Carcinoma-associated fibroblasts: Orchestrating the composition of malignancy

Genes and Development

Volumn 30, Issue 9, 2016, Pages 1002-1019

  Gascard, Philippe ^a   Tlsty, Thea D ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

CAF; CAF targeted therapies; Carcinoma associated fibroblasts; Field cancerization; Microenvironment; Stromal epithelial interactions

Indexed keywords

ANTIFIBROTIC AGENT; BH3 PROTEIN; BIOLOGICAL MARKER; CHEMOKINE RECEPTOR CXCR4 ANTAGONIST; CYTOKINE RECEPTOR ANTAGONIST; FIBROBLAST GROWTH FACTOR 5; FIBROBLAST GROWTH FACTOR RECEPTOR INHIBITOR; HEDGEHOG INHIBITOR; MONOCARBOXYLATE TRANSPORTER 4; MULTITARGET TYROSINE KINASE RECEPTOR INHIBITOR; NOTCH RECEPTOR INHIBITOR; PLATELET DERIVED GROWTH FACTOR RECEPTOR INHIBITOR; PROTEIN INHIBITOR; TRANSFORMING GROWTH FACTOR BETA INHIBITOR; UNCLASSIFIED DRUG;

CANCER GROWTH; CARCINOMA ASSOCIATED FIBROBLAST; EPIGENETICS; FIBROBLAST; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MODIFIER GENE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CARCINOMA; DISEASE COURSE; PATHOLOGY; PATHOPHYSIOLOGY;

ANIMALS; CARCINOMA; DISEASE PROGRESSION; FIBROBLASTS; HUMANS;

EID: 84965082206     PISSN: 08909369     EISSN: 15495477     Source Type: Journal    
DOI: 10.1101/gad.279737.116     Document Type: Review

References (143)

1. Albrengues J, Bertero T, Grasset E, Bonan S, Maiel M, Bourget I, Philippe C, Herraiz Serrano C, Benamar S, Croce O, et al. 2015. Epigenetic switch drives the conversion of fibroblasts into proinvasive cancer-associated fibroblasts. Nat Commun 6: 10204.
2. Arendt LM, Rudnick JA, Keller PJ, Kuperwasser C. 2010. Stroma in breast development and disease. Semin Cell Dev Biol 21: 11–18.
3. Augsten M. 2014. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4: 62.
4. Banerjee J, Mishra R, Li X, Jackson RS II, Sharma A, Bhowmick NA. 2014. A reciprocal role of prostate cancer on stromal DNA damage. Oncogene 33: 4924–4931.
5. Barcellos-Hoff MH, Medina D. 2005. New highlights on stroma– epithelial interactions in breast cancer. Breast Cancer Res 7: 33–36.
6. Barcellos-Hoff MH, Ravani SA. 2000. Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60: 1254–1260.
7. Berdiel-Acer M, Sanz-Pamplona R, Calon A, Cuadras D, Berenguer A, Sanjuan X, Paules MJ, Salazar R, Moreno V, Batlle E, et al. 2014. Differences between CAFs and their paired NCF from adjacent colonic mucosa reveal functional heterogeneity of CAFs, providing prognostic information. Mol Oncol 8: 1290–1305.
8. Berking C, Takemoto R, Schaider H, Showe L, Satyamoorthy K, Robbins P, Herlyn M. 2001. Transforming growth factor-β1 increases survival of human melanoma through stroma remodeling. Cancer Res 61: 8306–8316.
9. Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG, Moses HL. 2004. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 303: 848–851.
10. Bing C, Trayhurn P. 2009. New insights into adipose tissue atrophy in cancer cachexia. Proc Nutr Soc 68: 385–392.
11. Bissell MJ, Hines WC. 2011. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17: 320–329.
12. Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, Dray C, Guiet R, Maridonneau-Parini I, Le Gonidec S, et al. 2013. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res 73: 5657–5668.
13. Boulard M, Storck S, Cong R, Pinto R, Delage H, Bouvet P. 2010. Histone variant macroH2A1 deletion in mice causes female-specific steatosis. Epigenetics Chromatin 3: 8.
14. Brennen WN, Rosen DM, Wang H, Isaacs JT, Denmeade SR. 2012. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst 104: 1320–1334.
15. Callahan MK, Wolchok JD. 2015. Clinical activity, toxicity, biomarkers, and future development of CTLA-4 checkpoint antagonists. Semin Oncol 42: 573–586.
16. Calon A, Tauriello DV, Batlle E. 2014. TGF-β in CAF-mediated tumor growth and metastasis. Semin Cancer Biol 25: 15–22.
17. Castells M, Thibault B, Delord JP, Couderc B. 2012. Implication of tumor microenvironment in chemoresistance: tumor-associated stromal cells protect tumor cells from cell death. Int J Mol Sci 13: 9545–9571.
18. Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO. 2004. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2: E7.
19. Chang HY, Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sorlie T, Dai H, He YD, van’t Veer LJ, Bartelink H, et al. 2005. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci 102: 3738–3743.
20. Chen F, Zhuang X, Lin L, Yu P, Wang Y, Shi Y, Hu G, Sun Y. 2015a. New horizons in tumor microenvironment biology: challenges and opportunities. BMC Med 13: 45.
21. Chen H, Ruiz PD, McKimpson WM, Novikov L, Kitsis RN, Gamble MJ. 2015b. MacroH2A1 and ATM play opposing roles in paracrine senescence and the senescence-associated secretory phenotype. Mol Cell 59: 719–731.
22. Cheng N, Chytil A, Shyr Y, Joly A, Moses HL. 2007. Enhanced hepatocyte growth factor signaling by type II transforming growth factor-β receptor knockout fibroblasts promotes mammary tumorigenesis. Cancer Res 67: 4869–4877.
23. Chou J, Werb Z. 2012. MicroRNAs play a big role in regulating ovarian cancer-associated fibroblasts and the tumor microenvironment. Cancer Discov 2: 1078–1080.
24. Cirri P, Chiarugi P. 2011. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res 1: 482–497.
25. Corver WE, Ter Haar NT, Fleuren GJ, Oosting J. 2011. Cervical carcinoma-associated fibroblasts are DNA diploid and do not show evidence for somatic genetic alterations. Cell Oncol (Dordr) 34: 553–563.
26. Cuiffo BG, Karnoub AE. 2012. Mesenchymal stem cells in tumor development: emerging roles and concepts. Cell Adh Migr 6: 220–230.
27. DeFilippis RA, Chang H, Dumont N, Rabban JT, Chen YY, Fontenay GV, Berman HK, Gauthier ML, Zhao J, Hu D, et al. 2012. CD36 repression activates a multicellular stromal program shared by high mammographic density and tumor tissues. Cancer Discov 2: 826–839.
28. DeFilippis RA, Fordyce C, Patten K, Chang H, Zhao J, Fontenay GV, Kerlikowske K, Parvin B, Tlsty TD. 2014. Stress signaling from human mammary epithelial cells contributes to phenotypes of mammographic density. Cancer Res 74: 5032–5044.
29. Dhouailly D, Rogers GE, Sengel P. 1978. The specification of feather and scale protein synthesis in epidermal-dermal re-combinations. Dev Biol 65: 58–68.
30. Doldi V, Callari M, Giannoni E, D’Aiuto F, Maffezzini M, Valdagni R, Chiarugi P, Gandellini P, Zaffaroni N. 2015. Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget 6: 31441–31460.
31. Dumont N, Liu B, Defilippis RA, Chang H, Rabban JT, Karnezis AN, Tjoe JA, Marx J, Parvin B, Tlsty TD. 2013. Breast fibroblasts modulate early dissemination, tumorigenesis, and metastasis through alteration of extracellular matrix characteristics. Neoplasia 15: 249–262.
32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. 2009. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 228–247.
33. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. 2010. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17: 135–147.
34. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, et al. 2013. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci 110: 20212–20217.
35. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, et al. 2008. Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14: 518–527.
36. Fischer E, Chaitanya K, Wuest T, Wadle A, Scott AM, van den Broek M, Schibli R, Bauer S, Renner C. 2012. Radioimmuno-therapy of fibroblast activation protein positive tumors by rapidly internalizing antibodies. Clin Cancer Res 18: 6208–6218.
37. Fordyce C, Fessenden T, Pickering C, Jung J, Singla V, Berman H, Tlsty T. 2010. DNA damage drives an activin a–dependent induction of cyclooxygenase-2 in premalignant cells and lesions. Cancer Prev Res (Phila) 3: 190–201.
38. Fordyce CA, Patten KT, Fessenden TB, Defilippis R, Hwang ES, Zhao J, Tlsty TD. 2012. Cell-extrinsic consequences of epithelial stress: activation of protumorigenic tissue phenotypes. Breast Cancer Res 14: R155.
39. Gandellini P, Giannoni E, Casamichele A, Taddei ML, Callari M, Piovan C, Valdagni R, Pierotti MA, Zaffaroni N, Chiarugi P. 2014. miR-205 hinders the malignant interplay between prostate cancer cells and associated fibroblasts. Antioxid Redox Signal 20: 1045–1059.
40. Gialeli C, Nikitovic D, Kletsas D, Theocharis AD, Tzanakakis GN, Karamanos NK. 2014. PDGF/PDGFR signaling and targeting in cancer growth and progression: focus on tumor microenvironment and cancer-associated fibroblasts. Curr Pharm Des 20: 2843–2848.
41. Giulianelli S, Cerliani JP, Lamb CA, Fabris VT, Bottino MC, Gorostiaga MA, Novaro V, Gongora A, Baldi A, Molinolo A, et al. 2008. Carcinoma-associated fibroblasts activate progesterone receptors and induce hormone independent mammary tumor growth: a role for the FGF-2/FGFR-2 axis. Int J Cancer 123: 2518–2531.
42. Guan J, Chen J. 2014. Tumor microenvironment: the promising target for tumor therapy Cancer Cell Microenviron 1: e81.
43. Ha SY, Yeo SY, Xuan YH, Kim SH. 2014. The prognostic significance of cancer-associated fibroblasts in esophageal squamous cell carcinoma. PLoS One 9: e99955.
44. Haubeiss S, Schmid JO, Murdter TE, Sonnenberg M, Friedel G, van der Kuip H, Aulitzky WE. 2010. Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer 9: 168.
45. Hematti P. 2012. Mesenchymal stromal cells and fibroblasts: a case of mistaken identity? Cytotherapy 14: 516–521.
46. Hendrayani SF, Al-Khalaf HH, Aboussekhra A. 2013. Curcumin triggers p16-dependent senescence in active breast cancer-associated fibroblasts and suppresses their paracrine procarcinogenic effects. Neoplasia 15: 631–640.
47. Hofheinz RD, al-Batran SE, Hartmann F, Hartung G, Jager D, Renner C, Tanswell P, Kunz U, Amelsberg A, Kuthan H, et al. 2003. Stromal antigen targeting by a humanised monoclonal antibody: an early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer. Onkologie 26: 44–48.
48. Hosein AN, Wu M, Arcand SL, Lavallee S, Hebert J, Tonin PN, Basik M. 2010. Breast carcinoma-associated fibroblasts rarely contain p53 mutations or chromosomal aberrations. Cancer Res 70: 5770–5777.
49. Hu M, Yao J, Carroll DK, Weremowicz S, Chen H, Carrasco D, Richardson A, Violette S, Nikolskaya T, Nikolsky Y, et al. 2008. Regulation of in situ to invasive breast carcinoma transition. Cancer Cell 13: 394–406.
50. Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, Wu Y, Qin J. 2015. Fibroblast-derived exosomes contribute to chemoresistance through priming cancer stem cells in colorectal cancer. PLoS One 10: e0125625.
51. Ishii G, Ochiai A, Neri S. 2016. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliv Rev 99: 186–196.
52. Izumi D, Ishimoto T, Miyake K, Sugihara H, Eto K, Sawayama H, Yasuda T, Kiyozumi Y, Kaida T, Kurashige J, et al. 2016. CXCL12/CXCR4 activation by cancer-associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer. Int J Cancer 138: 1207–1219.
53. Jain RK, Lahdenranta J, Fukumura D. 2008. Targeting PDGF signaling in carcinoma-associated fibroblasts controls cervical cancer in mouse model. PLoS Med 5: e24.
54. Johansson AC, Ansell A, Jerhammar F, Lindh MB, Grenman R, Munck-Wikland E, Ostman A, Roberg K. 2012. Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Mol Cancer Res 10: 1158–1168.
55. Junttila MR, de Sauvage FJ. 2013. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501: 346–354.
56. Kalluri R, Zeisberg M. 2006. Fibroblasts in cancer. Nat Rev Cancer 6: 392–401.
57. Kang N, Shah VH, Urrutia R. 2015. Membrane-to-nucleus signals and epigenetic mechanisms for myofibroblastic activation and desmoplastic stroma: potential therapeutic targets for liver metastasis? Mol Cancer Res 13: 604–612.
58. Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. 2012. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res 10: 1403–1418.
59. Kerlikowske K, Molinaro AM, Gauthier ML, Berman HK, Wald-man F, Bennington J, Sanchez H, Jimenez C, Stewart K, Chew K, et al. 2010. Biomarker expression and risk of subsequent tumors after initial ductal carcinoma in situ diagnosis. J Natl Cancer Inst 102: 627–637.
60. Kim JS, Shukla SD. 2005. Histone h3 modifications in rat hepatic stellate cells by ethanol. Alcohol Alcohol 40: 367–372.
61. Kinugasa Y, Matsui T, Takakura N. 2014. CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment. Stem Cells 32: 145–156.
62. Koliaraki V, Pasparakis M, Kollias G. 2015. IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer. J Exp Med 212: 2235–2251.
63. Kornmann M, Ishiwata T, Beger HG, Korc M. 1997. Fibroblast growth factor-5 stimulates mitogenic signaling and is overexpressed in human pancreatic cancer: evidence for autocrine and paracrine actions. Oncogene 15: 1417–1424.
64. Kurashige J, Mima K, Sawada G, Takahashi Y, Eguchi H, Sugimachi K, Mori M, Yanagihara K, Yashiro M, Hirakawa K, et al. 2015. Epigenetic modulation and repression of miR-200b by cancer-associated fibroblasts contribute to cancer invasion and peritoneal dissemination in gastric cancer. Carcinogenesis 36: 133–141.
65. Lecomte J, Masset A, Blacher S, Maertens L, Gothot A, Delgaudine M, Bruyere F, Carnet O, Paupert J, Illemann M, et al. 2012. Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor. Neoplasia 14: 943–951.
66. Li Q, Zhang D, Wang Y, Sun P, Hou X, Larner J, Xiong W, Mi J. 2013. MiR-21/Smad 7 signaling determines TGF-β1-induced CAF formation. Sci Rep 3: 2038.
67. Li XY, Hu SQ, Xiao L. 2015. The cancer-associated fibroblasts and drug resistance. Eur Rev Med Pharmacol Sci 19: 2112–2119.
68. Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA. 2009. Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4: e7965.
69. Lin HJ, Zuo T, Lin CH, Kuo CT, Liyanarachchi S, Sun S, Shen R, Deatherage DE, Potter D, Asamoto L, et al. 2008. Breast cancer–associated fibroblasts confer AKT1-mediated epigenetic silencing of Cystatin M in epithelial cells. Cancer Res 68: 10257–10266.
70. Lin X, Jia J, Du T, Li W, Wang X, Wei J, Zeng H, Yao L, Chen X, Zhuang J, et al. 2015. Overexpression of miR-155 in the liver of transgenic mice alters the expression profiling of hepatic genes associated with lipid metabolism. PLoS One 10: e0118417.
71. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA. 2006. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest 116: 1955–1962.
72. Lyons TR, O’Brien J, Borges VF, Conklin MW, Keely PJ, Eliceiri KW, Marusyk A, Tan AC, Schedin P. 2011. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat Med 17: 1109–1115.
73. Ma XJ, Dahiya S, Richardson E, Erlander M, Sgroi DC. 2009. Gene expression profiling of the tumor microenvironment during breast cancer progression. Breast Cancer Res 11: R7.
74. Madar S, Goldstein I, Rotter V. 2013. ‘Cancer associated fibroblasts’—more than meets the eye. Trends Mol Med 19: 447–453.
75. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C. 2004. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 117: 1495–1502.
76. Maris P, Blomme A, Palacios AP, Costanza B, Bellahcene A, Bianchi E, Gofflot S, Drion P, Trombino GE, Di Valentin E, et al. 2015. Asporin is a fibroblast-derived TGF-β1 inhibitor and a tumor suppressor associated with good prognosis in breast cancer. PLoS Med 12: e1001871.
77. Marsh T, Pietras K, McAllister SS. 2013. Fibroblasts as architects of cancer pathogenesis. Biochim Biophys Acta 1832: 1070–1078.
78. Martinez-Outschoorn UE, Lin Z, Ko YH, Goldberg AF, Flomenberg N, Wang C, Pavlides S, Pestell RG, Howell A, Sotgia F, et al. 2011a. Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells. Cell Cycle 10: 2521–2528.
79. Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP. 2011b. Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol 43: 1045–1051.
80. Martinez-Outschoorn U, Sotgia F, Lisanti MP. 2014. Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Semin Oncol 41: 195–216.
81. Martinez-Outschoorn UE, Sotgia F, Lisanti MP. 2015. Caveolae and signalling in cancer. Nat Rev Cancer 15: 225–237.
82. McDonald LT, Russell DL, Kelly RR, Xiong Y, Motamarry A, Patel RK, Jones JA, Watson PM, Turner DP, Watson DK, et al. 2015. Hematopoietic stem cell-derived cancer-associated fibroblasts are novel contributors to the pro-tumorigenic microenvironment. Neoplasia 17: 434–448.
83. Meads MB, Gatenby RA, Dalton WS. 2009. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9: 665–674.
84. Micke P, Ostman A. 2004. Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 45(Suppl 2): S163–S175.
85. Mitra AK, Zillhardt M, Hua Y, Tiwari P, Murmann AE, Peter ME, Lengyel E. 2012. MicroRNAs reprogram normal fibroblasts into cancer-associated fibroblasts in ovarian cancer. Cancer Discov 2: 1100–1108.
86. Nakagawa S, Miki Y, Miyashita M, Hata S, Takahashi Y, Rai Y, Sagara Y, Ohi Y, Hirakawa H, Tamaki K, et al. 2016. Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets. Breast Cancer Res Treat 155: 65–75.
87. Ohlund D, Elyada E, Tuveson D. 2014. Fibroblast heterogeneity in the cancer wound. J Exp Med 211: 1503–1523.
88. Ohshio Y, Teramoto K, Hanaoka J, Tezuka N, Itoh Y, Asai T, Daigo Y, Ogasawara K. 2015. Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine. Cancer Sci 106: 134–142.
89. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, et al. 2009. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324: 1457–1461.
90. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. 1999. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 59: 5002–5011.
91. Orimo A, Weinberg RA. 2007. Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther 6: 618–619.
92. Ostermann E, Garin-Chesa P, Heider KH, Kalat M, Lamche H, Puri C, Kerjaschki D, Rettig WJ, Adolf GR. 2008. Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clin Cancer Res 14: 4584–4592.
93. Ostman A, Augsten M. 2009. Cancer-associated fibroblasts and tumor growth—bystanders turning into key players. Curr Opin Genet Dev 19: 67–73.
94. Osuala KO, Sameni M, Shah S, Aggarwal N, Simonait ML, Franco OE, Hong Y, Hayward SW, Behbod F, Mattingly RR, et al. 2015. Il-6 signaling between ductal carcinoma in situ cells and carcinoma-associated fibroblasts mediates tumor cell growth and migration. BMC Cancer 15: 584.
95. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, et al. 2014. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25: 719–734.
96. Pang W, Su J, Wang Y, Feng H, Dai X, Yuan Y, Chen X, Yao W. 2015. Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts. Cancer Sci 106: 1362–1369.
97. Paulsson J, Micke P. 2014. Prognostic relevance of cancer-associated fibroblasts in human cancer. Semin Cancer Biol 25: 61–68.
98. Peiris-Pages M, Sotgia F, Lisanti MP. 2015. Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog–GLI signalling in breast cancer cells. Oncotarget 6: 10728–10745.
99. Pennati M, Lopergolo A, Profumo V, De Cesare M, Sbarra S, Valdagni R, Zaffaroni N, Gandellini P, Folini M. 2014. miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells. Biochem Pharmacol 87: 579–597.
100. Perugorria MJ, Wilson CL, Zeybel M, Walsh M, Amin S, Robinson S, White SA, Burt AD, Oakley F, Tsukamoto H, et al. 2012. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 56: 1129–1139.
101. Pietras K, Ostman A. 2010. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316: 1324–1331.
102. Pietras K, Pahler J, Bergers G, Hanahan D. 2008. Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5: e19.
103. Procopio MG, Laszlo C, Al Labban D, Kim DE, Bordignon P, Jo SH, Goruppi S, Menietti E, Ostano P, Ala U, et al. 2015. Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation. Nat Cell Biol 17: 1193–1204.
104. Qiu W, Hu M, Sridhar A, Opeskin K, Fox S, Shipitsin M, Trivett M, Thompson ER, Ramakrishna M, Gorringe KL, et al. 2008. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet 40: 650–655.
105. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al. 2011. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19: 257–272.
106. Radisky DC, Kenny PA, Bissell MJ. 2007. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem 101: 830–839.
107. Ren Y, Zhou X, Liu X, Jia HH, Zhao XH, Wang QX, Han L, Song X, Zhu ZY, Sun T, et al. 2016. Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy. Cancer Lett 374: 96–106.
108. Rizvi S, Mertens JC, Bronk SF, Hirsova P, Dai H, Roberts LR, Kaufmann SH, Gores GJ. 2014. Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis. J Biol Chem 289: 22835–22849.
109. Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ. 1995. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 95: 859–873.
110. Rozenchan PB, Carraro DM, Brentani H, de Carvalho Mota LD, Bastos EP, e Ferreira EN, Torres CH, Katayama ML, Roela RA, Lyra EC, et al. 2009. Reciprocal changes in gene expression profiles of cocultured breast epithelial cells and primary fibroblasts. Int J Cancer 125: 2767–2777.
111. Saadi A, Shannon NB, Lao-Sirieix P, O’Donovan M, Walker E, Clemons NJ, Hardwick JS, Zhang C, Das M, Save V, et al. 2010. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc Natl Acad Sci 107: 2177–2182.
112. Sadlonova A, Bowe DB, Novak Z, Mukherjee S, Duncan VE, Page GP, Frost AR. 2009. Identification of molecular distinctions between normal breast-associated fibroblasts and breast cancer-associated fibroblasts. Cancer Microenviron 2: 9–21.
113. Santos AM, Jung J, Aziz N, Kissil JL, Pure E. 2009. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest 119: 3613–3625.
114. Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, et al. 2014. The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158: 564–578.
115. Schuberth PC, Hagedorn C, Jensen SM, Gulati P, van den Broek M, Mischo A, Soltermann A, Jungel A, Marroquin Belaunzaran O, Stahel R, et al. 2013. Treatment of malignant pleural mesothelioma by fibroblast activation protein-specific re-directed T cells. J Transl Med 11: 187.
116. Servais C, Erez N. 2013. From sentinel cells to inflammatory culprits: cancer-associated fibroblasts in tumour-related inflammation. J Pathol 229: 198–207.
117. Shah SH, Miller P, Garcia-Contreras M, Ao Z, Machlin L, Issa E, El-Ashry D. 2015. Hierarchical paracrine interaction of breast cancer associated fibroblasts with cancer cells via hMAPK-microRNAs to drive ER-negative breast cancer phenotype. Cancer Biol Ther 16: 1671–1681.
118. Shakya R, Gonda T, Quante M, Salas M, Kim S, Brooks J, Hirsch S, Davies J, Cullo A, Olive K, et al. 2013. Hypomethylating therapy in an aggressive stroma-rich model of pancreatic carcinoma. Cancer Res 73: 885–896.
119. Sharma M, Beck AH, Webster JA, Espinosa I, Montgomery K, Varma S, van de Rijn M, Jensen KC, West RB. 2010. Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ. Breast Cancer Res Treat 123: 397–404.
120. Silverstein RL, Febbraio M. 2009. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal 2: re3.
121. Slany A, Bileck A, Muqaku B, Gerner C. 2015. Targeting breast cancer-associated fibroblasts to improve anti-cancer therapy. Breast 24: 532–538.
122. Sriram G, Bigliardi PL, Bigliardi-Qi M. 2015. Fibroblast heterogeneity and its implications for engineering organotypic skin models in vitro. Eur J Cell Biol 94: 483–512.
123. Steele CW, Oien KA, McKay CJ, Jamieson NB. 2011. Clinical potential of microRNAs in pancreatic ductal adenocarcinoma. Pancreas 40: 1165–1171.
124. Sugimoto H, Mundel TM, Kieran MW, Kalluri R. 2006. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther 5: 1640–1646.
125. Taddei ML, Cavallini L, Comito G, Giannoni E, Folini M, Marini A, Gandellini P, Morandi A, Pintus G, Raspollini MR, et al. 2014. Senescent stroma promotes prostate cancer progression: the role of miR-210. Mol Oncol 8: 1729–1746.
126. Takebe N, Ivy P, Timmer W, Khan N, Schulz T, Harris PJ. 2013. Review of cancer-associated fibroblasts and therapies that interfere with their activity. Tumor Microenviron Ther 1: 19–36.
127. Tanaka K, Miyata H, Sugimura K, Fukuda S, Kanemura T, Yamashita K, Miyazaki Y, Takahashi T, Kurokawa Y, Yamasaki M, et al. 2015. miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts. Carcinogenesis 36: 894–903.
128. Tchou J, Kossenkov AV, Chang L, Satija C, Herlyn M, Showe LC, Pure E. 2012. Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Med Genomics 5: 39.
129. Tlsty TD, Coussens LM. 2006. Tumor stroma and regulation of cancer development. Annu Rev Pathol 1: 119–150.
130. Togo S, Polanska UM, Horimoto Y, Orimo A. 2013. Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers (Basel) 5: 149–169.
131. Tuxhorn JA, McAlhany SJ, Yang F, Dang TD, Rowley DR. 2002. Inhibition of transforming growth factor-β activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res 62: 6021–6025.
132. Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R. 2011. Interaction of tumor cells with the microenvironment. Cell Commun Signal 9: 18.
133. Vazquez-Villa F, Garcia-Ocana M, Galvan JA, Garcia-Martinez J, Garcia-Pravia C, Menendez-Rodriguez P, Gonzalez-del Rey C, Barneo-Serra L, de Los Toyos JR. 2015. COL11A1/(pro)collagen 11A1 expression is a remarkable biomarker of human invasive carcinoma-associated stromal cells and carcinoma progression. Tumour Biol 36: 2213–2222.
134. Verghese ET, Drury R, Green CA, Holliday DL, Lu X, Nash C, Speirs V, Thorne JL, Thygesen HH, Zougman A, et al. 2013. MiR-26b is down-regulated in carcinoma-associated fibroblasts from ER-positive breast cancers leading to enhanced cell migration and invasion. J Pathol 231: 388–399.
135. Wagner EF. 2016. Cancer: fibroblasts for all seasons. Nature 530: 42–43.
136. Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y, Zhang Y, Hua S, Fu Q, Zhao M, et al. 2014. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras–ERK signaling in oral squamous cell carcinoma. Cell Death Dis 5: e1155.
137. Wasserman JK, Parra-Herran C. 2015. Regressive change in high-grade ductal carcinoma in situ of the breast: histopathologic spectrum and biologic importance. Am J Clin Pathol 144: 503–510.
138. Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP, Marshall D, Fu L, Januario T, Kallop D, et al. 2008. A paracrine requirement for hedgehog signalling in cancer. Nature 455: 406–410.
139. Yeung TL, Leung CS, Mok SC. 2014. CAF reprogramming inhibits ovarian cancer progression. Cell Cycle 13: 3783–3784.
140. Yuan J, Liu M, Yang L, Tu G, Zhu Q, Chen M, Cheng H, Luo H, Fu W, Li Z, et al. 2015. Acquisition of epithelial–mesenchymal transition phenotype in the tamoxifen-resistant breast cancer cell: a new role for G protein-coupled estrogen receptor in mediating tamoxifen resistance through cancer-associated fibroblast-derived fibronectin and β1-integrin signaling pathway in tumor cells. Breast Cancer Res 17: 69.
141. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. 2007. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67: 10123–10128.
142. Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E, Smid M, Foekens JA, Massague J. 2013. Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154: 1060–1073.
143. Zhou L, Yang K, Andl T, Wickett RR, Zhang Y. 2015. Perspective of targeting cancer-associated fibroblasts in melanoma. J Cancer 6: 717–726.