Human carcinomas frequently exhibit significant stromal reactions such as the so-called “desmoplastic stroma” or “reactive stroma”, which is characterised by the existence of large numbers of stromal cells and extracellular matrix proteins. Carcinoma-associated fibroblasts (CAFs), which are rich in activated fibroblast populations exemplified by myofibroblasts, are among the predominant cell types present within the tumour-associated stroma. Increased numbers of stromal myofibroblasts are often associated with high-grade malignancies with poor prognoses in humans. CAF myofibroblasts possess abilities to promote primary tumour development, growth and progression by stimulating the processes of neoangiogenesis as well as tumour cell proliferation, survival, migration and invasion. Moreover, it has been demonstrated that CAFs serve as a niche supporting the metastatic colonisation of disseminated carcinoma cells in distant organs. Their contribution to primary and secondary malignancies makes these fibroblasts a potential therapeutic target and they also appear to be relevant to the development of drug resistance and tumour recurrence. This review summarises our current knowledge of tumour-promoting CAFs and discusses the therapeutic feasibility of targeting these cells as well as disrupting heterotypic interactions with other cell types in tumours that may improve the efficacy of current anti-tumour therapies.
References
[1]
Weinberg, R.A. The Biology of Cancer; Garland Science,Taylor & Francis Group LLC,: New York, NY, USA, 2007.
[2]
Nieman, K.M.; Kenny, H.A.; Penicka, C.V.; Ladanyi, A.; Buell-Gutbrod, R.; Zillhardt, M.R.; Romero, I.L.; Carey, M.S.; Mills, G.B.; Hotamisligil, G.S.; et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 2011, 17, 1498–1503.
[3]
Joyce, J.A.; Pollard, J.W. Microenvironmental regulation of metastasis. Nat. Rev. Cancer 2009, 9, 239–252, doi:10.1038/nrc2618.
[4]
Hanahan, D.; Coussens, L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 2012, 21, 309–322, doi:10.1016/j.ccr.2012.02.022.
[5]
Gupta, G.P.; Massague, J. Cancer metastasis: Building a framework. Cell 2006, 127, 679–695, doi:10.1016/j.cell.2006.11.001.
Meads, M.B.; Gatenby, R.A.; Dalton, W.S. Environment-mediated drug resistance: A major contributor to minimal residual disease. Nat. Rev. Cancer 2009, 9, 665–674, doi:10.1038/nrc2714.
[8]
Olive, K.P.; Jacobetz, M.A.; Davidson, C.J.; Gopinathan, A.; McIntyre, D.; Honess, D.; Madhu, B.; Goldgraben, M.A.; Caldwell, M.E.; Allard, D.; et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009, 324, 1457–1461.
[9]
Acharyya, S.; Oskarsson, T.; Vanharanta, S.; Malladi, S.; Kim, J.; Morris, P.G.; Manova-Todorova, K.; Leversha, M.; Hogg, N.; Seshan, V.E.; et al. A cxcl1 paracrine network links cancer chemoresistance and metastasis. Cell 2012, 150, 165–178, doi:10.1016/j.cell.2012.04.042.
[10]
Crawford, Y.; Kasman, I.; Yu, L.; Zhong, C.; Wu, X.; Modrusan, Z.; Kaminker, J.; Ferrara, N. Pdgf-c mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-vegf treatment. Cancer Cell 2009, 15, 21–34, doi:10.1016/j.ccr.2008.12.004.
[11]
Straussman, R.; Morikawa, T.; Shee, K.; Barzily-Rokni, M.; Qian, Z.R.; Du, J.; Davis, A.; Mongare, M.M.; Gould, J.; Frederick, D.T.; et al. Tumour micro-environment elicits innate resistance to raf inhibitors through hgf secretion. Nature 2012, 487, 500–504.
[12]
Joyce, J.A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005, 7, 513–520, doi:10.1016/j.ccr.2005.05.024.
[13]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674, doi:10.1016/j.cell.2011.02.013.
[14]
Kalluri, R.; Zeisberg, M. Fibroblasts in cancer. Nat. Rev. Cancer 2006, 6, 392–401, doi:10.1038/nrc1877.
[15]
Pietras, K.; Ostman, A. Hallmarks of cancer: Interactions with the tumor stroma. Exp. Cell Res. 2010, 316, 1324–1331, doi:10.1016/j.yexcr.2010.02.045.
[16]
Mifflin, R.C.; Pinchuk, I.V.; Saada, J.I.; Powell, D.W. Intestinal myofibroblasts: Targets for stem cell therapy. Am. J. Physiol. Gastrointest. Liver Physiol. 2011, 300, G684–G696, doi:10.1152/ajpgi.00474.2010.
[17]
Shimoda, M.; Mellody, K.T.; Orimo, A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin. Cell Dev. Biol. 2010, 21, 19–25, doi:10.1016/j.semcdb.2009.10.002.
[18]
Serini, G.; Gabbiani, G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp. Cell Res. 1999, 250, 273–283, doi:10.1006/excr.1999.4543.
[19]
Kidd, S.; Spaeth, E.; Watson, K.; Burks, J.; Lu, H.; Klopp, A.; Andreeff, M.; Marini, F.C. Origins of the tumor microenvironment: Quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One 2012, 7, e30563.
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.
[22]
Quante, M.; Tu, S.P.; Tomita, H.; Gonda, T.; Wang, S.S.; Takashi, S.; Baik, G.H.; Shibata, W.; Diprete, B.; Betz, K.S.; 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.
[23]
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, doi:10.1016/j.cell.2005.02.034.
[24]
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, doi:10.1016/j.ccr.2009.12.041.
[25]
Olumi, A.F.; Grossfeld, G.D.; Hayward, S.W.; Carroll, P.R.; Tlsty, T.D.; Cunha, G.R. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999, 59, 5002–5011.
[26]
Yang, G.; Rosen, D.G.; Zhang, Z.; Bast, R.C., Jr.; Mills, G.B.; Colacino, J.A.; Mercado-Uribe, I.; Liu, J. The chemokine growth-regulated oncogene 1 (gro-1) links ras signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc. Natl. Acad. Sci. USA 2006, 103, 16472–16477.
Hu, M.; Peluffo, G.; Chen, H.; Gelman, R.; Schnitt, S.; Polyak, K. Role of cox-2 in epithelial-stromal cell interactions and progression of ductal carcinoma in situ of the breast. Proc. Natl. Acad. Sci. USA 2009, 106, 3372–3377.
[29]
Medema, J.P.; Vermeulen, L. Microenvironmental regulation of stem cells in intestinal homeostasis and cancer. Nature 2011, 474, 318–326.
[30]
Malanchi, I.; Santamaria-Martinez, A.; Susanto, E.; Peng, H.; Lehr, H.A.; Delaloye, J.F.; Huelsken, J. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 2012, 481, 85–89.
[31]
Strell, C.; Rundqvist, H.; Ostman, A. Fibroblasts—A key host cell type in tumor initiation, progression, and metastasis. Ups. J. Med. Sci. 2012, 117, 187–195, doi:10.3109/03009734.2012.654859.
[32]
Horimoto, Y.; Polanska, U.; Takahashi, Y.; Orimo, A. Emerging roles of the tumor-associated stroma in promoting tumor metastasis. Cell. Adhes. Migr. 2012, 6, 193–202, doi:10.4161/cam.20631.
[33]
Desmouliere, A.; Guyot, C.; Gabbiani, G. The stroma reaction myofibroblast: A key player in the control of tumor cell behavior. Int. J. Dev. Biol. 2004, 48, 509–517, doi:10.1387/ijdb.041802ad.
[34]
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.
[35]
Kikuchi, Y.; Kashima, T.G.; Nishiyama, T.; Shimazu, K.; Morishita, Y.; Shimazaki, M.; Kii, I.; Horie, H.; Nagai, H.; Kudo, A.; et al. Periostin is expressed in pericryptal fibroblasts and cancer-associated fibroblasts in the colon. J. Histochem. Cytochem. 2008, 56, 753–764, doi:10.1369/jhc.2008.951061.
[36]
Pietras, K.; Sjoblom, T.; Rubin, K.; Heldin, C.H.; Ostman, A. PDGF receptors as cancer drug targets. Cancer Cell 2003, 3, 439–443, doi:10.1016/S1535-6108(03)00089-8.
Kojima, Y.; Acar, A.; Eaton, E.N.; Mellody, K.T.; Scheel, C.; Ben-Porath, I.; Onder, T.T.; Wang, Z.C.; Richardson, A.L.; Weinberg, R.A.; et al. Autocrine tgf-beta and stromal cell-derived factor-1 (sdf-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc. Natl. Acad. Sci. USA 2010, 107, 20009–20014.
[39]
Brentnall, T.A.; Lai, L.A.; Coleman, J.; Bronner, M.P.; Pan, S.; Chen, R. Arousal of cancer-associated stroma: Overexpression of palladin activates fibroblasts to promote tumor invasion. PLoS One 2012, 7, e30219.
[40]
Kawase, A.; Ishii, G.; Nagai, K.; Ito, T.; Nagano, T.; Murata, Y.; Hishida, T.; Nishimura, M.; Yoshida, J.; Suzuki, K.; et al. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int. J. Cancer 2008, 123, 1053–1059.
[41]
Mishra, P.J.; Mishra, P.J.; Humeniuk, R.; Medina, D.J.; Alexe, G.; Mesirov, J.P.; Ganesan, S.; Glod, J.W.; Banerjee, D. Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 2008, 68, 4331–4339.
[42]
Polanska, U.; Mellody, K.; Orimo, A. Tumour-promoting stromal myofibroblasts in human carcinomas. In The Tumor Microenvironment, Cancer Drug Discovery and Development; Bagley, R.G., Ed.; Springer: New York, NY, USA, 2010; Volume Chapter 16, pp. 325–349.
[43]
Wynn, T.A.; Ramalingam, T.R. Mechanisms of fibrosis: Therapeutic translation for fibrotic disease. Nat. Med. 2012, 18, 1028–1040, doi:10.1038/nm.2807.
[44]
Varga, J. Scleroderma and smads: Dysfunctional smad family dynamics culminating in fibrosis. Arthritis Rheum. 2002, 46, 1703–1713, doi:10.1002/art.10413.
[45]
Kim, K.K.; Wei, Y.; Szekeres, C.; Kugler, M.C.; Wolters, P.J.; Hill, M.L.; Frank, J.A.; Brumwell, A.N.; Wheeler, S.E.; Kreidberg, J.A.; et al. Epithelial cell alpha3beta1 integrin links beta-catenin and smad signaling to promote myofibroblast formation and pulmonary fibrosis. J. Clin. Invest. 2009, 119, 213–224.
[46]
Bechtel, W.; McGoohan, S.; Zeisberg, E.M.; Muller, G.A.; Kalbacher, H.; Salant, D.J.; Muller, C.A.; Kalluri, R.; Zeisberg, M. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 2010, 16, 544–550.
[47]
Polyak, K.; Haviv, I.; Campbell, I.G. Co-evolution of tumor cells and their microenvironment. Trends Genet. 2009, 25, 30–38, doi:10.1016/j.tig.2008.10.012.
Yauch, R.L.; Gould, S.E.; Scales, S.J.; Tang, T.; Tian, H.; Ahn, C.P.; Marshall, D.; Fu, L.; Januario, T.; Kallop, D.; et al. A paracrine requirement for hedgehog signalling in cancer. Nature 2008, 455, 406–410.
[50]
Anderberg, C.; Li, H.; Fredriksson, L.; Andrae, J.; Betsholtz, C.; Li, X.; Eriksson, U.; Pietras, K. Paracrine signaling by platelet-derived growth factor-cc promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res. 2009, 69, 369–378.
[51]
Stambolic, V.; Suzuki, A.; de la Pompa, J.L.; Brothers, G.M.; Mirtsos, C.; Sasaki, T.; Ruland, J.; Penninger, J.M.; Siderovski, D.P.; Mak, T.W. Negative regulation of pkb/akt-dependent cell survival by the tumor suppressor pten. Cell 1998, 95, 29–39, doi:10.1016/S0092-8674(00)81780-8.
[52]
Myers, M.P.; Pass, I.; Batty, I.H.; van der Kaay, J.; Stolarov, J.P.; Hemmings, B.A.; Wigler, M.H.; Downes, C.P.; Tonks, N.K. The lipid phosphatase activity of pten is critical for its tumor supressor function. Proc. Natl. Acad. Sci. USA 1998, 95, 13513–13518.
[53]
Bronisz, A.; Godlewski, J.; Wallace, J.A.; Merchant, A.S.; Nowicki, M.O.; Mathsyaraja, H.; Srinivasan, R.; Trimboli, A.J.; Martin, C.K.; Li, F.; et al. Reprogramming of the tumour microenvironment by stromal pten-regulated mir-320. Nat. Cell Biol 2012, 14, 159–167.
[54]
Bailey, J.M.; Mohr, A.M.; Hollingsworth, M.A. Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 2009, 28, 3513–3525, doi:10.1038/onc.2009.220.
[55]
Strand, M.F.; Wilson, S.R.; Dembinski, J.L.; Holsworth, D.D.; Khvat, A.; Okun, I.; Petersen, D.; Krauss, S. A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model. PLoS One 2011, 6, e19904.
[56]
Tian, H.; Callahan, C.A.; DuPree, K.J.; Darbonne, W.C.; Ahn, C.P.; Scales, S.J.; de Sauvage, F.J. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc. Natl. Acad. Sci. USA 2009, 106, 4254–4259.
[57]
Bailey, J.M.; Swanson, B.J.; Hamada, T.; Eggers, J.P.; Singh, P.K.; Caffery, T.; Ouellette, M.M.; Hollingsworth, M.A. Sonic hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 2008, 14, 5995–6004, doi:10.1158/1078-0432.CCR-08-0291.
[58]
Hosein, A.N.; Wu, M.; Arcand, S.L.; Lavallee, S.; Hebert, J.; Tonin, P.N.; Basik, M. Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations. Cancer Res. 2010, 70, 5770–5777.
[59]
Walter, K.; Omura, N.; Hong, S.M.; Griffith, M.; Goggins, M. Pancreatic cancer associated fibroblasts display normal allelotypes. Cancer Biol. Ther. 2008, 7, 882–888, doi:10.4161/cbt.7.6.5869.
[60]
Qiu, W.; Hu, M.; Sridhar, A.; Opeskin, K.; Fox, S.; Shipitsin, M.; Trivett, M.; Thompson, E.R.; Ramakrishna, M.; Gorringe, K.L.; et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat. Genet. 2008, 40, 650–655, doi:10.1038/ng.117.
[61]
Patocs, A.; Zhang, L.; Xu, Y.; Weber, F.; Caldes, T.; Mutter, G.L.; Platzer, P.; Eng, C. Breast-cancer stromal cells with tp53 mutations and nodal metastases. N. Engl. J. Med. 2007, 357, 2543–2551, doi:10.1056/NEJMoa071825.
[62]
Moinfar, F.; Man, Y.G.; Arnould, L.; Bratthauer, G.L.; Ratschek, M.; Tavassoli, F.A. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: Implications for tumorigenesis. Cancer Res. 2000, 60, 2562–2566.
[63]
Ashida, S.; Orloff, M.S.; Bebek, G.; Zhang, L.; Zheng, P.; Peehl, D.M.; Eng, C. Integrated analysis reveals critical genomic regions in prostate tumor microenvironment associated with clinicopathologic phenotypes. Clin. Cancer Res. 2012, 18, 1578–1587, doi:10.1158/1078-0432.CCR-11-2535.
[64]
Hu, M.; Yao, J.; Cai, L.; Bachman, K.E.; van den Brule, F.; Velculescu, V.; Polyak, K. Distinct epigenetic changes in the stromal cells of breast cancers. Nat. Genet. 2005, 37, 899–905, doi:10.1038/ng1596.
[65]
Jiang, L.; Gonda, T.A.; Gamble, M.V.; Salas, M.; Seshan, V.; Tu, S.; Twaddell, W.S.; Hegyi, P.; Lazar, G.; Steele, I.; et al. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res. 2008, 68, 9900–9908, doi:10.1158/0008-5472.CAN-08-1319.
[66]
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.
[67]
Huang, M.; Li, Y.; Zhang, H.; Nan, F. Breast cancer stromal fibroblasts promote the generation of CD44+CD24- cells through sdf-1/CXCR4 interaction. J. Exp. Clin. Cancer Res. 2010, 29, 80, doi:10.1186/1756-9966-29-80.
[68]
Liao, C.P.; Adisetiyo, H.; Liang, M.; Roy-Burman, P. Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells. Cancer Res. 2010, 70, 7294–7303, doi:10.1158/0008-5472.CAN-09-3982.
[69]
Vermeulen, L.; de Sousa, E.M.F.; van der Heijden, M.; Cameron, K.; de Jong, J.H.; Borovski, T.; Tuynman, J.B.; Todaro, M.; Merz, C.; Rodermond, H.; et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 2010, 12, 468–476.
[70]
Tsuyada, A.; Chow, A.; Wu, J.; Somlo, G.; Chu, P.; Loera, S.; Luu, T.; Li, A.X.; Wu, X.; Ye, W.; et al. CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells. Cancer Res. 2012, 72, 2768–2779, doi:10.1158/0008-5472.CAN-11-3567.
[71]
Dagouassat, M.; Suffee, N.; Hlawaty, H.; Haddad, O.; Charni, F.; Laguillier, C.; Vassy, R.; Martin, L.; Schischmanoff, P.O.; Gattegno, L.; et al. Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells. Int. J. Cancer 2010, 126, 1095–1108.
Goetz, J.G.; Minguet, S.; Navarro-Lerida, I.; Lazcano, J.J.; Samaniego, R.; Calvo, E.; Tello, M.; Osteso-Ibanez, T.; Pellinen, T.; Echarri, A.; et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 2011, 146, 148–163, doi:10.1016/j.cell.2011.05.040.
[75]
Gaggioli, C.; Hooper, S.; Hidalgo-Carcedo, C.; Grosse, R.; Marshall, J.F.; Harrington, K.; Sahai, E. Fibroblast-led collective invasion of carcinoma cells with differing roles for rhogtpases in leading and following cells. Nat. Cell Biol. 2007, 9, 1392–1400, doi:10.1038/ncb1658.
[76]
Sanz-Moreno, V.; Gaggioli, C.; Yeo, M.; Albrengues, J.; Wallberg, F.; Viros, A.; Hooper, S.; Mitter, R.; Feral, C.C.; Cook, M.; et al. Rock and jak1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 2011, 20, 229–245, doi:10.1016/j.ccr.2011.06.018.
[77]
O'Connell, J.T.; Sugimoto, H.; Cooke, V.G.; MacDonald, B.A.; Mehta, A.I.; LeBleu, V.S.; Dewar, R.; Rocha, R.M.; Brentani, R.R.; Resnick, M.B.; et al. Vegf-a and tenascin-c produced by s100a4+ stromal cells are important for metastatic colonization. Proc. Natl. Acad. Sci. USA 2011, 108, 16002–16007.
[78]
Oskarsson, T.; Massague, J. Extracellular matrix players in metastatic niches. EMBO J. 2011, 31, 254–256, doi:10.1038/emboj.2011.469.
[79]
Sethi, N.; Kang, Y. Unravelling the complexity of metastasis—Molecular understanding and targeted therapies. Nat. Rev. Cancer 2011, 11, 735–748, doi:10.1038/nrc3125.
[80]
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, doi:10.1158/1535-7163.MCT-11-0340.
[81]
Loeffler, M.; Kruger, J.A.; Niethammer, A.G.; Reisfeld, R.A. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J. Clin. Invest. 2006, 116, 1955–1962, doi:10.1172/JCI26532.
[82]
Pietras, K.; Pahler, J.; Bergers, G.; Hanahan, D. Functions of paracrine pdgf signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med. 2008, 5, e19, doi:10.1371/journal.pmed.0050019.
Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21, 418–429, doi:10.1016/j.ccr.2012.01.007.
[85]
Tan, W.; Zhang, W.; Strasner, A.; Grivennikov, S.; Cheng, J.Q.; Hoffman, R.M.; Karin, M. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through rankl-rank signalling. Nature 2011, 470, 548–553, doi:10.1038/nature09707.
[86]
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, doi:10.1158/1078-0432.CCR-07-5211.
[87]
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 cancer. Clin. Cancer Res. 2003, 9, 1639–1647.
[88]
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, doi:10.1159/000069863.
[89]
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 model. Cancer Res. 2002, 62, 4767–4772.
[90]
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, doi:10.4161/cbt.6.11.4874.
[91]
Santos, A.M.; Jung, J.; Aziz, N.; Kissil, J.L.; Pure, E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J. Clin. Invest. 2009, 119, 3613–3625, doi:10.1172/JCI38988.
[92]
Eager, R.M.; Cunningham, C.C.; Senzer, N.; Richards, D.A.; Raju, R.N.; Jones, B.; Uprichard, M.; Nemunaitis, J. Phase II trial of talabostat and docetaxel in advanced non-small cell lung cancer. Clin. Oncol. (R. Coll. Radiol.) 2009, 21, 464–472, doi:10.1016/j.clon.2009.04.007.
[93]
Huang, S.; Fang, R.; Xu, J.; Qiu, S.; Zhang, H.; Du, J.; Cai, S. Evaluation of the tumor targeting of a fapalpha-based doxorubicin prodrug. J. Drug Target. 2011, 19, 487–496, doi:10.3109/1061186X.2010.511225.
[94]
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.
[95]
Liao, D.; Luo, Y.; Markowitz, D.; Xiang, R.; Reisfeld, R.A. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4t1 murine breast cancer model. PLoS One 2009, 4, e7965.
[96]
Wang, W.; Li, Q.; Yamada, T.; Matsumoto, K.; Matsumoto, I.; Oda, M.; Watanabe, G.; Kayano, Y.; Nishioka, Y.; Sone, S.; et al. Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res. 2009, 15, 6630–6638, doi:10.1158/1078-0432.CCR-09-1001.
[97]
Kano, M.R.; Bae, Y.; Iwata, C.; Morishita, Y.; Yashiro, M.; Oka, M.; Fujii, T.; Komuro, A.; Kiyono, K.; Kaminishi, M.; et al. Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc. Natl. Acad. Sci. USA 2007, 104, 3460–3465.
[98]
Sounni, N.E.; Dehne, K.; van Kempen, L.; Egeblad, M.; Affara, N.I.; Cuevas, I.; Wiesen, J.; Junankar, S.; Korets, L.; Lee, J.; et al. Stromal regulation of vessel stability by MMP14 and TGFβ. Dis. Models Mech. 2010, 3, 317–332, doi:10.1242/dmm.003863.
[99]
Akhurst, R.J.; Hata, A. Targeting the TGFβ signalling pathway in disease. Nat. Rev. Drug Dis. 2012, 11, 790–811, doi:10.1038/nrd3810.
[100]
Liu, J.; Liao, S.; Diop-Frimpong, B.; Chen, W.; Goel, S.; Naxerova, K.; Ancukiewicz, M.; Boucher, Y.; Jain, R.K.; Xu, L. TGFβ blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc. Natl. Acad. Sci. USA 2012, 109, 16618–16623.
[101]
Hooper, S.; Gaggioli, C.; Sahai, E. A chemical biology screen reveals a role for RAB21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion. Br. J. Cancer 2010, 102, 392–402, doi:10.1038/sj.bjc.6605469.
[102]
Mueller, M.M.; Fusenig, N.E. Friends or foes—Bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 2004, 4, 839–849.
[103]
Heldin, C.H.; Rubin, K.; Pietras, K.; Ostman, A. High interstitial fluid pressure—An obstacle in cancer therapy. Nat. Rev. Cancer 2004, 4, 806–813, doi:10.1038/nrc1456.
[104]
Jain, R.K. Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev. 1990, 9, 253–266.
[105]
Haubeiss, S.; Schmid, J.O.; Murdter, T.E.; Sonnenberg, M.; Friedel, G.; van der Kuip, H.; Aulitzky, W.E. Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol. Cancer 2010, 9, 168, doi:10.1186/1476-4598-9-168.
[106]
Pietras, K.; Ostman, A.; Sjoquist, M.; Buchdunger, E.; Reed, R.K.; Heldin, C.H.; Rubin, K. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001, 61, 2929–2934.
[107]
Falcon, B.L.; Pietras, K.; Chou, J.; Chen, D.; Sennino, B.; Hanahan, D.; McDonald, D.M. Increased vascular delivery and efficacy of chemotherapy after inhibition of platelet-derived growth factor-b. Am. J. Pathol. 2011, 178, 2920–2930, doi:10.1016/j.ajpath.2011.02.019.
[108]
Iijima, J.; Konno, K.; Itano, N. Inflammatory alterations of the extracellular matrix in the tumor microenvironment. Cancers 2011, 3, 3189–3205, doi:10.3390/cancers3033189.
[109]
Singh, S.; Ross, S.R.; Acena, M.; Rowley, D.A.; Schreiber, H. Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J. Exp. Med. 1992, 175, 139–146, doi:10.1084/jem.175.1.139.
[110]
Schreiber, R.D.; Old, L.J.; Smyth, M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011, 331, 1565–1570, doi:10.1126/science.1203486.
[111]
Balko, J.M.; Cook, R.S.; Vaught, D.B.; Kuba, M.G.; Miller, T.W.; Bhola, N.E.; Sanders, M.E.; Granja-Ingram, N.M.; Smith, J.J.; Meszoely, I.M.; et al. Profiling of residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a mechanism of drug resistance. Nat. Med. 2012, 18, 1052–1059, doi:10.1038/nm.2795.
[112]
Roodhart, J.M.; Daenen, L.G.; Stigter, E.C.; Prins, H.J.; Gerrits, J.; Houthuijzen, J.M.; Gerritsen, M.G.; Schipper, H.S.; Backer, M.J.; van Amersfoort, M.; et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011, 20, 370–383, doi:10.1016/j.ccr.2011.08.010.
[113]
DeRose, Y.S.; Wang, G.; Lin, Y.C.; Bernard, P.S.; Buys, S.S.; Ebbert, M.T.; Factor, R.; Matsen, C.; Milash, B.A.; Nelson, E.; et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat. Med. 2011, 17, 1514–1520, doi:10.1038/nm.2454.
