Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy
Abstract
:Simple Summary
Abstract
1. Introduction
2. Definitions, Origins and Basic Biology of CAFs
2.1. Definition of CAFs
2.2. Distinction of CAFs from Resting Fibroblasts
2.3. Origin of CAFs
2.4. CAF Phenotypic and Functional Heterogeneity
2.5. Functional CAF Subsets in Human Cancers
2.6. Functional CAF Subsets in Murine Cancers
2.7. Challenges in Defining and Detecting CAFs
3. Protumorigenic Functions of CAFs
3.1. Tumor-Promoting Secretory Factors
3.2. Resistance to Chemotherapies and Radiation
3.3. Immunomodulatory Role of CAFs
4. Targeting CAFs: Anti-Cancer Therapies
4.1. Chemotherapy Targeting CAFs
4.2. Immunotherapy
4.3. Functional Modification/Reprogramming
5. Future Perspectives
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef] [PubMed]
- D’Arcangelo, E.; Wu, N.C.; Cadavid, J.L.; McGuigan, A.P. The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome. Br. J. Cancer 2020, 122, 931–942. [Google Scholar] [CrossRef]
- Monteran, L.; Erez, N. The dark side of fibroblasts: Cancer-associated fibroblasts as mediators of immunosuppression in the tumor microenvironment. Front. Immunol. 2019, 10, 1835. [Google Scholar] [CrossRef]
- Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186. [Google Scholar] [CrossRef] [PubMed]
- Belhabib, I.; Zaghdoudi, S.; Lac, C.; Bousquet, C.; Jean, C. Extracellular matrices and cancer-associated fibroblasts: Targets for cancer diagnosis and therapy? Cancers 2021, 13, 3466. [Google Scholar] [CrossRef]
- Valkenburg, K.C.; de Groot, A.E.; Pienta, K.J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 2018, 15, 366–381. [Google Scholar] [CrossRef] [PubMed]
- Pankova, D.; Chen, Y.; Terajima, M.; Schliekelman, M.J.; Baird, B.N.; Fahrenholtz, M.; Sun, L.; Gill, B.J.; Vadakkan, T.J.; Kim, M.P.; et al. Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma. Mol. Cancer Res. 2016, 14, 287–295. [Google Scholar] [CrossRef] [PubMed]
- Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 2016, 16, 582–598. [Google Scholar] [CrossRef] [PubMed]
- Ao, Z.; Shah, S.H.; Machlin, L.M.; Parajuli, R.; Miller, P.C.; Rawal, S.; Williams, A.J.; Cote, R.J.; Lippman, M.E.; Datar, R.H.; et al. Identification of cancer-associated fibroblasts in circulating blood from patients with metastatic breast cancer. Cancer Res. 2015, 75, 4681–4687. [Google Scholar] [CrossRef]
- Lindner, U.; Kramer, J.; Rohwedel, J.; Schlenke, P. Mesenchymal stem or stromal cells: Toward a better understanding of their biology? Transfus. Med. Hemother. 2010, 37, 75–83. [Google Scholar] [CrossRef] [PubMed]
- Paunescu, V.; Bojin, F.M.; Tatu, C.A.; Gavriliuc, O.I.; Rosca, A.; Gruia, A.T.; Tanasie, G.; Bunu, C.; Crisnic, D.; Gherghiceanu, M.; et al. Tumour-associated fibroblasts and mesenchymal stem cells: More similarities than differences. J. Cell Mol. Med. 2011, 15, 635–646. [Google Scholar] [CrossRef] [PubMed]
- Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef] [PubMed]
- Helms, E.; Onate, M.K.; Sherman, M.H. Fibroblast heterogeneity in the pancreatic tumor microenvironment. Cancer Discov. 2020, 10, 648–656. [Google Scholar] [CrossRef]
- Norton, J.; Foster, D.; Chinta, M.; Titan, A.; Longaker, M. Pancreatic cancer associated fibroblasts (CAF): Under-explored target for pancreatic cancer treatment. Cancers 2020, 12, 1347. [Google Scholar] [CrossRef]
- Liu, T.; Han, C.; Wang, S.; Fang, P.; Ma, Z.; Xu, L.; Yin, R. Cancer-associated fibroblasts: An emerging target of anti-cancer immunotherapy. J. Hematol. Oncol. 2019, 12, 86. [Google Scholar] [CrossRef]
- Long, K.B.; Tooker, G.; Tooker, E.; Luque, S.L.; Lee, J.W.; Pan, X.; Beatty, G.L. IL6 receptor blockade enhances chemotherapy efficacy in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 2017, 16, 1898–1908. [Google Scholar] [CrossRef] [PubMed]
- Jia, C.; Wang, G.; Wang, T.; Fu, B.; Zhang, Y.; Huang, L.; Deng, Y.; Chen, G.; Wu, X.; Chen, J.; et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition via the transglutaminase 2-dependent IL-6/IL6R/STAT3 axis in hepatocellular carcinoma. Int. J. Biol. Sci. 2020, 16, 2542–2558. [Google Scholar] [CrossRef] [PubMed]
- Sun, Q.; Zhang, B.; Hu, Q.; Qin, Y.; Xu, W.; Liu, W.; Yu, X.; Xu, J. The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. Theranostics 2018, 8, 5072–5087. [Google Scholar] [CrossRef] [PubMed]
- Lohr, M.; Schmidt, C.; Ringel, J.; Kluth, M.; Muller, P.; Nizze, H.; Jesnowski, R. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001, 61, 550–555. [Google Scholar] [PubMed]
- Aoyagi, Y.; Oda, T.; Kinoshita, T.; Nakahashi, C.; Hasebe, T.; Ohkohchi, N.; Ochiai, A. Overexpression of TGF-beta by infiltrated granulocytes correlates with the expression of collagen mRNA in pancreatic cancer. Br. J. Cancer 2004, 91, 1316–1326. [Google Scholar] [CrossRef] [PubMed]
- Erez, N.; Truitt, M.; Olson, P.; Arron, S.T.; Hanahan, D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell 2010, 17, 135–147. [Google Scholar] [CrossRef] [PubMed]
- Ringuette Goulet, C.; Bernard, G.; Tremblay, S.; Chabaud, S.; Bolduc, S.; Pouliot, F. Exosomes induce fibroblast differentiation into cancer-associated fibroblasts through TGFbeta signaling. Mol. Cancer Res. 2018, 16, 1196–1204. [Google Scholar] [CrossRef] [PubMed]
- Yeon, J.H.; Jeong, H.E.; Seo, H.; Cho, S.; Kim, K.; Na, D.; Chung, S.; Park, J.; Choi, N.; Kang, J.Y. Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the induction of cancer-associated fibroblasts. Acta Biomater. 2018, 76, 146–153. [Google Scholar] [CrossRef]
- LeBleu, V.S.; Taduri, G.; O’Connell, J.; Teng, Y.; Cooke, V.G.; Woda, C.; Sugimoto, H.; Kalluri, R. Origin and function of myofibroblasts in kidney fibrosis. Nat. Med. 2013, 19, 1047–1053. [Google Scholar] [CrossRef]
- Driskell, R.R.; Lichtenberger, B.M.; Hoste, E.; Kretzschmar, K.; Simons, B.D.; Charalambous, M.; Ferron, S.R.; Herault, Y.; Pavlovic, G.; Ferguson-Smith, A.C.; et al. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 2013, 504, 277–281. [Google Scholar] [CrossRef]
- Hanahan, D. Hallmarks of cancer: New dimensions. Cancer Discov. 2022, 12, 31–46. [Google Scholar] [CrossRef]
- Nurmik, M.; Ullmann, P.; Rodriguez, F.; Haan, S.; Letellier, E. In search of definitions: Cancer-associated fibroblasts and their markers. Int. J. Cancer 2020, 146, 895–905. [Google Scholar] [CrossRef]
- Ping, Q.; Yan, R.; Cheng, X.; Wang, W.; Zhong, Y.; Hou, Z.; Shi, Y.; Wang, C.; Li, R. Cancer-associated fibroblasts: Overview, progress, challenges, and directions. Cancer Gene Ther. 2021, 28, 984–999. [Google Scholar] [CrossRef]
- Togo, S.; Polanska, U.M.; Horimoto, Y.; Orimo, A. Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers 2013, 5, 149–169. [Google Scholar] [CrossRef]
- 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.; et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 20212–20217. [Google Scholar] [CrossRef]
- 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. 2014, 2, 121–126. [Google Scholar] [CrossRef] [PubMed]
- Lo, A.; Wang, L.S.; Scholler, J.; Monslow, J.; Avery, D.; Newick, K.; O’Brien, S.; Evans, R.A.; Bajor, D.J.; Clendenin, C.; et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 2015, 75, 2800–2810. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Lin, Y.; Shi, Y.; Li, B.; Liu, W.; Yin, W.; Dang, Y.; Chu, Y.; Fan, J.; He, R. FAP Promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling. Cancer Res. 2016, 76, 4124–4135. [Google Scholar] [CrossRef]
- Farahani, R.M.; Xaymardan, M. Platelet-derived growth factor receptor alpha as a marker of mesenchymal stem cells in development and stem cell biology. Stem Cells Int. 2015, 2015, 362753. [Google Scholar] [CrossRef]
- Sugimoto, H.; Mundel, T.M.; Kieran, M.W.; Kalluri, R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol. Ther. 2006, 5, 1640–1646. [Google Scholar] [CrossRef]
- Kitano, H.; Kageyama, S.; Hewitt, S.M.; Hayashi, R.; Doki, Y.; Ozaki, Y.; Fujino, S.; Takikita, M.; Kubo, H.; Fukuoka, J. Podoplanin expression in cancerous stroma induces lymphangiogenesis and predicts lymphatic spread and patient survival. Arch. Pathol. Lab. Med. 2010, 134, 1520–1527. [Google Scholar] [CrossRef]
- Astarita, J.L.; Acton, S.E.; Turley, S.J. Podoplanin: Emerging functions in development, the immune system, and cancer. Front. Immunol. 2012, 3, 283. [Google Scholar] [CrossRef]
- Kerrigan, A.M.; Navarro-Nuñez, L.; Pyz, E.; Finney, B.A.; Willment, J.A.; Watson, S.P.; Brown, G.D. Podoplanin-expressing inflammatory macrophages activate murine platelets via CLEC-2. J. Thromb. Haemost. 2012, 10, 484–486. [Google Scholar] [CrossRef]
- Shindo, K.; Aishima, S.; Ohuchida, K.; Fujiwara, K.; Fujino, M.; Mizuuchi, Y.; Hattori, M.; Mizumoto, K.; Tanaka, M.; Oda, Y. Podoplanin expression in cancer-associated fibroblasts enhances tumor progression of invasive ductal carcinoma of the pancreas. Mol. Cancer 2013, 12, 168. [Google Scholar] [CrossRef]
- Augsten, M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front. Oncol. 2014, 4, 62. [Google Scholar] [CrossRef]
- Zhu, C.Q.; Popova, S.N.; Brown, E.R.; Barsyte-Lovejoy, D.; Navab, R.; Shih, W.; Li, M.; Lu, M.; Jurisica, I.; Penn, L.Z.; et al. Integrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. Proc. Natl. Acad. Sci. USA 2007, 104, 11754–11759. [Google Scholar] [CrossRef] [PubMed]
- Blandin, A.F.; Renner, G.; Lehmann, M.; Lelong-Rebel, I.; Martin, S.; Dontenwill, M. β1 integrins as therapeutic targets to disrupt hallmarks of cancer. Front. Pharmacol. 2015, 6, 279. [Google Scholar] [CrossRef] [PubMed]
- Navab, R.; Strumpf, D.; To, C.; Pasko, E.; Kim, K.S.; Park, C.J.; Hai, J.; Liu, J.; Jonkman, J.; Barczyk, M.; et al. Integrin α11β1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer. Oncogene 2016, 35, 1899–1908. [Google Scholar] [CrossRef] [PubMed]
- Zeltz, C.; Primac, I.; Erusappan, P.; Alam, J.; Noel, A.; Gullberg, D. Cancer-associated fibroblasts in desmoplastic tumors: Emerging role of integrins. Semin. Cancer Biol. 2020, 62, 166–181. [Google Scholar] [CrossRef]
- Costa, A.; Kieffer, Y.; Scholer-Dahirel, A.; Pelon, F.; Bourachot, B.; Cardon, M.; Sirven, P.; Magagna, I.; Fuhrmann, L.; Bernard, C.; et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 2018, 33, 463–479. [Google Scholar] [CrossRef]
- 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. 2012, 227, 490–498. [Google Scholar] [CrossRef]
- Chen, D.; Che, G. Value of caveolin-1 in cancer progression and prognosis: Emphasis on cancer-associated fibroblasts, human cancer cells and mechanism of caveolin-1 expression (review). Oncol. Lett. 2014, 8, 1409–1421. [Google Scholar] [CrossRef]
- Shimizu, K.; Kirita, K.; Aokage, K.; Kojima, M.; Hishida, T.; Kuwata, T.; Fujii, S.; Ochiai, A.; Funai, K.; Yoshida, J.; et al. Clinicopathological significance of caveolin-1 expression by cancer-associated fibroblasts in lung adenocarcinoma. J. Cancer Res. Clin. Oncol. 2017, 143, 321–328. [Google Scholar] [CrossRef]
- Scatena, C.; Fanelli, G.; Fanelli, G.N.; Menicagli, M.; Aretini, P.; Ortenzi, V.; Civitelli, S.P.; Innocenti, L.; Sotgia, F.; Lisanti, M.P.; et al. New insights in the expression of stromal caveolin 1 in breast cancer spread to axillary lymph nodes. Sci. Rep. 2021, 11, 2755. [Google Scholar] [CrossRef]
- Su, S.; Chen, J.; Yao, H.; Liu, J.; Yu, S.; Lao, L.; Wang, M.; Luo, M.; Xing, Y.; Chen, F.; et al. CD10(+)GPR77(+) Cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 2018, 172, 841–856.e16. [Google Scholar] [CrossRef]
- Biffi, G.; Oni, T.E.; Spielman, B.; Hao, Y.; Elyada, E.; Park, Y.; Preall, J.; Tuveson, D.A. IL1-induced JAK/STAT signaling is antagonized by TGFbeta to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 2019, 9, 282–301. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Cross-Species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 2019, 9, 1102–1123. [Google Scholar] [CrossRef] [PubMed]
- Kisselbach, L.; Merges, M.; Bossie, A.; Boyd, A. CD90 Expression on human primary cells and elimination of contaminating fibroblasts from cell cultures. Cytotechnology 2009, 59, 31–44. [Google Scholar] [CrossRef]
- Takahashi, K.; Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 2016, 17, 183–193. [Google Scholar] [CrossRef] [PubMed]
- Schliekelman, M.J.; Creighton, C.J.; Baird, B.N.; Chen, Y.; Banerjee, P.; Bota-Rabassedas, N.; Ahn, Y.H.; Roybal, J.D.; Chen, F.; Zhang, Y.; et al. Thy-1(+) cancer-associated fibroblasts adversely impact lung cancer prognosis. Sci. Rep. 2017, 7, 6478. [Google Scholar] [CrossRef] [PubMed]
- Sauzay, C.; Voutetakis, K.; Chatziioannou, A.; Chevet, E.; Avril, T. CD90/Thy-1, a cancer-associated cell surface signaling molecule. Front. Cell Dev. Biol. 2019, 7, 66. [Google Scholar] [CrossRef] [PubMed]
- Satelli, A.; Li, S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell Mol. Life Sci. 2011, 68, 3033–3046. [Google Scholar] [CrossRef]
- Hsia, L.T.; Ashley, N.; Ouaret, D.; Wang, L.M.; Wilding, J.; Bodmer, W.F. Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers. Proc. Natl. Acad. Sci. USA 2016, 113, E2162–E2171. [Google Scholar] [CrossRef]
- 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.; et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2015, 28, 831–833. [Google Scholar] [CrossRef]
- Ohlund, 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.; et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 2017, 214, 579–596. [Google Scholar] [CrossRef]
- Strutz, F.; Okada, H.; Lo, C.W.; Danoff, T.; Carone, R.L.; Tomaszewski, J.E.; Neilson, E.G. Identification and characterization of a fibroblast marker: FSP1. J. Cell Biol. 1995, 130, 393–405. [Google Scholar] [CrossRef]
- Österreicher, C.H.; Penz-Österreicher, M.; Grivennikov, S.I.; Guma, M.; Koltsova, E.K.; Datz, C.; Sasik, R.; Hardiman, G.; Karin, M.; Brenner, D.A. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl. Acad. Sci. USA 2011, 108, 308–313. [Google Scholar] [CrossRef] [PubMed]
- Zhang, J.; Chen, L.; Liu, X.; Kammertoens, T.; Blankenstein, T.; Qin, Z. Fibroblast-specific protein 1/S100A4-positive cells prevent carcinoma through collagen production and encapsulation of carcinogens. Cancer Res. 2013, 73, 2770–2781. [Google Scholar] [CrossRef]
- De Wever, O.; Nguyen, Q.D.; Van Hoorde, L.; Bracke, M.; Bruyneel, E.; Gespach, C.; Mareel, M. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 2004, 18, 1016–1018. [Google Scholar] [CrossRef] [PubMed]
- Lowy, C.M.; Oskarsson, T. Tenascin C in metastasis: A view from the invasive front. Cell Adhes. Migr. 2015, 9, 112–124. [Google Scholar] [CrossRef]
- Yoshida, T.; Akatsuka, T.; Imanaka-Yoshida, K. Tenascin-C and integrins in cancer. Cell Adhes. Migr. 2015, 9, 96–104. [Google Scholar] [CrossRef] [PubMed]
- Planche, A.; Bacac, M.; Provero, P.; Fusco, C.; Delorenzi, M.; Stehle, J.C.; Stamenkovic, I. Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer. PLoS ONE 2011, 6, e18640. [Google Scholar] [CrossRef] [PubMed]
- Chen, S.X.; Xu, X.E.; Wang, X.Q.; Cui, S.J.; Xu, L.L.; Jiang, Y.H.; Zhang, Y.; Yan, H.B.; Zhang, Q.; Qiao, J.; et al. Identification of colonic fibroblast secretomes reveals secretory factors regulating colon cancer cell proliferation. J. Proteom. 2014, 110, 155–171. [Google Scholar] [CrossRef]
- Qin, X.; Yan, M.; Zhang, J.; Wang, X.; Shen, Z.; Lv, Z.; Li, Z.; Wei, W.; Chen, W. TGFβ3-mediated induction of Periostin facilitates head and neck cancer growth and is associated with metastasis. Sci. Rep. 2016, 6, 20587. [Google Scholar] [CrossRef]
- Yu, B.; Wu, K.; Wang, X.; Zhang, J.; Wang, L.; Jiang, Y.; Zhu, X.; Chen, W.; Yan, M. Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7. Cell Death Dis. 2018, 9, 1082. [Google Scholar] [CrossRef]
- Jia, D.; Liu, Z.; Deng, N.; Tan, T.Z.; Huang, R.Y.; Taylor-Harding, B.; Cheon, D.J.; Lawrenson, K.; Wiedemeyer, W.R.; Walts, A.E.; et al. A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets. Cancer Lett. 2016, 382, 203–214. [Google Scholar] [CrossRef]
- Nishishita, R.; Morohashi, S.; Seino, H.; Wu, Y.; Yoshizawa, T.; Haga, T.; Saito, K.; Hakamada, K.; Fukuda, S.; Kijima, H. Expression of cancer-associated fibroblast markers in advanced colorectal cancer. Oncol. Lett. 2018, 15, 6195–6202. [Google Scholar] [CrossRef]
- Vázquez-Villa, F.; García-Ocaña, M.; Galván, J.A.; García-Martínez, J.; García-Pravia, C.; Menéndez-Rodríguez, P.; González-del Rey, C.; Barneo-Serra, L.; de Los Toyos, J.R. COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression. Tumour. Biol. 2015, 36, 2213–2222. [Google Scholar] [CrossRef]
- Gascard, P.; Tlsty, T.D. Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy. Genes Dev. 2016, 30, 1002–1019. [Google Scholar] [CrossRef]
- Barrett, R.; Pure, E. Cancer-associated fibroblasts: Key determinants of tumor immunity and immunotherapy. Curr. Opin. Immunol. 2020, 64, 80–87. [Google Scholar] [CrossRef]
- Bayer, S.V.; Grither, W.R.; Brenot, A.; Hwang, P.Y.; Barcus, C.E.; Ernst, M.; Pence, P.; Walter, C.; Pathak, A.; Longmore, G.D. DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs. Elife 2019, 8, e45508. [Google Scholar] [CrossRef] [PubMed]
- Paszek, M.J.; Zahir, N.; Johnson, K.R.; Lakins, J.N.; Rozenberg, G.I.; Gefen, A.; Reinhart-King, C.A.; Margulies, S.S.; Dembo, M.; Boettiger, D.; et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 2005, 8, 241–254. [Google Scholar] [CrossRef] [PubMed]
- Zhang, K.; Grither, W.R.; Van Hove, S.; Biswas, H.; Ponik, S.M.; Eliceiri, K.W.; Keely, P.J.; Longmore, G.D. Mechanical signals regulate and activate SNAIL1 protein to control the fibrogenic response of cancer-associated fibroblasts. J. Cell Sci. 2016, 129, 1989–2002. [Google Scholar] [CrossRef]
- Dominguez, C.X.; Muller, S.; Keerthivasan, S.; Koeppen, H.; Hung, J.; Gierke, S.; Breart, B.; Foreman, O.; Bainbridge, T.W.; Castiglioni, A.; et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discov. 2020, 10, 232–253. [Google Scholar] [CrossRef]
- Lambrechts, D.; Wauters, E.; Boeckx, B.; Aibar, S.; Nittner, D.; Burton, O.; Bassez, A.; Decaluwe, H.; Pircher, A.; Van den Eynde, K.; et al. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 2018, 24, 1277–1289. [Google Scholar] [CrossRef]
- Avery, D.; Govindaraju, P.; Jacob, M.; Todd, L.; Monslow, J.; Pure, E. Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts. Matrix Biol. 2018, 67, 90–106. [Google Scholar] [CrossRef] [PubMed]
- Affo, S.; Nair, A.; Brundu, F.; Ravichandra, A.; Bhattacharjee, S.; Matsuda, M.; Chin, L.; Filliol, A.; Wen, W.; Song, X.; et al. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 2021, 39, 866–882. [Google Scholar] [CrossRef] [PubMed]
- Chen, Z.; Zhou, L.; Liu, L.; Hou, Y.; Xiong, M.; Yang, Y.; Hu, J.; Chen, K. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat. Commun. 2020, 11, 5077. [Google Scholar] [CrossRef] [PubMed]
- Kieffer, Y.; Hocine, H.R.; Gentric, G.; Pelon, F.; Bernard, C.; Bourachot, B.; Lameiras, S.; Albergante, L.; Bonneau, C.; Guyard, A.; et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020, 10, 1330–1351. [Google Scholar] [CrossRef]
- Givel, A.M.; Kieffer, Y.; Scholer-Dahirel, A.; Sirven, P.; Cardon, M.; Pelon, F.; Magagna, I.; Gentric, G.; Costa, A.; Bonneau, C.; et al. miR200-regulated CXCL12beta promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nat. Commun. 2018, 9, 1056. [Google Scholar] [CrossRef]
- Chen, S.; Zhu, G.; Yang, Y.; Wang, F.; Xiao, Y.T.; Zhang, N.; Bian, X.; Zhu, Y.; Yu, Y.; Liu, F.; et al. Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression. Nat. Cell Biol. 2021, 23, 87–98. [Google Scholar] [CrossRef] [PubMed]
- 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.; et al. Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck cancer. Cell 2017, 171, 1611–1624.e24. [Google Scholar] [CrossRef] [PubMed]
- Li, H.; Courtois, E.T.; Sengupta, D.; Tan, Y.; Chen, K.H.; Goh, J.J.L.; Kong, S.L.; Chua, C.; Hon, L.K.; Tan, W.S.; et al. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 2017, 49, 708–718. [Google Scholar] [CrossRef]
- Zhang, L.; Li, Z.; Skrzypczynska, K.M.; Fang, Q.; Zhang, W.; O’Brien, S.A.; He, Y.; Wang, L.; Zhang, Q.; Kim, A.; et al. Single-cell analyses inform mechanisms of myeloid-targeted therapies in colon cancer. Cell 2020, 181, 442–459.e29. [Google Scholar] [CrossRef]
- Davidson, S.; Efremova, M.; Riedel, A.; Mahata, B.; Pramanik, J.; Huuhtanen, J.; Kar, G.; Vento-Tormo, R.; Hagai, T.; Chen, X.; et al. Single-cell RNA sequencing reveals a dynamic stromal niche that supports tumor growth. Cell Rep. 2020, 31, 107628. [Google Scholar] [CrossRef]
- Pelon, F.; Bourachot, B.; Kieffer, Y.; Magagna, I.; Mermet-Meillon, F.; Bonnet, I.; Costa, A.; Givel, A.M.; Attieh, Y.; Barbazan, J.; et al. Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms. Nat. Commun. 2020, 11, 404. [Google Scholar] [CrossRef]
- 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.; et al. Stromal cell diversity associated with immune evasion in human triple-negative breast cancer. EMBO J. 2020, 39, e104063. [Google Scholar] [CrossRef] [PubMed]
- Bartoschek, M.; Oskolkov, N.; Bocci, M.; Lovrot, J.; Larsson, C.; Sommarin, M.; Madsen, C.D.; Lindgren, D.; Pekar, G.; Karlsson, G.; et al. Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nat. Commun. 2018, 9, 5150. [Google Scholar] [CrossRef]
- Valdés-Mora, F.; Salomon, R.; Gloss, B.S.; Law, A.M.K.; Venhuizen, J.; Castillo, L.; Murphy, K.J.; Magenau, A.; Papanicolaou, M.; Rodriguez de la Fuente, L.; et al. Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype. Cell Rep. 2021, 35, 108945. [Google Scholar] [CrossRef] [PubMed]
- Friedman, G.; Levi-Galibov, O.; David, E.; Bornstein, C.; Giladi, A.; Dadiani, M.; Mayo, A.; Halperin, C.; Pevsner-Fischer, M.; Lavon, H.; et al. Cancer-associated fibroblast compositions change with breast cancer progression linking the ratio of S100A4+ and PDPN+ CAFs to clinical outcome. Nat. Cancer. 2020, 1, 692–708. [Google Scholar] [CrossRef] [PubMed]
- Liao, Z.; Tan, Z.W.; Zhu, P.; Tan, N.S. Cancer-associated fibroblasts in tumor microenvironment-Accomplices in tumor malignancy. Cell Immunol. 2019, 343, 103729. [Google Scholar] [CrossRef] [PubMed]
- Biffi, G.; Tuveson, D.A. Diversity and biology of cancer-associated fibroblasts. Physiol. Rev. 2021, 101, 147–176. [Google Scholar] [CrossRef]
- Vickman, R.E.; Faget, D.V.; Beachy, P.; Beebe, D.; Bhowmick, N.A.; Cukierman, E.; Deng, W.M.; Granneman, J.G.; Hildesheim, J.; Kalluri, R.; et al. Deconstructing tumor heterogeneity: The stromal perspective. Oncotarget 2020, 11, 3621–3632. [Google Scholar] [CrossRef] [PubMed]
- Ribeiro, A.L.; Okamoto, O.K. Combined effects of pericytes in the tumor microenvironment. Stem Cells Int. 2015, 2015, 868475. [Google Scholar] [CrossRef]
- Kim, O.H.; Kang, G.H.; Noh, H.; Cha, J.Y.; Lee, H.J.; Yoon, J.H.; Mamura, M.; Nam, J.S.; Lee, D.H.; Kim, Y.A.; et al. Proangiogenic TIE2(+)/CD31 (+) macrophages are the predominant population of tumor-associated macrophages infiltrating metastatic lymph nodes. Mol. Cells 2013, 36, 432–438. [Google Scholar] [CrossRef] [PubMed]
- Shi, X.; Young, C.D.; Zhou, H.; Wang, X. Transforming growth factor-beta signaling in fibrotic diseases and cancer-associated fibroblasts. Biomolecules 2020, 10, 1666. [Google Scholar] [CrossRef] [PubMed]
- Goulet, C.R.; Champagne, A.; Bernard, G.; Vandal, D.; Chabaud, S.; Pouliot, F.; Bolduc, S. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer 2019, 19, 137. [Google Scholar] [CrossRef] [PubMed]
- Wang, L.; Zhang, F.; Cui, J.Y.; Chen, L.; Chen, Y.T.; Liu, B.W. CAFs enhance paclitaxel resistance by inducing EMT through the IL6/JAK2/STAT3 pathway. Oncol. Rep. 2018, 39, 2081–2090. [Google Scholar] [CrossRef] [PubMed]
- Quintero-Fabián, S.; Arreola, R.; Becerril-Villanueva, E.; Torres-Romero, J.C.; Arana-Argáez, V.; Lara-Riegos, J.; Ramírez-Camacho, M.A.; Alvarez-Sánchez, M.E. Role of matrix metalloproteinases in angiogenesis and cancer. Front. Oncol. 2019, 9, 1370. [Google Scholar] [CrossRef]
- Johnson, D.E.; O’Keefe, R.A.; Grandis, J.R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 2018, 15, 234–248. [Google Scholar] [CrossRef]
- Huber, R.M.; Lucas, J.M.; Gomez-Sarosi, L.A.; Coleman, I.; Zhao, S.; Coleman, R.; Nelson, P.S. DNA damage induces GDNF secretion in the tumor microenvironment with paracrine effects promoting prostate cancer treatment resistance. Oncotarget 2015, 6, 2134–2147. [Google Scholar] [CrossRef] [PubMed]
- Gilbert, L.A.; Hemann, M.T. DNA damage-mediated induction of a chemoresistant niche. Cell 2010, 143, 355–366. [Google Scholar] [CrossRef]
- Hu, Y.; Yan, C.; Mu, L.; Huang, K.; Li, X.; Tao, D.; Wu, Y.; Qin, J. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS ONE 2015, 10, e0125625. [Google Scholar] [CrossRef] [PubMed]
- Peiris-Pages, M.; Sotgia, F.; Lisanti, M.P. Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells. Oncotarget 2015, 6, 10728–10745. [Google Scholar] [CrossRef]
- Tang, Y.A.; Chen, Y.F.; Bao, Y.; Mahara, S.; Yatim, S.; Oguz, G.; Lee, P.L.; Feng, M.; Cai, Y.; Tan, E.Y.; et al. Hypoxic tumor microenvironment activates GLI2 via HIF-1alpha and TGF-beta2 to promote chemoresistance in colorectal cancer. Proc. Natl. Acad. Sci. USA 2018, 115, E5990–E5999. [Google Scholar] [CrossRef]
- Garvey, C.M.; Lau, R.; Sanchez, A.; Sun, R.X.; Fong, E.J.; Doche, M.E.; Chen, O.; Jusuf, A.; Lenz, H.J.; Larson, B.; et al. Anti-EGFR Therapy induces egf secretion by cancer-associated fibroblasts to confer colorectal cancer chemoresistance. Cancers 2020, 12, 1393. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.; Li, L.; Jiang, H.; Li, Q.; Wang-Gillam, A.; Yu, J.; Head, R.; Liu, J.; Ruzinova, M.B.; Lim, K.H. Tumor-stroma IL1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res. 2018, 78, 1700–1712. [Google Scholar] [CrossRef]
- Ishibashi, M.; Neri, S.; Hashimoto, H.; Miyashita, T.; Yoshida, T.; Nakamura, Y.; Udagawa, H.; Kirita, K.; Matsumoto, S.; Umemura, S.; et al. CD200-positive cancer associated fibroblasts augment the sensitivity of epidermal growth factor receptor mutation-positive lung adenocarcinomas to EGFR tyrosine kinase inhibitors. Sci. Rep. 2017, 7, 46662. [Google Scholar] [CrossRef]
- Wang, Z.; Tang, Y.; Tan, Y.; Wei, Q.; Yu, W. Cancer-associated fibroblasts in radiotherapy: Challenges and new opportunities. Cell Commun. Signal 2019, 17, 47. [Google Scholar] [CrossRef] [PubMed]
- Ansems, M.; Span, P.N. The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts. Clin. Transl. Radiat. Oncol. 2020, 22, 90–97. [Google Scholar] [CrossRef]
- Ragunathan, K.; Upfold, N.L.E.; Oksenych, V. Interaction between fibroblasts and immune cells following DNA damage induced by ionizing radiation. Int. J. Mol. Sci. 2020, 21, 8635. [Google Scholar] [CrossRef]
- Li, D.; Qu, C.; Ning, Z.; Wang, H.; Zang, K.; Zhuang, L.; Chen, L.; Wang, P.; Meng, Z. Radiation promotes epithelial-to-mesenchymal transition and invasion of pancreatic cancer cell by activating carcinoma-associated fibroblasts. Am. J. Cancer Res. 2016, 6, 2192–2206. [Google Scholar]
- Wang, Y.; Gan, G.; Wang, B.; Wu, J.; Cao, Y.; Zhu, D.; Xu, Y.; Wang, X.; Han, H.; Li, X.; et al. Cancer-associated fibroblasts promote irradiated cancer cell recovery through autophagy. EBioMedicine 2017, 17, 45–56. [Google Scholar] [CrossRef]
- Yang, N.; Lode, K.; Berzaghi, R.; Islam, A.; Martinez-Zubiaurre, I.; Hellevik, T. Irradiated tumor fibroblasts avoid immune recognition and retain immunosuppressive functions over natural killer cells. Front. Immunol. 2020, 11, 602530. [Google Scholar] [CrossRef]
- Flint, T.R.; Janowitz, T.; Connell, C.M.; Roberts, E.W.; Denton, A.E.; Coll, A.P.; Jodrell, D.I.; Fearon, D.T. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 2016, 24, 672–684. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Byrne, K.T.; Yan, F.; Yamazoe, T.; Chen, Z.; Baslan, T.; Richman, L.P.; Lin, J.H.; Sun, Y.H.; Rech, A.J.; et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 2018, 49, 178–193.e7. [Google Scholar] [CrossRef] [PubMed]
- Pickup, M.W.; Owens, P.; Gorska, A.E.; Chytil, A.; Ye, F.; Shi, C.; Weaver, V.M.; Kalluri, R.; Moses, H.L.; Novitskiy, S.V. Development of aggressive pancreatic ductal adenocarcinomas depends on granulocyte colony stimulating factor secretion in carcinoma cells. Cancer Immunol. Res. 2017, 5, 718–729. [Google Scholar] [CrossRef]
- Chen, I.X.; Chauhan, V.P.; Posada, J.; Ng, M.R.; Wu, M.W.; Adstamongkonkul, P.; Huang, P.; Lindeman, N.; Langer, R.; Jain, R.K. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc. Natl. Acad. Sci. USA 2019, 116, 4558–4566. [Google Scholar] [CrossRef]
- Mariathasan, S.; Turley, S.J.; Nickles, D.; Castiglioni, A.; Yuen, K.; Wang, Y.; Kadel, E.E., III; Koeppen, H.; Astarita, J.L.; Cubas, R.; et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018, 554, 544–548. [Google Scholar] [CrossRef]
- Flavell, R.A.; Sanjabi, S.; Wrzesinski, S.H.; Licona-Limón, P. The polarization of immune cells in the tumour environment by TGFbeta. Nat. Rev. Immunol. 2010, 10, 554–567. [Google Scholar] [CrossRef] [PubMed]
- Tauriello, D.V.F.; Palomo-Ponce, S.; Stork, D.; Berenguer-Llergo, A.; Badia-Ramentol, J.; Iglesias, M.; Sevillano, M.; Ibiza, S.; Cañellas, A.; Hernando-Momblona, X.; et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 2018, 554, 538–543. [Google Scholar] [CrossRef]
- Orimo, A.; Gupta, P.B.; Sgroi, D.C.; Arenzana-Seisdedos, F.; Delaunay, T.; Naeem, R.; Carey, V.J.; Richardson, A.L.; Weinberg, R.A. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005, 121, 335–348. [Google Scholar] [CrossRef]
- Kinoshita, T.; Ishii, G.; Hiraoka, N.; Hirayama, S.; Yamauchi, C.; Aokage, K.; Hishida, T.; Yoshida, J.; Nagai, K.; Ochiai, A. Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer Sci. 2013, 104, 409–415. [Google Scholar] [CrossRef]
- Balsamo, M.; Scordamaglia, F.; Pietra, G.; Manzini, C.; Cantoni, C.; Boitano, M.; Queirolo, P.; Vermi, W.; Facchetti, F.; Moretta, A.; et al. Melanoma-associated fibroblasts modulate NK cell phenotype and antitumor cytotoxicity. Proc. Natl. Acad. Sci. USA 2009, 106, 20847–20852. [Google Scholar] [CrossRef] [PubMed]
- Li, T.; Yi, S.; Liu, W.; Jia, C.; Wang, G.; Hua, X.; Tai, Y.; Zhang, Q.; Chen, G. Colorectal carcinoma-derived fibroblasts modulate natural killer cell phenotype and antitumor cytotoxicity. Med. Oncol. 2013, 30, 663. [Google Scholar] [CrossRef]
- Francescone, R.; Barbosa Vendramini-Costa, D.; Franco-Barraza, J.; Wagner, J.; Muir, A.; Lau, A.N.; Gabitova, L.; Pazina, T.; Gupta, S.; Luong, T.; et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov. 2021, 11, 446–479. [Google Scholar] [CrossRef] [PubMed]
- 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. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis 2016, 5, e198. [Google Scholar] [CrossRef] [PubMed]
- Rahma, O.E.; Hodi, F.S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 2019, 25, 5449–5457. [Google Scholar] [CrossRef] [PubMed]
- Kumar, V.; Donthireddy, L.; Marvel, D.; Condamine, T.; Wang, F.; Lavilla-Alonso, S.; Hashimoto, A.; Vonteddu, P.; Behera, R.; Goins, M.A.; et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell 2017, 32, 654–668.e5. [Google Scholar] [CrossRef] [PubMed]
- Xiang, H.; Ramil, C.P.; Hai, J.; Zhang, C.; Wang, H.; Watkins, A.A.; Afshar, R.; Georgiev, P.; Sze, M.A.; Song, X.S.; et al. Cancer-associated fibroblasts promote immunosuppression by inducing ROS-generating monocytic MDSCs in lung squamous cell carcinoma. Cancer Immunol. Res. 2020, 8, 436–450. [Google Scholar] [CrossRef] [PubMed]
- Ma, Y.; Hwang, R.F.; Logsdon, C.D.; Ullrich, S.E. Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res. 2013, 73, 3927–3937. [Google Scholar] [CrossRef] [PubMed]
- Pereira, B.A.; Lister, N.L.; Hashimoto, K.; Teng, L.; Flandes-Iparraguirre, M.; Eder, A.; Sanchez-Herrero, A.; Niranjan, B. Tissue engineered human prostate microtissues reveal key role of mast cell-derived tryptase in potentiating cancer-associated fibroblast (CAF)-induced morphometric transition in vitro. Biomaterials 2019, 197, 72–85. [Google Scholar] [CrossRef]
- Song, M.; He, J.; Pan, Q.Z.; Yang, J.; Zhao, J.; Zhang, Y.J.; Huang, Y.; Tang, Y.; Wang, Q.; He, J.; et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology 2021, 73, 1717–1735. [Google Scholar] [CrossRef]
- Cheng, Y.; Li, H.; Deng, Y.; Tai, Y.; Zeng, K.; Zhang, Y.; Liu, W.; Zhang, Q.; Yang, Y. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018, 9, 422. [Google Scholar] [CrossRef]
- Fridlender, Z.G.; Albelda, S.M. Tumor-associated neutrophils: Friend or foe? Carcinogenesis 2012, 33, 949–955. [Google Scholar] [CrossRef]
- Herrera, M.; Herrera, A.; Domínguez, G.; Silva, J.; García, V.; García, J.M.; Gómez, I.; Soldevilla, B.; Muñoz, C.; Provencio, M.; et al. Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci. 2013, 104, 437–444. [Google Scholar] [CrossRef] [PubMed]
- Comito, G.; Giannoni, E.; Segura, C.P.; Barcellos-de-Souza, P.; Raspollini, M.R.; Baroni, G.; Lanciotti, M.; Serni, S.; Chiarugi, P. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene 2014, 33, 2423–2431. [Google Scholar] [CrossRef] [PubMed]
- Mathew, E.; Brannon, A.L.; Del Vecchio, A.; Garcia, P.E.; Penny, M.K.; Kane, K.T.; Vinta, A.; Buckanovich, R.J.; di Magliano, M.P. Mesenchymal stem cells promote pancreatic tumor growth by inducing alternative polarization of macrophages. Neoplasia 2016, 18, 142–151. [Google Scholar] [CrossRef] [PubMed]
- Mace, T.A.; Ameen, Z.; Collins, A.; Wojcik, S.; Mair, M.; Young, G.S.; Fuchs, J.R.; Eubank, T.D.; Frankel, W.L.; Bekaii-Saab, T.; et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 2013, 73, 3007–3018. [Google Scholar] [CrossRef] [PubMed]
- Zhang, R.; Qi, F.; Zhao, F.; Li, G.; Shao, S.; Zhang, X.; Yuan, L.; Feng, Y. Cancer-associated fibroblasts enhance tumor-associated macrophages enrichment and suppress NK cells function in colorectal cancer. Cell Death Dis. 2019, 10, 273. [Google Scholar] [CrossRef]
- LeBeau, A.M.; Brennen, W.N.; Aggarwal, S.; Denmeade, S.R. Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin. Mol. Cancer Ther. 2009, 8, 1378–1386. [Google Scholar] [CrossRef]
- Adams, S.; Miller, G.T.; Jesson, M.I.; Watanabe, T.; Jones, B.; Wallner, B.P. PT-100, a small molecule dipeptidyl peptidase inhibitor, has potent antitumor effects and augments antibody-mediated cytotoxicity via a novel immune mechanism. Cancer Res. 2004, 64, 5471–5480. [Google Scholar] [CrossRef]
- Narra, K.; Mullins, S.R.; Lee, H.O.; Strzemkowski-Brun, B.; Magalong, K.; Christiansen, V.J.; McKee, P.A.; Egleston, B.; Cohen, S.J.; Weiner, L.M.; et al. Phase II trial of single agent Val-boroPro (Talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer. Cancer Biol. Ther. 2007, 6, 1691–1699. [Google Scholar] [CrossRef]
- Hofheinz, R.D.; al-Batran, S.E.; Hartmann, F.; Hartung, G.; Jager, D.; Renner, C.; Tanswell, P.; Kunz, U.; Amelsberg, A.; Kuthan, H.; et al. Stromal antigen targeting by a humanised monoclonal antibody: An early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 2003, 26, 44–48. [Google Scholar] [CrossRef]
- Scott, A.M.; Wiseman, G.; Welt, S.; Adjei, A.; Lee, F.-T.; Hopkins, W.; Divgi, C.R.; Hanson, L.H.; Mitchell, P.; Gansen, D.N.; et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer1. Clin. Cancer Res. 2003, 9, 1639–1647. [Google Scholar]
- Huang, S.; Fang, R.; Xu, J.; Qiu, S.; Zhang, H.; Du, J.; Cai, S. Evaluation of the tumor targeting of a FAPα-based doxorubicin prodrug. J. Drug Target 2011, 19, 487–496. [Google Scholar] [CrossRef] [PubMed]
- Brennen, W.N.; Isaacs, J.T.; Denmeade, S.R. Rationale behind targeting fibroblast activation protein–expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol. Cancer Ther. 2012, 11, 257–266. [Google Scholar] [CrossRef] [PubMed]
- Fang, J.; Xiao, L.; Joo, K.I.; Liu, Y.; Zhang, C.; Liu, S.; Conti, P.S.; Li, Z.; Wang, P. A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int. J. Cancer 2016, 138, 1013–1023. [Google Scholar] [CrossRef] [PubMed]
- Fang, J.; Hu, B.; Li, S.; Zhang, C.; Liu, Y.; Wang, P. A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. Mol. Ther. Oncolytics 2016, 3, 16007. [Google Scholar] [CrossRef] [PubMed]
- Tansi, F.L.; Rüger, R.; Böhm, C.; Steiniger, F.; Kontermann, R.E.; Teichgraeber, U.K.; Fahr, A.; Hilger, I. Activatable bispecific liposomes bearing fibroblast activation protein directed single chain fragment/Trastuzumab deliver encapsulated cargo into the nuclei of tumor cells and the tumor microenvironment simultaneously. Acta Biomater. 2017, 54, 281–293. [Google Scholar] [CrossRef] [PubMed]
- Rabenhold, M.; Steiniger, F.; Fahr, A.; Kontermann, R.E.; Rüger, R. Bispecific single-chain diabody-immunoliposomes targeting endoglin (CD105) and fibroblast activation protein (FAP) simultaneously. J. Control. Release 2015, 201, 56–67. [Google Scholar] [CrossRef]
- Chen, B.; Wang, Z.; Sun, J.; Song, Q.; He, B.; Zhang, H.; Wang, X.; Dai, W.; Zhang, Q. A tenascin C targeted nanoliposome with navitoclax for specifically eradicating of cancer-associated fibroblasts. Nanomedicine 2016, 12, 131–141. [Google Scholar] [CrossRef]
- Truffi, M.; Mazzucchelli, S.; Bonizzi, A.; Sorrentino, L.; Allevi, R.; Vanna, R.; Morasso, C.; Corsi, F. Nano-strategies to target breast cancer-associated fibroblasts: Rearranging the tumor microenvironment to achieve antitumor efficacy. Int. J. Mol. Sci. 2019, 20, 1263. [Google Scholar] [CrossRef]
- Ostermann, E.; Garin-Chesa, P.; Heider, K.H.; Kalat, M.; Lamche, H.; Puri, C.; Kerjaschki, D.; Rettig, W.J.; Adolf, G.R. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin. Cancer Res. 2008, 14, 4584–4592. [Google Scholar] [CrossRef]
- Cheng, J.D.; Dunbrack, R.L., Jr.; Valianou, M.; Rogatko, A.; Alpaugh, R.K.; Weiner, L.M. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model1. Cancer Res. 2002, 62, 4767–4772. [Google Scholar]
- Brünker, P.; Wartha, K.; Friess, T.; Grau-Richards, S.; Waldhauer, I.; Koller, C.F.; Weiser, B.; Majety, M.; Runza, V.; Niu, H.; et al. RG7386, a novel tetravalent FAP-DR5 antibody, effectively triggers FAP-dependent, avidity-driven DR5 hyperclustering and tumor cell apoptosis. Mol. Cancer Ther. 2016, 15, 946–957. [Google Scholar] [CrossRef] [PubMed]
- Lee, J.; Fassnacht, M.; Nair, S.; Boczkowski, D.; Gilboa, E. Tumor immunotherapy targeting fibroblast activation protein, a product expressed in tumor-associated fibroblasts. Cancer Res. 2005, 65, 11156–11163. [Google Scholar] [CrossRef] [PubMed]
- 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. Investig. 2006, 116, 1955–1962. [Google Scholar] [CrossRef]
- Zhang, Y.; Ertl, H.C. Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors. Oncotarget 2016, 7, 23282–23299. [Google Scholar] [CrossRef]
- Xia, Q.; Zhang, F.F.; Geng, F.; Liu, C.L.; Xu, P.; Lu, Z.Z.; Yu, B.; Wu, H.; Wu, J.X.; Zhang, H.H.; et al. Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model. Cancer Immunol. Immunother. 2016, 65, 613–624. [Google Scholar] [CrossRef] [PubMed]
- Freedman, J.D.; Duffy, M.R.; Lei-Rossmann, J.; Muntzer, A.; Scott, E.M.; Hagel, J.; Campo, L.; Bryant, R.J.; Verrill, C.; Lambert, A.; et al. An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells. Cancer Res. 2018, 78, 6852–6865. [Google Scholar] [CrossRef] [PubMed]
- Kraman, M.; Bambrough, P.J.; Arnold, J.N.; Roberts, E.W.; Magiera, L.; Jones, J.O.; Gopinathan, A.; Tuveson, D.A.; Fearon, D.T. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 2010, 330, 827–830. [Google Scholar] [CrossRef]
- Geng, F.; Bao, X.; Dong, L.; Guo, Q.-Q.; Guo, J.; Xie, Y.; Zhou, Y.; Yu, B.; Wu, H.; Wu, J.-X.; et al. Doxorubicin pretreatment enhances FAPα/survivin co-targeting DNA vaccine anti-tumor activity primarily through decreasing peripheral MDSCs in the 4T1 murine breast cancer model. Oncoimmunology 2020, 9, 1747350. [Google Scholar] [CrossRef]
- Wang, L.C.; Lo, A.; Scholler, J.; Sun, J.; Majumdar, R.S.; Kapoor, V.; Antzis, M.; Cotner, C.E.; Johnson, L.A.; Durham, A.C.; 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. 2014, 2, 154–166. [Google Scholar] [CrossRef]
- Roberts, E.W.; Deonarine, A.; Jones, J.O.; Denton, A.E.; Feig, C.; Lyons, S.K.; Espeli, M.; Kraman, M.; McKenna, B.; Wells, R.J.; et al. Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia. J. Exp. Med. 2013, 210, 1137–1151. [Google Scholar] [CrossRef]
- Tran, E.; Chinnasamy, D.; Yu, Z.; Morgan, R.A.; Lee, C.C.; Restifo, N.P.; Rosenberg, S.A. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 2013, 210, 1125–1135. [Google Scholar] [CrossRef] [PubMed]
- Watanabe, S.; Noma, K.; Ohara, T.; Kashima, H.; Sato, H.; Kato, T.; Urano, S.; Katsube, R.; Hashimoto, Y.; Tazawa, H.; et al. Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma. Cancer Biol. Ther. 2019, 20, 1234–1248. [Google Scholar] [CrossRef] [PubMed]
- Katsube, R.; Noma, K.; Ohara, T.; Nishiwaki, N.; Kobayashi, T.; Komoto, S.; Sato, H.; Kashima, H.; Kato, T.; Kikuchi, S.; et al. Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer. Sci. Rep. 2021, 11, 1693. [Google Scholar] [CrossRef] [PubMed]
- Ene-Obong, A.; Clear, A.J.; Watt, J.; Wang, J.; Fatah, R.; Riches, J.C.; Marshall, J.F.; Chin-Aleong, J.; Chelala, C.; Gribben, J.G.; et al. Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology 2013, 145, 1121–1132. [Google Scholar] [CrossRef] [PubMed]
- Froeling, F.E.; Feig, C.; Chelala, C.; Dobson, R.; Mein, C.E.; Tuveson, D.A.; Clevers, H.; Hart, I.R.; Kocher, H.M. Retinoic acid-induced pancreatic stellate cell quiescence reduces paracrine Wnt-β-catenin signaling to slow tumor progression. Gastroenterology 2011, 141, 1486–1497. [Google Scholar] [CrossRef]
- Han, X.; Li, Y.; Xu, Y.; Zhao, X.; Zhang, Y.; Yang, X.; Wang, Y.; Zhao, R.; Anderson, G.J.; Zhao, Y.; et al. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem. Nat. Commun. 2018, 9, 3390. [Google Scholar] [CrossRef]
- Banerjee, S.; Modi, S.; McGinn, O.; Zhao, X.; Dudeja, V.; Ramakrishnan, S.; Saluja, A.K. Impaired synthesis of stromal components in response to minnelide improves vascular function, drug delivery, and survival in pancreatic cancer. Clin. Cancer Res. 2016, 22, 415–425. [Google Scholar] [CrossRef]
- Dauer, P.; Zhao, X.; Gupta, V.K.; Sharma, N.; Kesh, K.; Gnamlin, P.; Dudeja, V.; Vickers, S.M.; Banerjee, S.; Saluja, A. Inactivation of cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression. Cancer Res. 2018, 78, 1321–1333. [Google Scholar] [CrossRef]
- Ding, N.; Yu, R.T.; Subramaniam, N.; Sherman, M.H.; Wilson, C.; Rao, R.; Leblanc, M.; Coulter, S.; He, M.; Scott, C.; et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 2013, 153, 601–613. [Google Scholar] [CrossRef]
- 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.; et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014, 159, 80–93. [Google Scholar] [CrossRef]
- Chauhan, V.P.; Chen, I.X.; Tong, R.; Ng, M.R.; Martin, J.D.; Naxerova, K.; Wu, M.W.; Huang, P.; Boucher, Y.; Kohane, D.S.; et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc. Natl. Acad. Sci. USA 2019, 116, 10674–10680. [Google Scholar] [CrossRef] [PubMed]
- Chauhan, V.P.; Martin, J.D.; Liu, H.; Lacorre, D.A.; Jain, S.R.; Kozin, S.V.; Stylianopoulos, T.; Mousa, A.S.; Han, X.; Adstamongkonkul, P.; et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 2013, 4, 2561. [Google Scholar] [CrossRef]
- Diop-Frimpong, B.; Chauhan, V.P.; Krane, S.; Boucher, Y.; Jain, R.K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl. Acad. Sci. USA 2011, 108, 2909–2914. [Google Scholar] [CrossRef]
- Murphy, J.E.; Wo, J.Y.; Ryan, D.P.; Clark, J.W.; Jiang, W.; Yeap, B.Y.; Drapek, L.C.; Ly, L.; Baglini, C.V.; Blaszkowsky, L.S.; et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: A phase 2 clinical trial. JAMA Oncol. 2019, 5, 1020–1027. [Google Scholar] [CrossRef] [PubMed]
- Mace, T.A.; Shakya, R.; Pitarresi, J.R.; Swanson, B.; McQuinn, C.W.; Loftus, S.; Nordquist, E.; Cruz-Monserrate, Z.; Yu, L.; Young, G.; et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 2018, 67, 320–332. [Google Scholar] [CrossRef]
- Zhang, Y.; Yan, W.; Collins, M.A.; Bednar, F.; Rakshit, S.; Zetter, B.R.; Stanger, B.Z.; Chung, I.; Rhim, A.D.; di Magliano, M.P. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res. 2013, 73, 6359–6374. [Google Scholar] [CrossRef] [PubMed]
- Shi, Y.; Gao, W.; Lytle, N.K.; Huang, P.; Yuan, X.; Dann, A.M.; Ridinger-Saison, M.; DelGiorno, K.E.; Antal, C.E.; Liang, G.; et al. Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 2019, 569, 131–135. [Google Scholar] [CrossRef]
- Grauel, A.L.; Nguyen, B.; Ruddy, D.; Laszewski, T.; Schwartz, S.; Chang, J.; Chen, J.; Piquet, M.; Pelletier, M.; Yan, Z.; et al. TGFβ-blockade uncovers stromal plasticity in tumors by revealing the existence of a subset of interferon-licensed fibroblasts. Nat. Commun. 2020, 11, 6315. [Google Scholar] [CrossRef]
- Godwin, P.; Baird, A.M.; Heavey, S.; Barr, M.P.; O’Byrne, K.J.; Gately, K. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front. Oncol. 2013, 3, 120. [Google Scholar] [CrossRef]
- Steele, N.G.; Biffi, G.; Kemp, S.B.; Zhang, Y.; Drouillard, D.; Syu, L.; Hao, Y.; Oni, T.E.; Brosnan, E.; Elyada, E.; et al. Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2021, 27, 2023–2037. [Google Scholar] [CrossRef]
- Tirosh, I.; Izar, B.; Prakadan, S.M.; Wadsworth, M.H., 2nd; Treacy, D.; Trombetta, J.J.; Rotem, A.; Rodman, C.; Lian, C.; Murphy, G.; et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 2016, 352, 189–196. [Google Scholar] [CrossRef] [PubMed]
- Waise, S.; Parker, R.; Rose-Zerilli, M.J.J.; Layfield, D.M.; Wood, O.; West, J.; Ottensmeier, C.H.; Thomas, G.J.; Hanley, C.J. An optimised tissue disaggregation and data processing pipeline for characterising fibroblast phenotypes using single-cell RNA sequencing. Sci. Rep. 2019, 9, 9580. [Google Scholar] [CrossRef] [PubMed]
- Giesel, F.L.; Kratochwil, C.; Schlittenhardt, J.; Dendl, K.; Eiber, M.; Staudinger, F.; Kessler, L.; Fendler, W.P.; Lindner, T.; Koerber, S.A.; et al. Head-to-head intra-individual comparison of biodistribution and tumor uptake of (68)Ga-FAPI and (18)F-FDG PET/CT in cancer patients. Eur. J. Nucl. Med. Mol. Imaging 2021, 48, 4377–4385. [Google Scholar] [CrossRef] [PubMed]
Marker | Localization | Expressed by | Role in Tumor Functionality/ Progression | References |
---|---|---|---|---|
Fibroblast Activation Protein (FAP) | Membrane | Fibroblasts, immune cells | Tumor progression and metastasis, shaping the immunosuppressive TME, ECM remodeling, fibrogenesis | [30,31,32,33] |
Platelet derived growth factor receptor α/β (PDGFRα/β) | Membrane | Fibroblasts, vascular smooth muscle cells, pericytes | M2 polarization, angiogenesis | [27,34,35] |
Podoplanin (PDPN) | Membrane | Endothelial cells | Immunosuppression, tumor growth | [36,37,38,39,40] |
α11β1 integrin (ITGA11) | Membrane | Mesenchymal cells | Cancer cell migration, adhesion, tumor cell invasion, desmoplasia | [41,42,43,44] |
Caveolin-1 (CAV1) | Membrane | Endothelial cells, epithelial cells, adipocytes, smooth muscle cells, pneumocytes | Vascular and pleural invasion of cancer cells, metastasis | [45,46,47,48,49] |
CD10 | Membrane | Bone marrow mesenchymal stem cells, pre-B lymphocytes | Sustaining cancer stemness, cancer formation, chemoresistance | [50] |
CD74 | Membrane | Fibroblasts, monocytes, macrophages, epithelial cells | Antigen presentation | [51,52] |
Ly6C | Membrane | Inflammatory CAFs, myeloid cells | Protumorigenic inflammation | [51,52] |
Thy-1 (CD90) | Membrane | Fibroblasts, neurons, endothelial cells, tumor cells, immune cells | Tumor cell invasion, migration, tumor-associated endothelial cells | [53,54,55,56] |
Vimentin | Cytoplasmic | Fibroblasts, mesenchymal cells | Tumor growth, invasion, migration, endothelial to mesenchymal transition | [57,58] |
α-smooth muscle actin (α-SMA) | Cytoplasmic | Fibroblasts, smooth muscle cells | Tumor cell proliferation, protection mechanism, impediment to drug delivery, ECM remodeling, desmoplasia, cancer stemness | [45,59,60] |
FSP-1/S100A4 | Cytoplasmic, nuclear | Fibroblasts, epithelial and endothelial cells | Promotion of metastasis, immune evasion, immune surveillance, cell motility, fibrosis | [35,61,62,63] |
Tenascin-C | ECM protein | Fibroblasts, tumor cells, endothelial cells | Driver of metastasis, Epithelial–mesenchymal transition, desmoplasia, angiogenesis | [64,65,66] |
Periostin (POSTN, OSF-2) | ECM protein | Fibroblasts, tumor cells, mesenchymal stem cells | Cancer cell stemness, promotes tumor progression and metastasis | [67,68,69,70] |
Type-I collagen (COL1) and COL11α1 | Cytoplasmic | Fibroblasts, tumor cells, endothelial cells (COL1), COL11α1 considered to be highly CAF-specific | Epithelial–mesenchymal transition, metastasis | [35,71,72,73,74] |
Tumor Type | Species | CAF Subtype | Relevant Biomarker (s) or Major Feature (s) | Reference (s): |
---|---|---|---|---|
Pancreatic cancer | Patient samples, Murine tumors (KPC) | myCAF–ECM producing | FAP, α-SMAhi, Thy1, TAGLN | [51,52,60,79] |
iCAF-inflammatory | Ly6Chi, α-SMAlo, PDGFRαhi, IL-1, IL-6 | |||
ApCAF–Ag presenting | MHCII | |||
Colorectal cancer | Patient samples | CAF-A | α-SMAlo, FAP, MMP2, DCN, ECM remodeling | [88,89] |
CAF-B | α-SMAhi, TAGLNhi, PDGFRα, FAP-; activated myofibroblasts | |||
Head and neck cancer | Patient samples | Myofibroblast | α-SMAhi, MYL9, MYLK, contractile | [87] |
Activated CAFs (2 subclusters; CAF1 and CAF2) | FAP, PDPN, PDGFRα; ECM-producing | |||
Lung cancer | Patient samples | Cluster 1 | ECM-producing, TGF-β signature | [80] |
Cluster 2 | α-SMAhi | |||
Cluster 4 | Enriched at leading edge | |||
Cluster 5 | High mTOR; enriched at tumor core | |||
Cluster 7 | High mTOR; enriched at leading edge | |||
Melanoma | Murine tumors (B16-F10) | S1–immune CAFs | CD34hi, CXCL12, C3, immunosuppressive | [90] |
S2–desmoplastic CAFs | CD34lo, CTGF, TNC; PDGFRα, ECM-producing | |||
S3–contractile CAFs | α-SMAhi, RGS5 | |||
Breast cancer and ovarian cancer | Patient samples | CAF-S1 | FAPhi, α-SMAhi, CXCL12, IL-6 | [45,84,85,91] |
CAF-S2 | Low/no marker expression; contractile | |||
CAF-S3 | α-SMAlo, FSP1, PDGFRβ+ | |||
CAF-S4 | CD29hi, α-SMAhi, FAPlo | |||
Breast cancer | Patient samples | iCAF | CXCL12 | [92] |
myCAF | α-SMA, FAP, PDPN, COL1A1, COL1A2 | |||
Breast cancer | Murine tumors (MMTV-PyVT) | Vascular CAF (vCAF) | α-SMA, PDGFRβ; angiogenesis | [93,94] |
Matrix CAF (mCAF) | α-SMAlo, PDGFRα; ECM-producing | |||
Cycling CAF (cCAF) | PDGFRβhi, angiogenesis | |||
Developmental CAF (dCAF) | PDGFRβ-, SCRG1, SOX9; differentiation | |||
Breast cancer | Murine tumors (4T1) | PDPN-CAF | 6 subclusters | [95] |
S100A4-CAF | 2 subclusters | |||
Bladder cancer | Patient samples | Myo-CAF | RGS5, MYL9, MYH11 | [83] |
iCAF | PDGFRα, CXCL12, IL-6, CXCL14, CXCL1, CXCL2 | |||
Prostate cancer | Patient samples | CAF-S1 | α-SMA, PDGFRβ | [86] |
CAF-S2 | PDGFRα, PLAGL1 | |||
CAF-S3 | α-SMA, HOXB2, MAFB | |||
Cholangiocarcinoma | Patient samples, Murine tumors (KRASG12D/p19-induced, YAPS127A/AKT-induced) | myCAF | COL1A1, α-SMA | [82] |
iCAF | COL8A1, COL15A1, SERPINF1 | |||
mesCAF | CXCL12, HGF, RGS5 Mesothelin |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Glabman, R.A.; Choyke, P.L.; Sato, N. Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy. Cancers 2022, 14, 3906. https://doi.org/10.3390/cancers14163906
Glabman RA, Choyke PL, Sato N. Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy. Cancers. 2022; 14(16):3906. https://doi.org/10.3390/cancers14163906
Chicago/Turabian StyleGlabman, Raisa A., Peter L. Choyke, and Noriko Sato. 2022. "Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy" Cancers 14, no. 16: 3906. https://doi.org/10.3390/cancers14163906