Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance

Micol Eleonora Fiori, Simone Di Franco, Lidia Villanova, Paola Bianca, Giorgio Stassi, Ruggero De Maria, Micol Eleonora Fiori, Simone Di Franco, Lidia Villanova, Paola Bianca, Giorgio Stassi, Ruggero De Maria

Abstract

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

Conflict of interest statement

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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

Figures

Fig. 1
Fig. 1
Schematic diagram showing the effects of CAFs on cancer cell metastatic behavior. a) Activated fibroblasts (NAF) originate from normal fibroblasts (NF) upon exposure to inflammatory cytokines. Following contact with cancer cells, they can originate the cancer-associated fibroblasts (CAFs) with enhanced proliferative and paracrine potential. The paracrine activity of CAFs and cancer cells underlying the bidirectional crosstalk between the two cell populations with the specific involved deregulated pathways are depicted. The arrows indicate the stimulatory effect of each cytokine. The induction of EMT in cancer cells relies on the activation of transcription factors, lncRNAs and epigenetic changes. b) CAFs-mediated effect on mesenchymal-independent (cancer cells maintain an epithelial-like phenotype) invasive potential. Different strategies are adopted by CAFs to facilitate cancer cells invasion of ECM, thus favoring their metastatic potential. Among these, we find the co-migration, by which CAFs and cancer cells migrate together thanks to the expression of cell membrane junctions; the ECM digestion that consists in the production of proteases by CAFs that is accompanied by the release of chemokines acting as chemoattractants for cancer cells; the force-mediated ECM remodeling that consists in the augmented contractility of the ECM and the concomitant alignment of Fibronectin (Fn), thus offering to the cancer cells a preferential route in the invasive process
Fig. 2
Fig. 2
CAFs promote resistance to anti-cancer therapies through paracrine signals and mutual metabolic reprogramming. Upon exposure to a therapeutic insult, CAFs support an adaptive response in cancer cells that ultimately leads to therapy failure. a) Drug treatment triggers NF-kB and JAK/STAT signaling in CAFs. CAFs-released paracrine signals include exosome-mediated delivery of mRNAs and ncRNAs and a broad range of cytokines (mainly interleukins and growth factors). Activated pathways in cancer cells include pro-survival, anti-apoptotic and stemness programs. Signaling loops are depicted with rectangular-shaped arrows. b) As a mechanism of mutual adaptation to low levels of glutamine and glucose, CAFs provide metabolites that boost mitochondrial metabolism in cancer cells, hence fueling a resistant phenotype. Metabolites can also function as signaling molecules, as for the lactate secreted by cancer cells that induces NF-kB-mediated transcription in CAFs, which results in secretion of HGF that mediates TKIs resistance

References

    1. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19:1423–1437. doi: 10.1038/nm.3394.
    1. Yu M, Tannock IF. Targeting tumor architecture to favor drug penetration: a new weapon to combat chemoresistance in pancreatic cancer? Cancer Cell. 2012;21:327–329. doi: 10.1016/j.ccr.2012.03.002.
    1. Kendall RT, Feghali-Bostwick CA. Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol. 2014;5:123. doi: 10.3389/fphar.2014.00123.
    1. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–598. doi: 10.1038/nrc.2016.73.
    1. Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 2018.
    1. Prakash J. Cancer-Associated Fibroblasts: Perspectives in Cancer Therapy. Trends Cancer. 2016;2:277–279. doi: 10.1016/j.trecan.2016.04.005.
    1. Ohlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, Corbo V, Oni TE, Hearn SA, Lee EJ, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–596.
    1. 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. doi: 10.1016/j.ccell.2018.01.011.
    1. Neuzillet C, Tijeras-Raballand A, Ragulan C, Cros J, Patil Y, Martinet M, Erkan M, Kleeff J, Wilson J, Apte M, Tosolini M, Wilson AS, Delvecchio FR, Bousquet C, Paradis V, Hammel P, Sadanandam A, Kocher HM. Inter- and intra-tumoral heterogeneity in cancer-associated fibroblasts of human pancreatic ductal adenocarcinoma. J Pathol. 2019. 10.1002/path.5224.
    1. 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. doi: 10.1038/s41591-018-0096-5.
    1. 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. doi: 10.1016/j.cell.2018.01.009.
    1. Costea DE, Hills A, Osman AH, Thurlow J, Kalna G, Huang X, Pena Murillo C, Parajuli H, Suliman S, Kulasekara KK, et al. Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer Res. 2013;73:3888–3901. doi: 10.1158/0008-5472.CAN-12-4150.
    1. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–734. doi: 10.1016/j.ccr.2014.04.005.
    1. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, Dekleva EN, Saunders T, Becerra CP, Tattersall IW, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25:735–747. doi: 10.1016/j.ccr.2014.04.021.
    1. Patel AK, 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;7:78. doi: 10.1038/s41389-018-0087-x.
    1. Brechbuhl HM, Finlay-Schultz J, Yamamoto TM, Gillen AE, Cittelly DM, Tan AC, Sams SB, Pillai MM, Elias AD, Robinson WA, et al. Fibroblast Subtypes Regulate Responsiveness of Luminal Breast Cancer to Estrogen. Clin Cancer Res. 2017;23:1710–1721. doi: 10.1158/1078-0432.CCR-15-2851.
    1. Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30:1002–1019. doi: 10.1101/gad.279737.116.
    1. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med. 2009;15:1010–1012. doi: 10.1038/nm0909-1010.
    1. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–737. doi: 10.1038/nm0797-730.
    1. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–648. doi: 10.1038/367645a0.
    1. Tang C, Ang BT, Pervaiz S. Cancer stem cell: target for anti-cancer therapy. FASEB J. 2007;21:3777–3785. doi: 10.1096/fj.07-8560rev.
    1. Morel AP, Hinkal GW, Thomas C, Fauvet F, Courtois-Cox S, Wierinckx A, Devouassoux-Shisheboran M, Treilleux I, Tissier A, Gras B, et al. EMT inducers catalyze malignant transformation of mammary epithelial cells and drive tumorigenesis towards claudin-low tumors in transgenic mice. PLoS Genet. 2012;8:e1002723. doi: 10.1371/journal.pgen.1002723.
    1. Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One. 2008;3:e2888. doi: 10.1371/journal.pone.0002888.
    1. Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, Apuzzo T, Sperduti I, Volpe S, Cocorullo G, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014;14:342–356. doi: 10.1016/j.stem.2014.01.009.
    1. Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer. 2018;18:128–134. doi: 10.1038/nrc.2017.118.
    1. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–981. doi: 10.1083/jcb.200601018.
    1. Skrypek N, Goossens S, De Smedt E, Vandamme N, Berx G. Epithelial-to-Mesenchymal Transition: Epigenetic Reprogramming Driving Cellular Plasticity. Trends Genet. 2017;33:943–959. doi: 10.1016/j.tig.2017.08.004.
    1. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 2004;303:848–851. doi: 10.1126/science.1090922.
    1. Colak S, Ten Dijke P. Targeting TGF-beta Signaling in Cancer. Trends Cancer. 2017;3:56–71. doi: 10.1016/j.trecan.2016.11.008.
    1. Mu Y, Gudey SK, Landstrom M. Non-Smad signaling pathways. Cell Tissue Res. 2012;347:11–20. doi: 10.1007/s00441-011-1201-y.
    1. Massague J. TGFbeta signalling in context. Nat Rev Mol Cell Biol. 2012;13:616–630. doi: 10.1038/nrm3434.
    1. Massague J. TGFbeta in Cancer. Cell. 2008;134:215–230. doi: 10.1016/j.cell.2008.07.001.
    1. Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10:415–424. doi: 10.1038/nrc2853.
    1. Moustakas A, Heldin CH. Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci. 2007;98:1512–1520. doi: 10.1111/j.1349-7006.2007.00550.x.
    1. Fessler E, Drost J, van Hooff SR, Linnekamp JF, Wang X, Jansen M, De Sousa EMF, Prasetyanti PR, JE IJ, Franitza M, et al: TGFbeta signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype. EMBO Mol Med 2016, 8:745–760.
    1. Heldin CH, Vanlandewijck M, Moustakas A. Regulation of EMT by TGFbeta in cancer. FEBS Lett. 2012;586:1959–1970. doi: 10.1016/j.febslet.2012.02.037.
    1. Nakano M, Kikushige Y, Miyawaki K, Kunisaki Y, Mizuno S, Takenaka K, Tamura S, Okumura Y, Ito M, Ariyama H, et al. Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer. Oncogene. 2019;38(6):780–93.
    1. Bellomo C, Caja L, Moustakas A. Transforming growth factor beta as regulator of cancer stemness and metastasis. Br J Cancer. 2016;115:761–769. doi: 10.1038/bjc.2016.255.
    1. Zhuang J, Lu Q, Shen B, Huang X, Shen L, Zheng X, Huang R, Yan J, Guo H. TGFbeta1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT. Sci Rep. 2015;5:11924. doi: 10.1038/srep11924.
    1. Ren Y, Jia HH, Xu YQ, Zhou X, Zhao XH, Wang YF, Song X, Zhu ZY, Sun T, Dou Y, et al. Paracrine and epigenetic control of CAF-induced metastasis: the role of HOTAIR stimulated by TGF-ss1 secretion. Mol Cancer. 2018;17:5. doi: 10.1186/s12943-018-0758-4.
    1. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, Tsai MC, Hung T, Argani P, Rinn JL, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–1076. doi: 10.1038/nature08975.
    1. Xue X, Yang YA, Zhang A, Fong KW, Kim J, Song B, Li S, Zhao JC, Yu J. LncRNA HOTAIR enhances ER signaling and confers tamoxifen resistance in breast cancer. Oncogene. 2016;35:2746–2755. doi: 10.1038/onc.2015.340.
    1. Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ, Feng YM. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer. 2014;110:724–732. doi: 10.1038/bjc.2013.768.
    1. Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47:320–329. doi: 10.1038/ng.3225.
    1. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–196. doi: 10.1038/nrm3758.
    1. Lau EY, Lo J, Cheng BY, Ma MK, Lee JM, Ng JK, Chai S, Lin CH, Tsang SY, Ma S, et al. Cancer-Associated Fibroblasts Regulate Tumor-Initiating Cell Plasticity in Hepatocellular Carcinoma through c-Met/FRA1/HEY1 Signaling. Cell Rep. 2016;15:1175–1189. doi: 10.1016/j.celrep.2016.04.019.
    1. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–348. doi: 10.1016/j.cell.2005.02.034.
    1. Lenos KJ, Miedema DM, Lodestijn SC, Nijman LE, van den Bosch T, Romero Ros X, Lourenco FC, Lecca MC, van der Heijden M, van Neerven SM, et al. Stem cell functionality is microenvironmentally defined during tumour expansion and therapy response in colon cancer. Nat Cell Biol. 2018;20:1193–1202. doi: 10.1038/s41556-018-0179-z.
    1. Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. Tumour Biol. 2017;39:1010428317712592.
    1. Wu X, Tao P, Zhou Q, Li J, Yu Z, Wang X, Li J, Li C, Yan M, Zhu Z, et al. IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget. 2017;8:20741–20750.
    1. Ding X, Ji J, Jiang J, Cai Q, Wang C, Shi M, Yu Y, Zhu Z, Zhang J. HGF-mediated crosstalk between cancer-associated fibroblasts and MET-unamplified gastric cancer cells activates coordinated tumorigenesis and metastasis. Cell Death Dis. 2018;9:867. doi: 10.1038/s41419-018-0922-1.
    1. Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer. 2018;18:341–358. doi: 10.1038/s41568-018-0002-y.
    1. Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18:773–789. doi: 10.1038/s41577-018-0066-7.
    1. 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. doi: 10.1038/s41419-018-1116-6.
    1. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13:140–156. doi: 10.1038/nrd4204.
    1. Calon A, Espinet E, Palomo-Ponce S, Tauriello DV, Iglesias M, Cespedes MV, Sevillano M, Nadal C, Jung P, Zhang XH, et al. Dependency of colorectal cancer on a TGF-beta-driven program in stromal cells for metastasis initiation. Cancer Cell. 2012;22:571–584. doi: 10.1016/j.ccr.2012.08.013.
    1. Valenti G, Quinn HM, Heynen G, Lan L, Holland JD, Vogel R, Wulf-Goldenberg A, Birchmeier W. Cancer Stem Cells Regulate Cancer-Associated Fibroblasts via Activation of Hedgehog Signaling in Mammary Gland Tumors. Cancer Res. 2017;77:2134–2147. doi: 10.1158/0008-5472.CAN-15-3490.
    1. Del Pozo MY, Park D, Ramachandran A, Ombrato L, Calvo F, Chakravarty P, Spencer-Dene B, Derzsi S, Hill CS, Sahai E, Malanchi I. Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization. Cell Rep. 2015;13:2456–2469. doi: 10.1016/j.celrep.2015.11.025.
    1. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, Chiarugi P. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010;70:6945–6956. doi: 10.1158/0008-5472.CAN-10-0785.
    1. Malandrino A, Mak M, Kamm RD, Moeendarbary E. Complex mechanics of the heterogeneous extracellular matrix in cancer. Extreme Mech Lett. 2018;21:25–34. doi: 10.1016/j.eml.2018.02.003.
    1. Hynes RO. The extracellular matrix: not just pretty fibrils. Science. 2009;326:1216–1219. doi: 10.1126/science.1176009.
    1. Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14:608–616. doi: 10.1016/S0955-0674(02)00361-7.
    1. Chiodoni C, Colombo MP, Sangaletti S. Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev. 2010;29:295–307. doi: 10.1007/s10555-010-9221-8.
    1. Gilbert PM, Havenstrite KL, Magnusson KE, Sacco A, Leonardi NA, Kraft P, Nguyen NK, Thrun S, Lutolf MP, Blau HM. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science. 2010;329:1078–1081. doi: 10.1126/science.1191035.
    1. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139:891–906. doi: 10.1016/j.cell.2009.10.027.
    1. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19:257–272. doi: 10.1016/j.ccr.2011.01.020.
    1. Simian M, Hirai Y, Navre M, Werb Z, Lochter A, Bissell MJ. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. Development. 2001;128:3117–3131.
    1. Miles FL, Sikes RA. Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res. 2014;12:297–312. doi: 10.1158/1541-7786.MCR-13-0535.
    1. Yamauchi M, Shiiba M. Lysine hydroxylation and cross-linking of collagen. Methods Mol Biol. 2008;446:95–108. doi: 10.1007/978-1-60327-084-7_7.
    1. Thomasset N, Lochter A, Sympson CJ, Lund LR, Williams DR, Behrendtsen O, Werb Z, Bissell MJ. Expression of autoactivated stromelysin-1 in mammary glands of transgenic mice leads to a reactive stroma during early development. Am J Pathol. 1998;153:457–467. doi: 10.1016/S0002-9440(10)65589-7.
    1. Takahashi M, Fukami S, Iwata N, Inoue K, Itohara S, Itoh H, Haraoka J, Saido T. In vivo glioma growth requires host-derived matrix metalloproteinase 2 for maintenance of angioarchitecture. Pharmacol Res. 2002;46:155–163. doi: 10.1016/S1043-6618(02)00081-6.
    1. Wandel E, Grasshoff A, Mittag M, Haustein UF, Saalbach A. Fibroblasts surrounding melanoma express elevated levels of matrix metalloproteinase-1 (MMP-1) and intercellular adhesion molecule-1 (ICAM-1) in vitro. Exp Dermatol. 2000;9:34–41. doi: 10.1034/j.1600-0625.2000.009001034.x.
    1. Poola I, DeWitty RL, Marshalleck JJ, Bhatnagar R, Abraham J, Leffall LD. Identification of MMP-1 as a putative breast cancer predictive marker by global gene expression analysis. Nat Med. 2005;11:481–483. doi: 10.1038/nm1243.
    1. Tan BB, Li Y, Fan LQ, Zhao Q, Liu QW, Liu Y, Wang D, Jia N. Upregulated Vav2 in gastric cancer tissues promotes tumor invasion and metastasis. Tumour Biol. 2017;39:1010428317698392. doi: 10.1177/1010428317698392.
    1. Labernadie A, Kato T, Brugues A, Serra-Picamal X, Derzsi S, Arwert E, Weston A, Gonzalez-Tarrago V, Elosegui-Artola A, Albertazzi L, et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat Cell Biol. 2017;19:224–237. doi: 10.1038/ncb3478.
    1. Jolly MK, Ware KE, Gilja S, Somarelli JA, Levine H. EMT and MET: necessary or permissive for metastasis? Mol Oncol. 2017;11:755–769. doi: 10.1002/1878-0261.12083.
    1. Somarelli JA, Schaeffer D, Marengo MS, Bepler T, Rouse D, Ware KE, Hish AJ, Zhao Y, Buckley AF, Epstein JI, et al. Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways. Oncogene. 2016;35:4302–4311. doi: 10.1038/onc.2015.497.
    1. Santi A, Kugeratski FG, Zanivan S. Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics. 2018;18:e1700167. doi: 10.1002/pmic.201700167.
    1. Neri S, Miyashita T, Hashimoto H, Suda Y, Ishibashi M, Kii H, Watanabe H, Kuwata T, Tsuboi M, Goto K, et al. Fibroblast-led cancer cell invasion is activated by epithelial-mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma. Cancer Lett. 2017;395:20–30. doi: 10.1016/j.canlet.2017.02.026.
    1. Burridge K, Fath K. Focal contacts: transmembrane links between the extracellular matrix and the cytoskeleton. Bioessays. 1989;10:104–108. doi: 10.1002/bies.950100403.
    1. Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, Washington MK, Shi C, Franco OE, Weaver AM, et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J Cell Biol. 2017;216:3799–3816. doi: 10.1083/jcb.201704053.
    1. Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, Gantt GA, Jr, Sukhdeo K, DeVecchio J, Vasanji A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013;210:2851–2872. doi: 10.1084/jem.20131195.
    1. Apicella M, Giannoni E, Fiore S, Ferrari KJ, Fernandez-Perez D, Isella C, Granchi C, Minutolo F, Sottile A, Comoglio PM, et al. Increased Lactate Secretion by Cancer Cells Sustains Non-cell-autonomous Adaptive Resistance to MET and EGFR Targeted Therapies. Cell Metab. 2018;28:848–865. doi: 10.1016/j.cmet.2018.08.006.
    1. Chan TS, Hsu CC, Pai VC, Liao WY, Huang SS, Tan KT, Yen CJ, Hsu SC, Chen WY, Shan YS, et al. Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med. 2016;213:2967–2988. doi: 10.1084/jem.20151665.
    1. Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, True L, Nelson PS. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18:1359–1368. doi: 10.1038/nm.2890.
    1. Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J, Head R, Liu J, Ruzinova MB, Lim KH. Tumor-Stroma IL1beta-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer. Cancer Res. 2018;78:1700–1712. doi: 10.1158/0008-5472.CAN-17-1366.
    1. Qiao Y, Zhang C, Li A, Wang D, Luo Z, Ping Y, Zhou B, Liu S, Li H, Yue D, et al. IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene. 2018;37:873–883. doi: 10.1038/onc.2017.387.
    1. Che Y, Wang J, Li Y, Lu Z, Huang J, Sun S, Mao S, Lei Y, Zang R, Sun N, He J. Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance. Cell Death Dis. 2018;9:759. doi: 10.1038/s41419-018-0808-2.
    1. Fiori ME, Villanova L, De Maria R. Cancer stem cells: at the forefront of personalized medicine and immunotherapy. Curr Opin Pharmacol. 2017;35:1–11. doi: 10.1016/j.coph.2017.04.006.
    1. Zhao J. Cancer stem cells and chemoresistance: The smartest survives the raid. Pharmacol Ther. 2016;160:145–158. doi: 10.1016/j.pharmthera.2016.02.008.
    1. Tang YA, Chen YF, Bao Y, Mahara S, Yatim S, Oguz G, Lee PL, Feng M, Cai Y, Tan EY, et al. Hypoxic tumor microenvironment activates GLI2 via HIF-1alpha and TGF-beta2 to promote chemoresistance in colorectal cancer. Proc Natl Acad Sci U S A. 2018;115:E5990–E5999. doi: 10.1073/pnas.1801348115.
    1. Cazet AS, Hui MN, Elsworth BL, Wu SZ, Roden D, Chan CL, Skhinas JN, Collot R, Yang J, Harvey K, et al. Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nat Commun. 2018;9:2897. doi: 10.1038/s41467-018-05220-6.
    1. Roswall P, Bocci M, Bartoschek M, Li H, Kristiansen G, Jansson S, Lehn S, Sjolund J, Reid S, Larsson C, et al. Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling. Nat Med. 2018;24:463–473. doi: 10.1038/nm.4494.
    1. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012;487:500–504. doi: 10.1038/nature11183.
    1. Luraghi P, Reato G, Cipriano E, Sassi F, Orzan F, Bigatto V, De Bacco F, Menietti E, Han M, Rideout WM, 3rd, et al. MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors. Cancer Res. 2014;74:1857–1869. doi: 10.1158/0008-5472.CAN-13-2340-T.
    1. Vaquero J, Lobe C, Tahraoui S, Claperon A, Mergey M, Merabtene F, Wendum D, Coulouarn C, Housset C, Desbois-Mouthon C, et al. The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma. Clin Cancer Res. 2018;24:4282–4296. doi: 10.1158/1078-0432.CCR-17-3725.
    1. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR, Chiu E, Buchanan M, Hosein AN, Basik M, Wrana JL. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151:1542–1556. doi: 10.1016/j.cell.2012.11.024.
    1. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, Garcia-Santos G, Ghajar C, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18:883–891. doi: 10.1038/nm.2753.
    1. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–659. doi: 10.1038/ncb1596.
    1. Richards KE, Zeleniak AE, Fishel ML, Wu J, Littlepage LE, Hill R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene. 2017;36:1770–1778. doi: 10.1038/onc.2016.353.
    1. Au Yeung CL, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, Li Y, Lu ES, Kwan K, Wong KK, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nat Commun. 2016;7:11150. doi: 10.1038/ncomms11150.
    1. Sansone P, Berishaj M, Rajasekhar VK, Ceccarelli C, Chang Q, Strillacci A, Savini C, Shapiro L, Bowman RL, Mastroleo C, et al. Evolution of Cancer Stem-like Cells in Endocrine-Resistant Metastatic Breast Cancers Is Mediated by Stromal Microvesicles. Cancer Res. 2017;77:1927–1941. doi: 10.1158/0008-5472.CAN-16-2129.
    1. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, Azzam DJ, Twyman-Saint Victor C, Wiemann BZ, Ishwaran H, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159:499–513. doi: 10.1016/j.cell.2014.09.051.
    1. Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, Lanciotti M, Serni S, Cirri P, Chiarugi P. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72:5130–5140. doi: 10.1158/0008-5472.CAN-12-1949.
    1. Salem AF, Whitaker-Menezes D, Lin Z, Martinez-Outschoorn UE, Tanowitz HB, Al-Zoubi MS, Howell A, Pestell RG, Sotgia F, Lisanti MP. Two-compartment tumor metabolism: autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. Cell Cycle. 2012;11:2545–2556. doi: 10.4161/cc.20920.
    1. Yang L, Achreja A, Yeung TL, Mangala LS, Jiang D, Han C, Baddour J, Marini JC, Ni J, Nakahara R, et al. Targeting Stromal Glutamine Synthetase in Tumors Disrupts Tumor Microenvironment-Regulated Cancer Cell Growth. Cell Metab. 2016;24:685–700. doi: 10.1016/j.cmet.2016.10.011.
    1. Mishra R, Haldar S, Placencio V, Madhav A, Rohena-Rivera K, Agarwal P, Duong F, Angara B, Tripathi M, Liu Z, et al. Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming. J Clin Invest. 2018;128:4472–4484. doi: 10.1172/JCI99397.
    1. Yu T, Yang G, Hou Y, Tang X, Wu C, Wu XA, Guo L, Zhu Q, Luo H, Du YE, et al. Cytoplasmic GPER translocation in cancer-associated fibroblasts mediates cAMP/PKA/CREB/glycolytic axis to confer tumor cells with multidrug resistance. Oncogene. 2017;36:2131–2145. doi: 10.1038/onc.2016.370.
    1. Pennacchietti S, Cazzanti M, Bertotti A, Rideout WM, 3rd, Han M, Gyuris J, Perera T, Comoglio PM, Trusolino L, Michieli P. Microenvironment-derived HGF overcomes genetically determined sensitivity to anti-MET drugs. Cancer Res. 2014;74:6598–6609. doi: 10.1158/0008-5472.CAN-14-0761.
    1. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest. 2006;116:1955–1962. doi: 10.1172/JCI26532.
    1. Duperret EK, Trautz A, Ammons D, Perales-Puchalt A, Wise MC, Yan J, Reed C, Weiner DB. Alteration of the Tumor Stroma Using a Consensus DNA Vaccine Targeting Fibroblast Activation Protein (FAP) Synergizes with Antitumor Vaccine Therapy in Mice. Clin Cancer Res. 2018;24:1190–1201. doi: 10.1158/1078-0432.CCR-17-2033.
    1. Kakarla S, Gottschalk S. CAR T cells for solid tumors: armed and ready to go? Cancer J. 2014;20:151–155. doi: 10.1097/PPO.0000000000000032.
    1. Wang LC, Lo A, Scholler J, Sun J, Majumdar RS, Kapoor V, Antzis M, Cotner CE, Johnson LA, Durham AC, 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. doi: 10.1158/2326-6066.CIR-13-0027.
    1. Lo A, Wang LS, Scholler J, Monslow J, Avery D, Newick K, O'Brien S, Evans RA, Bajor DJ, Clendenin C, et al. Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells. Cancer Res. 2015;75:2800–2810. doi: 10.1158/0008-5472.CAN-14-3041.
    1. Roberts EW, Deonarine A, Jones JO, Denton AE, Feig C, Lyons SK, Espeli M, Kraman M, McKenna B, Wells RJ, et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med. 2013;210:1137–1151. doi: 10.1084/jem.20122344.
    1. Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med. 2014;211:1503–1523. doi: 10.1084/jem.20140692.
    1. De Wever O, Van Bockstal M, Mareel M, Hendrix A, Bracke M. Carcinoma-associated fibroblasts provide operational flexibility in metastasis. Semin Cancer Biol. 2014;25:33–46. doi: 10.1016/j.semcancer.2013.12.009.
    1. Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, Collisson EA, 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. doi: 10.1016/j.cell.2014.08.007.
    1. Miao L, Liu Q, Lin CM, Luo C, Wang Y, Liu L, Yin W, Hu S, Kim WY, Huang L. Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors. Cancer Res. 2017;77:719–731. doi: 10.1158/0008-5472.CAN-16-0866.
    1. Ghebeh H, Dermime S. Comment on "Characterization of human lung tumor-associated fibroblasts and their ability to modulate the activation of tumor-associated T cells". J Immunol. 2007;179:732. doi: 10.4049/jimmunol.179.2.732.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner