Transforming growth factor-beta 1 increases survival of human melanoma through stroma remodeling

Transforming growth factor (TGF)-beta is growth inhibitory for normal epith elial 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-beta, because its production is inc reased with melanoma progression. Whether TGF-beta has an autocrine functio n for melanoma cells or is important for paracrine stimulation of the tumor stroma is not known. In this study, TGF-beta1 was expressed in melanoma ce lls via adenoviral gene transfer, and tumor growth was analyzed in vitro, i n human skin grafts, and in mixtures with fibroblasts that were injected s. c. into immunodeficient mice. The TGF-beta1 produced by the melanoma cells activated the fibroblasts to produce matrix within and around the tumor mas s, whereas control tumors showed less stroma and more cell death. High expr ession of collagen, fibronectin, tenascin, and alpha2 integrin was detected in the TGF-beta1-expressing tumors by immunohistochemistry. Number and siz e of lung metastases were significantly increased. cDNA expression array an alysis of TGF-beta1-transduced fibroblasts embedded in type I collagen and of TGF-beta1-transduced melanoma cells demonstrated induction of types XV, XVIII, and VI collagens, tenascin, plasminogen activator inhibitor-1, vascu lar endothelial growth factor, cysteine-rich fibroblast growth factor recep tor-1, and platelet-derived growth factor receptor-beta, which could be lin ked to promotion of growth and survival in melanoma. These data suggest tha t remodeling of the neighboring stroma, which provides a supporting scaffol ding and a positive feedback stimulation of tumor growth, is an important f unction of TGF-betaI in melanoma.