Clinical, histopathological, and experimental biological investigations have defined the characteristics of human melanocytes as they progress from benign to malignant lesions. Each of 5 steps of progression has been delineated in its relation to others and in its clinical significance. However, the molecular mechanisms of melanoma progression are still poorly understood. Similarly, the functions of most molecules that are overexpressed on melanoma cells have not been clarified nor has a useful approach been defined to use patients' anti-tumor response for melanoma therapy. This program focuses on 3 research areas: molecular genetics of melanoma; biology of melanoma progression; and immune response to melanoma. These areas are all interrelated and each project contributes to and benefits from the other projects. In molecular genetics of melanoma (project #1), the hypothesis is tested that chromosome 10 contains a melanoma suppressor gene. These studies will complement ongoing research efforts to isolate a melanoma susceptibility gene on chromosome arm 9p. The biology of melanoma development and progression is addressed in four projects (#2-5). Project #2 uses two experimental approaches to drive cells from one step of tumor progression to the next. The first employs one-step and two-step carcinogenesis models in human/mouse chimeras in which ultraviolet (UV) light in the UV-B range is tested for its tumor promoting activity in normal human skin, benign nevi and biological early melanomas. The second uses a skin reconstruction model in which melanocytic cells ar engineered to overexpress an adhesion receptor (MUC18) or growth factors (pleiotrophin and PDGF). In project #3, a pleiotropic cytokine, TGF-beta, is tested for its paracrine activities during tumor growth and invasion, and for its immunosuppressive role using a melanoma model in immunocompetent mice. In project #4, three adhesion receptors MUC18, vitronectin receptor, and ICAM-1 are characterized for their ability to assess the risk for recurrence in primary melanoma. Because of its potential clinical significance, the cellular adhesion molecule MUC18 is structurally and functionally analyzed in project #5. The immune response to melanoma is investigated in project #6 through a molecular dissection of patients; B and T cell responses with the goal of developing cancer vaccines specific for individual melanoma-associated antigens, and through evolution of a therapeutic strategy based on stimulation of T cell responses to a variety of melanoma-associated antigens in melanoma patients by engineering metastatic melanoma cells to express the co-stimulatory molecule B-7-1 and the multifunctional cytokine IL-12 (project #7). This program continues to function as a focal group for progress in melanoma research in molecular biology , biology, and immunology.
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