of Genetics and Breeding
Vol. 26
No. 1
pp. 14-21
·
Institute of Cytology and Genetics, SB RAS
Abstract
The stromal elements of a malignant tumor can promote cancer progression and metastasis. The structure of the tumor stroma includes connective tissue elements, blood vessels, nerves, and extracellular matrix (ECM). Some of the cellular elements of the tumor stroma are cancer-associated fibroblasts (CAFs). The origin and function of CAFs have been actively studied over the past thirty years. CAFs produce collagen, the main scaffold protein of the extracellular matrix. Collagen in the tumor stroma stimulates fibrosis, enhances the rigidity of tumor tissue, and disrupts the transmission of proliferation and differentiation signaling pathways. CAFs control tumor angiogenesis, cell motility, tumor immunogenic properties, and the development of resistance to chemo- and immunotherapy. As a result of metabolic adaptation of rapidly growing tumor tissue to the nutrients and oxygen deprivation, the main type of energy production in cells changes from oxidative phosphorylation to anaerobic glycolysis. These changes lead to sequential molecular alterations, including the induction of specified transcriptional factors that result in the CAFs activation. The molecular phenotype of activated CAFs is similar to fibroblasts activated during inflammation. In activated CAFs, alpha-smooth muscle actin (α-SMA) is synthetized de novo and various proteases and fibronectin are produced. Since CAFs are found in all types of carcinomas, these cells are potential targets for the development of new approaches for anticancer therapy. Some CAFs originate from resident fibroblasts of the organs invaded by the tumor, while others originate from epithelial tumor cells, which are undergoing an epithelial-mesenchymal transition (EMT). To date, many molecular and metabolic inducers of the EMT have been discovered including the transforming growth factor-beta (TGF-β), hypoxia, and inflammation. This review classifies modern concepts of molecular markers of CAFs, their functional features, and discusses the stages of epithelial-mesenchymal transition, and the potential of CAFs as a target for antitumor therapy.
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References
64
[1]
Alkasalias T., Moyano-Galceran L., Arsenian-Henriksson M., Lehti K. Fibroblasts in the tumor microenvironment: shield or spear? Int. J. Mol. Sci. 2018;19(5):1532. DOI 10.3390/ijms19051532.
10.3390/ijms19051532
[2]
Al-Mahmood S., Sapiezynski J., Garbuzenko O.B., Minko T. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv. Transl. Res. 2018;8(5):1483-1507. DOI 10.1007/ s13346-018-0551-3.
10.1007/s13346-018-0551-3
[3]
Ambartsumian N., Klingelhöfer J., Grigorian M. The multifaceted S100A4 protein in cancer and inflammation. In: Heizmann C. (Ed.). Calcium-Binding Proteins of the EF-Hand Superfamily: From Basics to Medical Applications. (Ser. Methods in Molecular Biology). New York: Humana Press, 2019;1929:339-365. DOI 10.1007/978- 1-4939-9030-6_22.
10.1007/978-1-4939-9030-6_22
[4]
Anderberg C., Li H., Fredriksson L., Andrae J., Betsholtz C., Li X., Eriksson U., Pietras K. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 2009;69(1):369-378. DOI 10.1158/0008-5472.CAN-08-2724.
10.1158/0008-5472.can-08-2724
[5]
Bochet L., Lehuede C., Dauvillier S., Wang Y.Y., Dirat B., Laurent V., Dray C., Guiet R., Maridonneau-Parini I., Le Gonidec S., Couderc B., Escourrou G., Valet P., Muller C. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 2013;73(18):5657-5668. DOI 10.1158/0008-5472.CAN-13-0530.
10.1158/0008-5472.can-13-0530
[6]
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. Dualism of FGF and TGF-β signaling in heterogeneous cancer-associated fibroblast activation with ETV1 as a critical determinant. Cell Rep. 2019;28(9):2358-2372.e6. DOI 10.1016/j.celrep.2019.07.092.
10.1016/j.celrep.2019.07.092
[7]
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. Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin. Cancer Res. 2017;23(7):1710-1721. DOI 10.1158/1078-0432.CCR-15-2851.
10.1158/1078-0432.ccr-15-2851
[8]
Bu L., Baba H., Yoshida N., Miyake K., Yasuda T., Uchihara T., Tan P., Ishimoto T. Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene. 2019; 38(25):4887-4901. DOI 10.1038/s41388-019-0765-y.
10.1038/s41388-019-0765-y
[9]
Calon A., Tauriello D.V.F., Batlle E. TGF-beta in CAF-mediated tumor growth and metastasis. Semin. Cancer Biol. 2014;25:15-22. DOI 10.1016/j.semcancer.2013.12.008.
10.1016/j.semcancer.2013.12.008
[10]
Chen C., Zhang R., Ma L., Li Q., Zhao Y., Zhang G., Zhang D., Li W., Cao S., Wang L., Geng Z. Neuropilin-1 is up-regulated by cancerassociated fibroblast-secreted IL-8 and associated with cell proliferation of gallbladder cancer. J. Cell. Mol. Med. 2020;24(21):12608- 12618. DOI 10.1111/jcmm.15825.
10.1111/jcmm.15825
[11]
Chen Z., Gao H., Dong Z., Shen Y., Wang Z., Wei W., Yi J., Wang R., Wu N., Jin S. NRP1 regulates radiation-induced EMT via TGF-β/ Smad signaling in lung adenocarcinoma cells. Int. J. Radiat. Biol. 2020;96(10):1281-1295. DOI 10.1080/09553002.2020.1793015.
10.1080/09553002.2020.1793015
[12]
Dang T.T., Prechtl A.M., Pearson G.W. Breast cancer subtype-specific interactions with the microenvironment dictate mechanisms of invasion. Cancer Res. 2011;71(21):6857-6866. DOI 10.1158/0008- 5472.CAN-11-1818.
10.1158/0008-5472.can-11-1818
[13]
Fei F., Qu J., Zhang M., Li Y., Zhang S. S100A4 in cancer progression and metastasis: a systematic review. Oncotarget. 2017;8(42):73219- 73239. DOI 10.18632/oncotarget.18016.
10.18632/oncotarget.18016
[14]
Franzè E., Di Grazia A., Sica G.S., Biancone L., Laudisi F., Monteleone G. Interleukin-34 enhances the tumor promoting function of colorectal cancer-associated fibroblasts. Cancers. 2020;12(12):3537. DOI 10.3390/cancers12123537.
10.3390/cancers12123537
[15]
Glentis A., Oertle P., Mariani P., Chikina A., El Marjou F., Attieh Y., Zaccarini F., Lae M., Loew D., Dingli F., Sirven P., Schoumacher M., Gurchenkov B.G., Plodinec M., Vignjevic D.M. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 2017;8(1):924. DOI 10.1038/s41467-017-00985-8.
10.1038/s41467-017-00985-8
[16]
Goetz J.G., Minguet S., Navarro-Lérida I., Lazcano J.J., Samaniego R., Calvo E., Tello M., Osteso-Ibáñez T., Pellinen T., Echarri A., Cerezo A., Klein-Szanto A.J.P., Garcia R., Keely P.J., Sánchez-Mateos P., Cukierman E., Del Pozo M.A. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell. 2011;146(1):148-163. DOI 10.1016/j.cell.2011.05. 040.
10.1016/j.cell.2011.05.040
[17]
Gonzalez-Avila G., Sommer B., Mendoza-Posada D.A., Ramos C., Garcia-Hernandez A.A., Falfan-Valencia R. Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit. Rev. Oncol. Hematol. 2019; 137:57-83. DOI 10.1016/j.critrevonc.2019.02.010.
10.1016/j.critrevonc.2019.02.010
[18]
Grantham J. The molecular chaperone CCT/TRiC: an essential component of proteostasis and a potential modulator of protein aggregation. Front. Genet. 2020;11:172. DOI 10.3389/fgene.2020.00172.
10.3389/fgene.2020.00172
[19]
Grum-Schwensen B., Klingelhöfer J., Beck M., Bonefeld C.M., Hamerlik P., Guldberg P., Grigorian M., Lukanidin E., Ambartsumian N. S100A4-neutralizing antibody suppresses spontaneous tumor progression, pre-metastatic niche formation and alters T-cell polarization balance. BMC Cancer. 2015;15(1):44. DOI 10.1186/ s12885-015-1034-2.
10.1186/s12885-015-1034-2
[20]
Grum-Schwensen B., Klingelhofer J., Berg C.H., El-Naaman C., Grigorian M., Lukanidin E., Ambartsumian N. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. Cancer Res. 2005;65(9):3772-3780. DOI 10.1158/0008-5472. CAN-04-4510.
10.1158/0008-5472.can-04-4510
[21]
Hosein A.N., Wu M., Arcand S.L., Lavallée S., Hébert J., Tonin P.N., Basik M. Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations. Cancer Res. 2010; 70(14):5770-5777. DOI 10.1158/0008-5472.CAN-10-0673.
10.1158/0008-5472.can-10-0673
[22]
Huang Yingying, Zhou S., Huang Yong, Zheng D., Mao Q., He J., Wang Y., Xue D., Lu X., Yang N., Zhao Y. Isolation of fibroblast-activation protein-specific cancer-associated fibroblasts. BioMed Res. Int. 2017;2017:4825108. DOI 10.1155/2017/4825108.
10.1155/2017/4825108
[23]
Jansson S., Aaltonen K., Bendahl P.-O., Falck A.-K., Karlsson M., Pietras K., Rydén L. The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence. Breast Cancer Res. Treat. 2018;169(2):231-241. DOI 10.1007/ s10549-018-4664-7.
10.1007/s10549-018-4664-7
[24]
Microenvironmental regulation of metastasis
Johanna A. Joyce, Jeffrey W. Pollard
Nature Reviews Cancer
10.1038/nrc2618
[25]
Jung Y., Kim J.K., Shiozawa Y., Wang Jingcheng, Mishra A., Joseph J., Berry J.E., McGee S., Lee E., Sun H., Wang Jianhua, Jin T., Zhang H., Dai J., Krebsbach P.H., Keller E.T., Pienta K.J., Taichman R.S. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat. Commun. 2013;4(1):1795. DOI 10.1038/ncomms2766.
10.1038/ncomms2766
[26]
Kim D., Xing T., Yang Z., Dudek R., Lu Q., Chen Y.-H. Epithelial mesenchymal transition in embryonic development, tissue repair and cancer: a comprehensive overview. J. Clin. Med. 2017;7(1):1. DOI 10.3390/jcm7010001.
10.3390/jcm7010001
[27]
Cancer-Associated Fibroblast Density, Prognostic Characteristics, and Recurrence in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis
Alexander M. Knops, Andrew South, Ulrich Rodeck et al.
Frontiers in Oncology
10.3389/fonc.2020.565306
[28]
Liotta L.A., Kohn E.C. The microenvironment of the tumour–host interface. Nature. 2001;411(6835):375-379. DOI 10.1038/35077241.
10.1038/35077241
[29]
Liu B., Pan S., Liu J., Kong C. Cancer-associated fibroblasts and the related Runt-related transcription factor 2 (RUNX2) promote bladder cancer progression. Gene. 2021;775:145451. DOI 10.1016/j.gene. 2021.145451.
10.1016/j.gene.2021.145451
[30]
Lobba A.R.M., Carreira A.C.O., Cerqueira O.L.D., Fujita A., DeOcesano-Pereira C., Osorio C.A.B., Soares F.A., Rameshwar P., Sogayar M.C. High CD90 (THY-1) expression positively correlates with cell transformation and worse prognosis in basal-like breast cancer tumors. PLoS One. 2018;13(6):e0199254. DOI 10.1371/journal. pone.0199254.
10.1371/journal.pone.0199254
[31]
Fibroblast heterogeneity: implications for human disease
Magnus D. Lynch, Fiona M. Watt
Journal of Clinical Investigation
10.1172/jci93555
[32]
Madar S., Brosh R., Buganim Y., Ezra O., Goldstein I., Solomon H., Kogan I., Goldfinger N., Klocker H., Rotter V. Modulated expression of WFDC1 during carcinogenesis and cellular senescence. Carcinogenesis. 2009;30(1):20-27. DOI 10.1093/carcin/bgn232.
10.1093/carcin/bgn232
[33]
Marlow R., Strickland P., Lee J.S., Wu X., Pebenito M., Binnewies M., Le E.K., Moran A., Macias H., Cardiff R.D., Sukumar S., Hinck L. SLITs suppress tumor growth in vivo by silencing Sdf1/Cxcr4 within breast epithelium. Cancer Res. 2008;68(19):7819-7827. DOI 10.1158/0008-5472.CAN-08-1357.
10.1158/0008-5472.can-08-1357
[34]
Massagué J. TGFβ in cancer. Cell. 2008;134(2):215-230. DOI 10.1016/ j.cell.2008.07.001.
10.1016/j.cell.2008.07.001
[35]
Mossahebi-Mohammadi M., Quan M., Zhang J.-S., Li X. FGF signaling pathway: a key regulator of stem cell pluripotency. Front. Cell Dev. Biol. 2020;8:79. DOI 10.3389/fcell.2020.00079.
10.3389/fcell.2020.00079
[36]
Mukaida N., Sasaki S. Fibroblasts, an inconspicuous but essential player in colon cancer development and progression. World J. Gastroenterol. 2016;22(23):5301. DOI 10.3748/wjg.v22.i23.5301.
10.3748/wjg.v22.i23.5301
[37]
Nushtaeva A.A., Karpushina A.A., Ermakov M.S., Gulyaeva L.F., Gerasimov A.V., Sidorov S.V., Gayner T.A., Yunusova A.Y., Tkachenko A.V., Richter V.A., Koval O.A. Establishment of primary human breast cancer cell lines using “pulsed hypoxia” method and development of metastatic tumor model in immunodeficient mice. Cancer Cell Int. 2019;19(1):46. DOI 10.1186/s12935-019-0766-5.
10.1186/s12935-019-0766-5
[38]
Nushtaeva A.A., Stepanov G.A., Semenov D.V., Juravlev E.S., Balahonova E.A., Gerasimov A.V., Sidorov S.V., Savelyev E.I., Kuligina E.V., RichterV.A., Koval O.A. Characterization of primary normal and malignant breast cancer cell and their response to chemotherapy and immunostimulatory agents. BMC Cncer. 2018;18(1):728. DOI 10.1186/s12885-018-4635-8.
10.1186/s12885-018-4635-8
[39]
Orimo A., Weinberg R.A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle. 2006;5(15):1597-1601. DOI 10.4161/cc.5.15.3112.
10.4161/cc.5.15.3112
[40]
Patel A.K., Vipparthi K., Thatikonda V., Arun I., Bhattacharjee S., Sharan R., Arun P., Singh S. A subtype of cancer-associated fibroblasts with lower expression of alpha-smooth muscle actin suppresses stemness through BMP4 in oral carcinoma. Oncogenesis. 2018; 7(10):78. DOI 10.1038/s41389-018-0087-x.
10.1038/s41389-018-0087-x
[41]
Puré E., Hingorani S.R. Mesenchymal cell plasticity and perfidy in epithelial malignancy. Trends Cancer. 2018;4(4):273-277. DOI 10.1016/j.trecan.2018.02.007.
10.1016/j.trecan.2018.02.007
[42]
Rhim A.D., Oberstein P.E., Thomas D.H., Mirek E.T., Palermo C.F., Sastra S.A., Dekleva E.N., Saunders T., Becerra C.P., Tattersall I.W., Westphalen C.B., Kitajewski J., Fernandez-Barrena M.G., Fernandez-Zapico M.E., Iacobuzio-Donahue C., Olive K.P., Stanger B.Z. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735-747. DOI 10.1016/j.ccr.2014.04.021.
10.1016/j.ccr.2014.04.021
[43]
Rønnov-Jessen L., Petersen O.W., Koteliansky V.E., Bissell M.J. 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. Invest. 1995;95(2):859-873. DOI 10.1172/JCI117736.
10.1172/jci117736
[44]
The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy
Ruth Scherz-Shouval, Sandro Santagata, Marc L. Mendillo et al.
Cell
10.1016/j.cell.2014.05.045
[45]
Sha M., Jeong S., Qiu B., Tong Y., Xia L., Xu N., Zhang J., Xia Q. Isolation of cancer-associated fibroblasts and its promotion to the progression of intrahepatic cholangiocarcinoma. Cancer Med. 2018; 7(9):4665-4677. DOI 10.1002/cam4.1704.
10.1002/cam4.1704
[46]
Sharon Y., Alon L., Glanz S., Servais C., Erez N. Isolation of normal and cancer-associated fibroblasts from fresh tissues by Fluorescence Activated Cell Sorting (FACS). J. Vis. Exp. 2013;71:4425. DOI 10.3791/4425.
10.3791/4425
[47]
Taddei M.L., Cavallini L., Comito G., Giannoni E., Folini M., Marini A., Gandellini P., Morandi A., Pintus G., Raspollini M.R., Zaffaroni N., Chiarugi P. Senescent stroma promotes prostate cancer progression: the role of miR-210. Mol. Oncol. 2014;8(8):1729-1746. DOI 10.1016/j.molonc.2014.07.009.
10.1016/j.molonc.2014.07.009
[48]
Tam S.Y., Wu V.W.C., Law H.K.W. Hypoxia-induced epithelial-mesenchymal transition in cancers: HIF-1α and beyond. Front. Oncol. 2020;10:468. DOI 10.3389/fonc.2020.00486.
10.3389/fonc.2020.00486
[49]
Tripathi M., Billet S., Bhowmick N.A. Understanding the role of stromal fibroblasts in cancer progression. Cell Adh. Migr. 2012;6(3): 231-235. DOI 10.4161/cam.20419.
10.4161/cam.20419
[50]
True L.D., Zhang H., Ye M., Huang C.-Y., Nelson P.S., von Haller P.D., Tjoelker L.W., Kim J.-S., Qian W.-J., Smith R.D., Ellis W.J., Liebeskind E.S., Liu A.Y. CD90/THY1 is overexpressed in prostate cancerassociated fibroblasts and could serve as a cancer biomarker. Mod. Pathol. 2010;23(10):1346-1356. DOI 10.1038/modpathol.2010.122.
10.1038/modpathol.2010.122
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- Published
- Feb 28, 2022
- Vol/Issue
- 26(1)
- Pages
- 14-21
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Cite This Article
M. S. Ermakov, A. A. Nushtaeva, V. A. Richter, et al. (2022). Cancer-associated fibroblasts and their role in tumor progression. Vavilov Journal of Genetics and Breeding, 26(1), 14-21. https://doi.org/10.18699/vjgb-22-03
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