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Cancer-Associated Fibroblasts and the Role of TGF-β

  • Chapter
Transforming Growth Factor-β in Cancer Therapy, Volume II

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Tumors present a complex composition of cancer and stromal cells that interact by direct cell-to-cell contact, extracellular matrix (ECM) proteins, cytokines, and growth factors. Fibroblasts represent a major cell type in the tumor stroma and participate actively in the process of tumorigenesis. These stromal cells, commonly termed cancer-associated fibroblasts (CAFs), are phenotypically different to their normal counterparts in physiological tissues, and often show myofibroblastic characteristics. Based on similarities with wound healing and inflammatory diseases, transforming growth factor-β (TGF-β) is considered to be the main factor involved in fibroblast recruitment, activation, and also differentiation to myofibroblasts. This review presents experimental evidence on the important role of TGF-β in fibroblast-epithelial interaction, as obtained from in vitro studies and from animal models. Additionally, global gene expression analyses of TGF-β stimulated fibroblasts and CAFs from the in situ environment suggest a TGF-β signature in the tumor stroma. While previous studies support a tumor stimulating effect of TGF-β via fibroblast activation, some recent studies utilizing genetically engineered mice models, indicate an opposite effect on tumor growth. Thus, similar to the dualistic effects of TGF-β on epithelial cells, the TGF-β response on CAFs is also highly context-dependent. The general connection between CAF biology and TGF-β function in tumorigenesis provides a new opportunity for novel stroma-based strategies in anticancer therapy.

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References

  1. Hanahan D, Weinberg RA. the hallmarks of cancer. Cell 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  2. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789–799.

    Article  CAS  PubMed  Google Scholar 

  3. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer 2001;1:46–54.

    Article  CAS  PubMed  Google Scholar 

  4. Erickson AC, Barcellos-Hoff MH. The not-so innocent bystander: the microenvironment as a therapeutic target in cancer. Expert Opin Ther Targets 2003;7:71–88.

    Article  CAS  PubMed  Google Scholar 

  5. Mueller MM, Fusenig NE. Friends or foes — bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 2004;4:839–849.

    Article  CAS  PubMed  Google Scholar 

  6. Micke P, Ostman A, Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer 2004;45Suppl 2:S163–S175.

    Article  PubMed  Google Scholar 

  7. Folkman J, Kalluri R. Cancer without disease. Nature 2004;427:787.

    Article  CAS  PubMed  Google Scholar 

  8. Brigati C, Noonan DM, Albini A, Benelli R. Tumors and inflammatory infiltrates: friends or foes? Clin Exp Metastasis 2002;19:247–258.

    Article  CAS  PubMed  Google Scholar 

  9. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med 2004;10:909–915.

    Article  CAS  PubMed  Google Scholar 

  10. Bhowmick NA, Moses HL. Tumor-stroma interactions. Curr Opin Genet Dev 2005;15:97–101.

    Article  CAS  PubMed  Google Scholar 

  11. Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Cell 2005;7:513–520.

    Article  CAS  PubMed  Google Scholar 

  12. Hast J, Schiffer IB, Neugebauer B, et al. Angiogenesis and fibroblast proliferation precede formation of recurrent tumors after radiation therapy in nude mice. Anticancer Res 2002;22:677–688.

    CAS  PubMed  Google Scholar 

  13. Moustakas A, Pardali K, Gaal A, Heldin CH. Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation. Immunol Lett 2002;82:85–91.

    Article  CAS  PubMed  Google Scholar 

  14. Elliott RL, Blobe GC. Role of transforming growth factor beta in human cancer. J Clin Oncol 2005;23:2078–2093.

    Article  CAS  PubMed  Google Scholar 

  15. Willis RA. Pathology of Tumors, Ed. 3, London: Butterworth & Co. (Publishers) Ltd., 1960; pp. 130–140.

    Google Scholar 

  16. DeCosse JJ, Gossens C, Kuzma JF, Unsworth BR. Embryonic inductive tissues that cause histologic differentiation of murine mammary carcinoma in vitro. J Natl Cancer Inst 1975;54:913–922.

    CAS  PubMed  Google Scholar 

  17. DeCosse JJ, Gossens CL, Kuzma JF, Unsworth BR. Breast cancer: induction of differentiation by embryonic tissue. Science 1973;181:1057–1058.

    Article  CAS  PubMed  Google Scholar 

  18. Cooper M, Pinkus H. Intrauterine transplantation of rat basal cell carcinoma as a model for reconversion of malignant to benign growth. Cancer Res 1977;37:2544–2552.

    CAS  PubMed  Google Scholar 

  19. Maehara N, Matsumoto K, Kuba K, Mizumoto K, Tanaka M, Nakamura T. NK4, a four-kringle antagonist of HGF, inhibits spreading and invasion of human pancreatic cancer cells. Br J Cancer 2001;84:864–873.

    Article  CAS  PubMed  Google Scholar 

  20. Hayward SW, Wang Y, Cao M, et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 2001;61:8135–8142.

    CAS  PubMed  Google Scholar 

  21. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59:5002–5011.

    CAS  PubMed  Google Scholar 

  22. Sato N, Maehara N, Goggins M. Gene expression profiling of tumor-stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 2004;64:6950–6956.

    Article  CAS  PubMed  Google Scholar 

  23. Camps JL, Chang SM, Hsu TC, et al. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci USA 1990;87:75–79.

    Article  CAS  PubMed  Google Scholar 

  24. Noel A, Nusgens B, Lapiere CH, Foidart JM. Interactions between tumoral MCF7 cells and fibroblasts on matrigel and purified la-inin. Matrix 1993;13:267–273.

    CAS  PubMed  Google Scholar 

  25. Gleave M, Hsieh JT, Gao CA, von Eschenbach AC, Chung LW. Acceleration of human prostate cancer growth in vivo by factors produced by prostate and bone fibroblasts. Cancer Res 1991;51: 3753–3761.

    CAS  PubMed  Google Scholar 

  26. Tuxhorn JA, McAlhany SJ, Dang TD, Ayala GE, Rowley DR. Stromal cells promote angiogenesis and growth of human prostate tumors in a differential reactive stroma (DRS) xenograft model. Cancer Res 2002;62:3298–3307.

    CAS  PubMed  Google Scholar 

  27. Parrott JA, Nilsson E, Mosher R, et al. Stromal-epithelial interactions in the progression of ovarian cancer: influence and source of tumor stromal cells. Mol Cell Endocrinol 2001;175:29–39.

    Article  CAS  PubMed  Google Scholar 

  28. Yashiro M, Ikeda K, Tendo M, Ishikawa T, Hirakawa K. Effect of organ-specific fibroblasts on proliferation and differentiation of breast cancer cells. Breast Cancer Res Treat 2005;90: 307–313.

    Article  PubMed  Google Scholar 

  29. Barclay WW, Woodruff RD, Hall MC, Cramer SD. A system for studying epithelial-stromal interactions reveals distinct inductive abilities of stromal cells from benign prostatic hyperplasia and prostate cancer. Endocrinology 2005;146:13–18.

    Article  CAS  PubMed  Google Scholar 

  30. Orimo A, Gupta PB, Sgroi DC., et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 2005; 121:335–348.

    Article  CAS  PubMed  Google Scholar 

  31. Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 1999;277:C1–C9.

    CAS  PubMed  Google Scholar 

  32. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–545.

    Article  CAS  PubMed  Google Scholar 

  33. Dolberg DS, Hollingsworth R, Hertle M, Bissell MJ. Wounding and its role in RSV-mediated tumor formation. Science 1985;230:676–678.

    Article  CAS  PubMed  Google Scholar 

  34. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315:1650–1659.

    CAS  PubMed  Google Scholar 

  35. Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 1971;27:549–550.

    Article  CAS  PubMed  Google Scholar 

  36. Ronnov-Jessen L, Petersen OW, Koteliansky VE, Bissell MJ. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest 1995;95:859–873.

    Article  CAS  PubMed  Google Scholar 

  37. Tsukada T, Tippens D, Gordon D, Ross R, Gown AM. HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization. Am J Pathol 1987;126:51–60.

    CAS  PubMed  Google Scholar 

  38. De Wever O, mareel M. Role of myofibroblasts at the invasion front. Biol Chem 2002;383:55–67.

    Article  PubMed  Google Scholar 

  39. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev 1996;76:69–125.

    CAS  PubMed  Google Scholar 

  40. Serini G, Gabbiani G. Mechanisms of myofibroblast activity and phenotypic modulation. Exp Cell Res 1999;250:273–283.

    Article  CAS  PubMed  Google Scholar 

  41. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 2002;3:349–363.

    Article  CAS  PubMed  Google Scholar 

  42. Schurch W, Seemayer TA, Lagace R. Stromal myofibroblasts in primary invasive and metastatic carcinomas. A combined immunological, light and electron microscopic study. Virchows Arch A Pathol Anat Histol 1981;391:125–139.

    Article  CAS  PubMed  Google Scholar 

  43. Chauhan H, Abraham A, Phillips JR, Pringle JH, Walker RA, Jones JL. There is more than one kind of myofibroblast: analysis of CD34 expression in benign, in situ, and invasive breast lesions. J Clin Pathol 2003;56:271–276.

    Article  CAS  PubMed  Google Scholar 

  44. Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res 2001;264:169–184.

    Article  CAS  PubMed  Google Scholar 

  45. Nakayama H, Enzan H, Miyazaki E, Naruse K, Kiyoku H, Hiroi M. The role of myofibroblasts at the tumor border of invasive colorectal adenocarcinomas. Jpn J Clin Oncol 1998;28:615–620.

    Article  CAS  PubMed  Google Scholar 

  46. Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res 2002;8:2912–2923.

    CAS  PubMed  Google Scholar 

  47. Orimo A, Tomioka Y, Shimizu Y, et al. Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression. Clin Cancer Res 2001;7:3097–3105.

    CAS  PubMed  Google Scholar 

  48. Ronnov-Jessen L, Petersen OW Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofbroblast generation in breast neoplasia. Lab Invest 1993;68:696–707.

    CAS  PubMed  Google Scholar 

  49. Ronnov-Jessen L, van Deurs B, Celis JE, Petersen OW. Smooth muscle differentiation in cultured human breast gland stromal cells. Lab Invest 1990;63:532–543.

    CAS  PubMed  Google Scholar 

  50. Gabbiani G. The cellular derivation and the life-span of the myofibroblast. Pathol Res Pract 1996;192:708–711.

    CAS  PubMed  Google Scholar 

  51. Petersen OW, Nielsen HL, Gudjonsson T, et al. Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 2003;162:391–402.

    CAS  PubMed  Google Scholar 

  52. Sangai T, Ishii G, Kodama K, et al. Effect of differences in, cancer cells and tumor growth sites on recruiting bone marrow-derived endothelial cells and myofibroblasts in cancer-induced stroma. Int J Cancer 2005;115:885–892.

    Article  CAS  PubMed  Google Scholar 

  53. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997;276:71–74.

    Article  CAS  PubMed  Google Scholar 

  54. Untergasser G, Gander R, Lilg C, Lepperdinger G, Plas E, Berger P. Profiling molecular targets of TGF-beta1 in prostate fibroblast-to-myofibroblast transdifferentiation. Mech Ageing Dev 2005;126:59–69.

    Article  CAS  PubMed  Google Scholar 

  55. Peehl DM, Sellers, RG. Induction of smooth muscle cell phenotype in cultured human prostatic stromal cells. Exp Cell Res 1997;232:208–215.

    Article  CAS  PubMed  Google Scholar 

  56. Serini G, Bochaton-Piallat ML, Popraz P, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1 J Cell Biol 1998;142: 873–881.

    Article  CAS  PubMed  Google Scholar 

  57. Masur SK, Dewal HS, Dinh TT, Erenburg I, Petridou S. Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci USA 1996;93:4219–4223.

    Article  CAS  PubMed  Google Scholar 

  58. Lieubeau B, Garrigue L, Barbieux I, Meflah K, Gregoire M. The role of transforming growth factor beta 1 in the fibroblastic reaction associated with rat colorectal tumor development. Cancer Res 1994;54:6526–6532.

    CAS  PubMed  Google Scholar 

  59. Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993;122:103–111.

    Article  CAS  PubMed  Google Scholar 

  60. Rosenthal E, McCrory A, Talbert M, Young G, Murphy-Ullrich J, Gladson C. Elevated expression of TGF-beta1 in head and neck cancer-associated fibroblasts. Mol Carcinog 2004;40:116–121.

    Article  CAS  PubMed  Google Scholar 

  61. Shariat SF, Menesses-Diaz A, Kim IY, Muramoto M, Wheeler TM, Slawin KM. Tissue expression of transforming growth factor-beta1 and its receptors: correlation with pathologic features and biochemical progression in patients undergoing radical prostatectomy. Urology 2004;63: 1191–1197.

    Article  PubMed  Google Scholar 

  62. Hazelbag S, Gorter A, Kenter GG, van den Broek L, Fleuren G. Transforming growth factor-betal induces tumor stroma and reduces tumor infiltrate in cervical cancer. Hum Pathol 2002;33: 1193–1199.

    Article  CAS  PubMed  Google Scholar 

  63. Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA. Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res 1992;52:6949–6952.

    CAS  PubMed  Google Scholar 

  64. Friess H, Yamanaka Y, Buchler M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993;105:1846–1856.

    CAS  PubMed  Google Scholar 

  65. Wikstrom P, Stattin P, Franck-Lissbrant I, Damber JE, Bergh A. Transforming growth factor beta1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. Prostate 1998;37:19–29.

    Article  CAS  PubMed  Google Scholar 

  66. Kim JH, Shariat SF, Kim IY, et al. Predictive value of expression of transforming growth factorbeta(1) and its receptors in transitional cell carcinoma of the urinary bladder. Cancer 2001;92: 1475–1483.

    Article  CAS  PubMed  Google Scholar 

  67. Walker RA, Dearing SJ, Gallacher B. Relationship of transforming growth factor in 1 to extracellular matrix and stromal infiltrates in invasive breast carcinoma. Br J Cancer 1994;69:1160–1165.

    CAS  PubMed  Google Scholar 

  68. Barrett-Lee P, Travers M, Luqmani Y, Coombes RC. Transcripts for transforming growth factors in human breast cancer: clinical correlates. Br J Cancer 1990;61:612–617.

    CAS  PubMed  Google Scholar 

  69. Murray PA, Barrett-Lee P, Travers M, Luqmani Y, Powles T, Coombes R. C. The prognostic significance of transforming growth factors in human breast cancer. Br J Cancer 1993;67:1408–1412.

    CAS  PubMed  Google Scholar 

  70. Kaklamani VG, Pasche B. Role of TGF-beta in cancer and the potential for therapy and prevention. Expert Rev Anticancer Ther 2004;4:649–661.

    Article  CAS  PubMed  Google Scholar 

  71. McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 2000;6:149–156.

    Article  CAS  PubMed  Google Scholar 

  72. Salo T, Lyons JG, Rahemtulla F, Birkedal-Hansen H, Larjava H. Transforming growth factor-beta 1 up-regulates type IV collagenase expression in cultured human keratinocytes. J Biol Chem 1991;266:11,436–11,441.

    CAS  PubMed  Google Scholar 

  73. Berking C, Takemoto R, Schaider H, et al. Transforming growth factor-betal increases survival of human melanoma through stroma remodeling. Cancer Res 2001;61:8306–8316.

    CAS  PubMed  Google Scholar 

  74. Tuxhorn JA, McAlhany SJ, Yang F, Dang TD, Rowley DR. Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograft model. Cancer Res 2002;62:6021–6025.

    CAS  PubMed  Google Scholar 

  75. de Jong JS, van Diest PJ, van der Valk P, Baak JP. Expression of growth factors, growth inhibiting factors, and their receptors in invasive breast cancer. I: An inventory in search of autocrine and paracrine loops. J Pathol 1998;184:44–52.

    Article  PubMed  Google Scholar 

  76. de Jong JS, van Diest PJ, van der Valk P, Baak JP. Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis. J Pathol 1998;184:53–57.

    Article  PubMed  Google Scholar 

  77. Pertovaara L, Kaipainen A, Mustonen T, et al. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fribroblastic and epithelial cells. J Biol Chem 1994; 269:6271–6274.

    CAS  PubMed  Google Scholar 

  78. Jussila L, Alitalo K. Vascular growth factors and lymphangiogenesis. Physiol Rev 2002;82:673–700.

    CAS  PubMed  Google Scholar 

  79. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 1999;103:197–206.

    Article  CAS  PubMed  Google Scholar 

  80. Bhowmick NA, Chytil A, Plieth D, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848–851.

    Article  CAS  PubMed  Google Scholar 

  81. Cheng N, Bhowmick NA, Chytil A, et al. Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP-and HGF-mediated signaling networks. Oncogene 2005;24:5053–5068.

    Article  CAS  PubMed  Google Scholar 

  82. Vindevoghel L, Kon A, Lechleider RJ, Uitto J, Roberts AB, Mauviel A. Smad-dependent transcriptional activation of human type VII collagen gene (COL7A1) promoter by transforming growth factor-beta. J Biol Chem 1998;273:13,053–13,057.

    Article  CAS  PubMed  Google Scholar 

  83. Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998;17:3091–3100.

    Article  CAS  PubMed  Google Scholar 

  84. Taylor LM, Khachigian LM. Induction of platelet-derived growth factor B-chain expression by transforming growth factor-beta involves transactivation by Smads. J Biol Chem 2000;275:16,709–16,716.

    Article  CAS  PubMed  Google Scholar 

  85. Overall CM, Wrana JL, Sodek J. Transforming growth factor-beta regulation of collagenase, 72 kDa-progelatinase, TIMP and PAI-1 expression in rat bone cell populations and human fibroblasts. Connect Tissue Res 1989;20:289–294.

    Article  CAS  PubMed  Google Scholar 

  86. Overall CM, Wrana JL, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase, and metalloendoproteinase inhibitor expression in human fibroblasts by transforming growth factor-beta. J Biol Chem 1989;264:1860–1869.

    CAS  PubMed  Google Scholar 

  87. Overall CM, Wrana JL, Sodek J. Transcriptional and post-transcriptional regulation of 72-kDa gelatinase/type IV collagenase by transforming growth factor-beta 1 in human fibroblasts. Comparisons with collagenase and tissue inhibitor of matrix metalloproteinase gene expression. J Biol Chem 1991;266:14,064–14,071.

    CAS  PubMed  Google Scholar 

  88. Overall CM, Kleifeld O. Tumour microenvironment — Opinion: Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 2006;6:227–239.

    Article  CAS  PubMed  Google Scholar 

  89. Lyons RM, Gentry LE, Purchio AF, Moses HL. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 1990;110:1361–1367.

    Article  CAS  PubMed  Google Scholar 

  90. Crawford SE, Stellmach V, Murphy-Ullrich JE, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998;93:1159–1170.

    Article  CAS  PubMed  Google Scholar 

  91. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 2000;14:163–176.

    PubMed  Google Scholar 

  92. Sieuwerts AM, Klijn JG, Henzen-Logmand SC, et al. Urokinase-type-plasminogen-activator (uPA) production by human breast (myo) fibroblasts in vitro: influence of transforming growth factor-beta(1) (TGF beta(1)) compared with factor(s) released by human epithelial-carcinoma cells. Int J Cancer 1998;76:829–835.

    Article  CAS  PubMed  Google Scholar 

  93. Dano K, Behrendt N, Hoyer-Hansen G, et al. Plasminogen activation and cancer. Thromb Haemost 2005;93:676–681.

    CAS  PubMed  Google Scholar 

  94. Tan K, Powe DG, Gray T, Turner DR, Hewitt RE. Regional variations of urokinase-type plasminogen activator in human colorectal cancer: a quantitative study by image analysis. Int J Cancer 1995;60:308–314.

    CAS  PubMed  Google Scholar 

  95. Stuelten CH, Byfield SD, Arany PR, Karpova TS, Stetler-Stevenson WG, Roberts AB. Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β. J Cell Sci 2005;118:2143–2153.

    Article  CAS  PubMed  Google Scholar 

  96. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res 1997;57:3305–3313.

    CAS  PubMed  Google Scholar 

  97. Gmyrek GA, Walburg M, Webb CP, et al. Normal and malignant prostate epithelial cells differ in their response to hepatocyte growth factor/scatter factor. Am J Pathol 2001;159:579–590.

    CAS  PubMed  Google Scholar 

  98. Beviglia L, Matsumoto K, Lin CS, Ziober BL, Kramer RH. Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. Int J Cancer 1997;74:301–309.

    Article  CAS  PubMed  Google Scholar 

  99. Yamashita J, Ogawa M, Yamashita S, et al. Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res 1994;54: 1630–1633.

    CAS  PubMed  Google Scholar 

  100. Takada N, Yano Y, Matsuda T, et al. Expression of immunoreactive human hepatocyte growth factor in human esophageal squamous cell carcinomas. Cancer Lett 1995;97:145–148.

    Article  CAS  PubMed  Google Scholar 

  101. Masuya D, Huang C, Liu D, et al. The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br J Cancer 2004;90:1555–1562.

    Article  CAS  PubMed  Google Scholar 

  102. Lewis MP, Lygoe KA, Nystrom ML, et al. Tumour-derived TGF-betal modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells. Br J Cancer 2004;90:822–832.

    Article  CAS  PubMed  Google Scholar 

  103. Ohira H, Miyata M, Kuroda M, et al. Interleukin-6 induces proliferation of rat hepatocytes in vivo. J Hepatol 1996;25:941–947.

    Article  CAS  PubMed  Google Scholar 

  104. Joseph H, Gorska AE, Sohn P, Moses HL, Serra R. Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching. Mol Biol Cell 1999;10:1221–1234.

    CAS  PubMed  Google Scholar 

  105. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 2003;22:309–325.

    Article  CAS  PubMed  Google Scholar 

  106. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4:915–925.

    Article  CAS  PubMed  Google Scholar 

  107. Michieli P, Mazzone M, Basilico C, et al. Targeting the tumor and its microenvironment by a dualfunction decoy. Met receptor. Cancer Cell 2004;6:61–73.

    CAS  Google Scholar 

  108. Leask A Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J 2004;18:816–827.

    Article  CAS  PubMed  Google Scholar 

  109. Yang F, Tuxhorn JA, Ressler SJ, McAlhany SJ, Dang TD, Rowley DR. Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Res 2005;65:8887–8895.

    Article  CAS  PubMed  Google Scholar 

  110. Suzuki K, Obara K, Kobayashi K, et al. Role of connective tissue growth factor in fibronectin synthesis in cultured human prostate stromal cells. Urology 2006;67:647–653.

    Article  PubMed  Google Scholar 

  111. Koliopanos A, Friess H, di Mola FF, et al. Connective tissue growth factor gene expression alters tumor progression in esophageal cancer. World J Surg 2002;26:420–427.

    Article  PubMed  Google Scholar 

  112. Frazier KS, Grotendorst GR. Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors. Int J Biochem Cell Biol 1997;29:153–161.

    Article  CAS  PubMed  Google Scholar 

  113. Chang CC, Shih JY, Jeng YM, et al. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis. J Natl Cancer Inst 2004;96:364–375.

    Article  CAS  PubMed  Google Scholar 

  114. Lin BR, Chang CC, Che TF, et al. Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer. Gastroenterology 2005;128:9–23.

    Article  CAS  PubMed  Google Scholar 

  115. Hartel M, Di Mola FF, Gardini A, et al. Desmoplastic reaction influences pancreatic cancer growth behavior. World J Surg 2004;28:818–825.

    Article  PubMed  Google Scholar 

  116. Chambers RC, Leoni P, Kaminski N, Laurent GJ, Heller RA. Global expression profiling of fibroblast responses to transforming growth factor-betal reveals the induction of inhibitor of differentiation-1 and provides evidence of smooth muscle cell phenotypic switching. Am J Pathol 2003; 162:533–546.

    CAS  PubMed  Google Scholar 

  117. Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 2001;276:17,058–17,062.

    Article  CAS  PubMed  Google Scholar 

  118. Renzoni EA, Abraham DJ, Howat S, et al. Gene expression profiling reveals novel TGFbeta targets in adult lung fibroblasts. Respir Res 2004;5:24.

    Article  PubMed  CAS  Google Scholar 

  119. Sawdey M, Podor TJ, Loskutoff DJ. Regulation of type 1 plasminogen activator inhibitor gene expression in cultured bovine aortic endothelial cells. Induction by transforming growth factor-beta, lipopolysaccharide, and tumor necrosis factor-alpha. J Biol Chem 1989;264:10,396–10,401.

    CAS  PubMed  Google Scholar 

  120. Andreasen PA, Kjoller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997;72:1–22.

    Article  CAS  PubMed  Google Scholar 

  121. Fine A, Poliks CF, Donahue LP, Smith BD, Goldstein RH. The differential effect of prostaglandin E2 on transforming growth factor-beta and insulin-induced collagen formation in lung fibroblasts. J Biol Chem 1989;264:16,988–16,991.

    CAS  PubMed  Google Scholar 

  122. Coussens LM, Yokoyama K, Chiu R. Transforming growth factor beta 1-mediated induction of junB is selectively inhibited by expression of Ad. 12-E1A. J Cell Physiol 1994;160:435–444.

    Article  CAS  PubMed  Google Scholar 

  123. Bronzert DA, Bates SE, Sheridan JP, et al. Transforming growth factor-beta induces platelet-derived growth factor (PDGF) messenger RNA and PDGF secretion while inhibiting growth in normal human mammary epithelial cells. Mol Endocrinol 1990;4:981–989.

    Article  CAS  PubMed  Google Scholar 

  124. Nakagawa H, Liyanarachchi S, Davuluri RV, et al. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene 2004;23:7366–7377.

    Article  CAS  PubMed  Google Scholar 

  125. Micke P, Ostman A, Lundeberg J, Ponten F. Laser-assisted cell microdissection using the PALM system. Methods Mol Biol 2005;293:151–166.

    CAS  PubMed  Google Scholar 

  126. Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 2004;6:17–32.

    Article  CAS  PubMed  Google Scholar 

  127. Fukushima N, Sato N, Prasad N, Leach SD, Hruban RH, Goggins M. Characterization of gene expression in mucinous cystic neoplasms of the pancreas using oligonucleotide microarrays. Oncogene 2004;23:9042–9051.

    Article  CAS  PubMed  Google Scholar 

  128. Micke P, Ostman A. Exploring the tumour environment: cancer-associated fibroblasts as targets in cancer therapy. Expert Opin Ther Targets 2005;9:1217–1233.

    Article  CAS  PubMed  Google Scholar 

  129. Micke P, Kappert K, Ohshima M, et al. In situ identification of genes regulated specifically in fibroblasts of human basal cell carcinoma. J Invest Dermatol 2007;127:1516–1523.

    Article  CAS  PubMed  Google Scholar 

  130. Wrana JL, Overall CM, Sodek J. Regulation of the expression of a secreted acidic protein rich in cysteine (SPARC) in human fibroblasts by transforming growth factor beta. Comparison of transcriptional and post-transcriptional control with fibronectin and type I collagen. Eur J Biochem 1991;197:519–528.

    Article  CAS  PubMed  Google Scholar 

  131. Aycock RL, Bradshaw AC, Sage EH, Starcher B. Development of UV-induced squamous cell carcinomas is suppressed in the absence of SPARC. J Invest Dermatol 2004;123:592–599.

    Article  CAS  PubMed  Google Scholar 

  132. Ledda F, Bravo AI, Adris S, Bover L, Mordoh J, Podhajcer OL. The expression of the secreted protein acidic and rich in cysteine (SPARC) is associated with the neoplastic progression of human melanoma. J Invest Dermatol 1997;108:210–214.

    Article  CAS  PubMed  Google Scholar 

  133. Massi D, Franchi A, Borgognoni L, Reali UM, Santucci M. Osteonectin expression correlates with clinical outcome in thin cutaneous malignant melanomas. Hum Pathol 1999;30:339–344.

    Article  CAS  PubMed  Google Scholar 

  134. Said N, and Motamed K. Absence of host-secreted protein acidic and rich in cysteine (SPARC) augments peritoneal ovarian carcinomatosis. Am J Pathol 2005;167:1739–1752.

    CAS  PubMed  Google Scholar 

  135. Koblinski JE, Kaplan-Singer BR, VanOsdol SJ, et al. Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer Res 2005;65:7370–7377.

    Article  CAS  PubMed  Google Scholar 

  136. Chlenski A, Liu S, Crawford SE, et al. SPARC is a key Schwannian-derived inhibitor controlling neuroblastoma tumor angiogenesis. Cancer Res 2002;62:7357–7363.

    CAS  PubMed  Google Scholar 

  137. Chlenski A, Liu S, Guerrero LJ, et al. SPARC expression is associated with impaired tumor growth, inhibited angiogenesis and changes in the extracellular matrix. Int J Cancer 2006;118:310–316.

    Article  CAS  PubMed  Google Scholar 

  138. Brekken RA, Puolakkainen P, Graves DC, Workman G, Lubkin SR, Sage EH. Enhanced growth of tumors in SPARC null mice is associated with changes in the ECM. J Clin Invest 2003;111:487–495.

    CAS  PubMed  Google Scholar 

  139. Scholzen T, Solursh M, Suzuki S, et al. The murine decorin. Complete cDNA cloning, genomic organization, chromosomal assignment, and expression during organogenesis and tissue differentiation. J Biol Chem 1994;269:28,270–28,281.

    CAS  PubMed  Google Scholar 

  140. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 1990;346:281–284.

    Article  CAS  PubMed  Google Scholar 

  141. Patel S, Santra M, McQuillan DJ, Iozzo RV, Thomas AP. Decorin activates the epidermal growth factor receptor and elevates cytosolic Ca2+ in A431 carcinoma cells. J Biol Chem 1998;273:3121–3124.

    Article  CAS  PubMed  Google Scholar 

  142. Kahari VM, Larjava H, Uitto J. Differential regulation of extracellular matrix proteoglycan (PG) gene expression. Transforming growth factor-beta 1 up-regulates biglycan (PGI), and versican (large fibroblast PG) but downregulates decorin (PGII) mRNA levels in human fibroblasts in culture. J Biol Chem 1991;266:10,608–10,615.

    CAS  PubMed  Google Scholar 

  143. Iozzo RV, Bolender RP, Wight TN. Proteoglycan changes in the intercellular matrix of human colon carcinoma: an integrated biochemical and stereologic analysis. Lab Invest 1982;47:124–138.

    CAS  PubMed  Google Scholar 

  144. Iozzo RV, Wight TN. Isolation and characterization of proteoglycans synthesized by human colon and colon carcinoma. J Biol Chem 1982;257:11,135–11,144.

    CAS  PubMed  Google Scholar 

  145. Koninger J, Giese NA, di Mola FF, et al. Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attenuation of chemotherapeutic action. Clin Cancer Res 2004;10:4776–4783.

    Article  PubMed  Google Scholar 

  146. Hunzelmann N, Schonherr E, Bonnekoh B, Hartmann C, Kresse H, Krieg T. Altered immunohistochemical expression of small proteoglycans in the tumor tissue and stroma of basal cell carcinoma. J Invest Dermatol 1995;104:509–513.

    Article  CAS  PubMed  Google Scholar 

  147. Troup S, Njue C, Kliewer EV, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res 2003;9:207–214.

    CAS  PubMed  Google Scholar 

  148. Iozzo RV, Sampson PM, Schmitt GK. Neoplastic modulation of extracellular matrix: stimulation of chondroitin sulfate proteoglycan and hyaluronic acid synthesis in co-cultures of human colon carcinoma and smooth muscle cells. J Cell Biochem 1989;39:355–378.

    Article  CAS  PubMed  Google Scholar 

  149. Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res 1994;211:90–98.

    Article  CAS  PubMed  Google Scholar 

  150. Stander M, Naumann U, Wick W, Weller M. Transforming growth factor-beta and p-21: multiple molecular targets of decorin-mediated suppression of neoplastic growth. Cell Tissue Res 1999;296: 221–227.

    Article  CAS  PubMed  Google Scholar 

  151. Santra M, Skorski T, Calabretta B, Lattime EC, Iozzo RV. De novo decorin gene expression suppresses the malignant phenotype in human colon cancer cells. Proc Natl Acad Sci USA 1995;92: 7016–7020.

    Article  CAS  PubMed  Google Scholar 

  152. De Luca A, Santra M, Baldi A, Giordano A, Iozzo RV. Decorin-induced growth suppression is associated with up-regulation of p21, an inhibitor of cyclin-dependent kinases. J Biol Chem 1996;271: 18,961–18,965.

    Article  PubMed  Google Scholar 

  153. Moscatello DK, Santra M, Mann DM, McQuillan DJ, Wong AJ, Iozzo RV. Decorin suppresses tumor cell growth by activating the epidermal growth factor receptor. J Clin Invest 1998;101:406–412.

    Article  CAS  PubMed  Google Scholar 

  154. Grant DS, Yenisey C, Rose RW, Tootell M, Santra M, Iozzo RV. Decorin suppresses tumor cell-mediated angiogenesis. Oncogene 2002;21:4765–4777.

    Article  CAS  PubMed  Google Scholar 

  155. Cohn DH, Briggs MD, King LM, et al. Mutations in the cartilage oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Ann N Y Acad Sci 1996;785:188–194.

    Article  CAS  PubMed  Google Scholar 

  156. Esteller M, Corn PG, Baylin SB, Herman JG. A gene hypermethylation profile of human cancer. Cancer Res 2001;61:3225–3229.

    CAS  PubMed  Google Scholar 

  157. Brueckl WM, Grombach J, Wein A, et al. Alterations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) are found frequently in human colorectal tumours displaying either microsatellite stability (MSS) or instability (MSI). Cancer Lett 2005;223:137–142.

    Article  CAS  PubMed  Google Scholar 

  158. Lui EL, Loo WT, Zhu L, Cheung MN, Chow LW. DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Biomed Pharmacother 59 Suppl 2005;2:S363–S365.

    Article  Google Scholar 

  159. Sun Y, Zhang JQ, Zhang J, Lamparter S. Cardiac remodeling by fibrous tissue after infarction in rats. J Lab Clin Med 2000;135:316–323.

    Article  CAS  PubMed  Google Scholar 

  160. Ramos C, Montano M, Garcia-Alvarez J, et al. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am J Respir Cell Mol Biol 2001;24:591–598.

    CAS  PubMed  Google Scholar 

  161. Cruz-Munoz W, Kim I, Khokha R. TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis. Oncogene 2006;25:650–655.

    Article  CAS  PubMed  Google Scholar 

  162. Ronnov-Jessen L, Villadsen R, Edwards JC, Petersen OW. Differential expression of a chloride intracellular channel gene, CLIC4, in transforming growth factor-beta1-mediated conversion of fibroblasts to myofibroblasts. Am J Pathol 2002;161:471–480.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Patrick Micke MD

  2. Ludwig Institute for Cancer Research, Biomedical Center, Uppsala, Sweden

    Aristidis Moustakas PhD

  3. Department of Biochemistry, Nihon University School of Dentistry, Tokyo, Japan

    Mitsuhiro Ohshima DDS, PhD

  4. Institute of Pharmacology, Center for Cardiovascular Research, Charité, Berlin, Germany

    Kai Kappert MD

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  1. Patrick Micke MD
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  2. Aristidis Moustakas PhD
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  3. Mitsuhiro Ohshima DDS, PhD
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  4. Kai Kappert MD
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  1. Cancer Training Branch, Office of Centers, Training and Resources, National Cancer Institute, Bethesda, MD

    Sonia B. Jakowlew PhD

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Micke, P., Moustakas, A., Ohshima, M., Kappert, K. (2008). Cancer-Associated Fibroblasts and the Role of TGF-β. In: Jakowlew, S.B. (eds) Transforming Growth Factor-β in Cancer Therapy, Volume II. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-293-9_27

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