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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.

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