This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Berking, C. Articles by Herlyn, M. Search for Related Content PubMed PubMed Citation Articles by Berking, C. Articles by Herlyn, M.

Transforming Growth Factor-ß1 Increases Survival of Human Melanoma through Stroma Remodeling¹

The Wistar Institute, Philadelphia, Pennsylvania 19104 [C. B., R. T., H. S., L. S., K. S., M. H.], and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 [P. R.]

Transforming growth factor (TGF)-ß is growth inhibitory for normal epithelial cells and melanocytes but can stimulate mesenchymal cells. Resistance to its inhibitory effects is characteristic of human melanoma, the growth of which may instead be promoted by TGF-ß, because its production is increased with melanoma progression. Whether TGF-ß has an autocrine function for melanoma cells or is important for paracrine stimulation of the tumor stroma is not known. In this study, TGF-ß1 was expressed in melanoma cells via adenoviral gene transfer, and tumor growth was analyzed in vitro, in human skin grafts, and in mixtures with fibroblasts that were injected s.c. into immunodeficient mice. The TGF-ß1 produced by the melanoma cells activated the fibroblasts to produce matrix within and around the tumor mass, whereas control tumors showed less stroma and more cell death. High expression of collagen, fibronectin, tenascin, and 2 integrin was detected in the TGF-ß1-expressing tumors by immunohistochemistry. Number and size of lung metastases were significantly increased. cDNA expression array analysis of TGF-ß1-transduced fibroblasts embedded in type I collagen and of TGF-ß1-transduced melanoma cells demonstrated induction of types XV, XVIII, and VI collagens, tenascin, plasminogen activator inhibitor-I, vascular endothelial growth factor, cysteine-rich fibroblast growth factor receptor-1, and platelet-derived growth factor receptor-ß, which could be linked to promotion of growth and survival in melanoma. These data suggest that remodeling of the neighboring stroma, which provides a supporting scaffolding and a positive feedback stimulation of tumor growth, is an important function of TGF-ß1 in melanoma.

This article has been cited by other articles:

				D. Javelaud, K. S. Mohammad, C. R. McKenna, P. Fournier, F. Luciani, M. Niewolna, J. Andre, V. Delmas, L. Larue, T. A. Guise, et al. Stable Overexpression of Smad7 in Human Melanoma Cells Impairs Bone Metastasis Cancer Res., March 1, 2007; 67(5): 2317 - 2324. [Abstract] [Full Text] [PDF]

				Y. Sheffer, O. Leon, J. H. Pinthus, A. Nagler, Y. Mor, O. Genin, M. Iluz, N. Kawada, K. Yoshizato, and M. Pines Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect Mol. Cancer Ther., February 1, 2007; 6(2): 570 - 577. [Abstract] [Full Text] [PDF]

				V. N. Ivanov, Z. Ronai, and T. K. Hei Opposite Roles of FAP-1 and Dynamin in the Regulation of Fas (CD95) Translocation to the Cell Surface and Susceptibility to Fas Ligand-mediated Apoptosis J. Biol. Chem., January 20, 2006; 281(3): 1840 - 1852. [Abstract] [Full Text] [PDF]

				V. N. Ivanov and T. K. Hei Arsenite Sensitizes Human Melanomas to Apoptosis via Tumor Necrosis Factor {alpha}-mediated Pathway J. Biol. Chem., May 21, 2004; 279(21): 22747 - 22758. [Abstract] [Full Text] [PDF]

				C. Berking, R. Takemoto, K. Satyamoorthy, T. Shirakawa, M. Eskandarpour, J. Hansson, P. A. VanBelle, D. E. Elder, and M. Herlyn Induction of Melanoma Phenotypes in Human Skin by Growth Factors and Ultraviolet B Cancer Res., February 1, 2004; 64(3): 807 - 811. [Abstract] [Full Text] [PDF]

				J. Huang, S. Z. Soffer, E. S. Kim, K. W. McCrudden, J. Huang, T. New, C. A. Manley, W. Middlesworth, K. O'Toole, D. J. Yamashiro, et al. Vascular Remodeling Marks Tumors That Recur During Chronic Suppression of Angiogenesis Mol. Cancer Res., January 1, 2004; 2(1): 36 - 42. [Abstract] [Full Text] [PDF]

				E. S. Doubrovina, M. M. Doubrovin, E. Vider, R. B. Sisson, R. J. O'Reilly, B. Dupont, and Y. M. Vyas Evasion from NK Cell Immunity by MHC Class I Chain-Related Molecules Expressing Colon Adenocarcinoma J. Immunol., December 15, 2003; 171(12): 6891 - 6899. [Abstract] [Full Text] [PDF]

				R. S. Muraoka, Y. Koh, L. R. Roebuck, M. E. Sanders, D. Brantley-Sieders, A. E. Gorska, H. L. Moses, and C. L. Arteaga Increased Malignancy of Neu-Induced Mammary Tumors Overexpressing Active Transforming Growth Factor {beta}1 Mol. Cell. Biol., December 1, 2003; 23(23): 8691 - 8703. [Abstract] [Full Text] [PDF]

				R. Castriconi, C. Cantoni, M. Della Chiesa, M. Vitale, E. Marcenaro, R. Conte, R. Biassoni, C. Bottino, L. Moretta, and A. Moretta Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: Consequences for the NK-mediated killing of dendritic cells PNAS, April 1, 2003; 100(7): 4120 - 4125. [Abstract] [Full Text] [PDF]

				N. Dumont, A. V. Bakin, and C. L. Arteaga Autocrine Transforming Growth Factor-beta Signaling Mediates Smad-independent Motility in Human Cancer Cells J. Biol. Chem., January 24, 2003; 278(5): 3275 - 3285. [Abstract] [Full Text] [PDF]

				D. P. Simmons, F. Andreola, and L. M. De Luca Human melanomas of fibroblast and epithelial morphology differ widely in their ability to synthesize retinyl esters Carcinogenesis, November 1, 2002; 23(11): 1821 - 1830. [Abstract] [Full Text] [PDF]

				M. Zheng and P. J. McKeown-Longo Regulation of HEF1 Expression and Phosphorylation by TGF-beta 1 and Cell Adhesion J. Biol. Chem., October 11, 2002; 277(42): 39599 - 39608. [Abstract] [Full Text] [PDF]