The goal of this application is to define the role of tumor-associated transforming growth factor (TGF)-beta in the development of malignant melanoma. Previous work by this group demonstrated that TGF-beta is constitutively and persistently expressed by primary and malignant melanomas in vitro and in situ although TGF-beta inhibits melanoma growth in vitro. Based on these observations it is hypothesized that TGF-beta exerts effects in vivo that are essential to melanoma development and, thus, outweigh the growth-inhibitory effects observed in vitro. Relevant effects of TGF-beta include altered expression of adhesion molecules and proteolytic enzymes by melanoma cells, recruitment of host cells for local tumor growth and metastatic spread, and suppression of immune responses to tumor cells. Indirect evidence from other tumor systems suggests significant contributions of TGF-beta to all of these phenomena. The proposed experiments represent a direct approach to determine which of these potential effects of melanoma-derived TGF-beta are essential to melanoma development. Melanoma cell lines derived from distinct stages of progression and with defined tumorigenicity, metastatic capacity, immunogenicity, and TGF-beta effects is achieved by upregulation or suppression of TGF-beta production using sense, antisense, and negative dominant expression vectors in selected cell lines followed by in depth analysis of tumor growth and metastatic behavior. Effects on tumorigenicity in nude mice are studied by overexpressing TGF-beta in the non-tumorigenic human primary melanoma cell WM 1650. Effects on metastatic behavior are analyzed by suppressing TGF- beta production in the highly metastatic human 1205-LU cells. Effects on immunogenicity are examined by downmodulation of TGF-beta production in non-immunogenic mouse K1735 melanoma cell variants and the subsequent determination of immunogenicity in syngeneic, immunocompetent mice. In vitro studies will focus on TGF-beta dependent effects on adhesion, migration, and modulation of adhesion molecules and proteolytic enzymes in melanoma cells; immunological studies will focus on the effects of TGF-beta on different lymphocyte subsets. The long-term goal of these studies is to determine whether melanoma- derived TGF-beta provides a suitable therapeutic target.
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