Clinical, histopathological, and experimental biological investigations have defined the characteristics of human melanocytes as they progress from benign to malignant lesions. Each of the five clinicopathologic steps of progress has been delineated in its relation to others and its clinical significance. However, the molecular mechanisms are melanoma progression are still poorly understood. Similarly, the functions of most molecules that are over-expressed on melanoma cells have not been clarified, nor has a useful approach been defined to access the patient's anti-tumor immune response for melanoma therapy. Thus, the overall program combines biological (Projects 1 & 2), molecular (Projects 3), immunological (Project 4), and translational (Projects 2-4) aspects. In Projects 1 & 2, we will identify the gens that drive progression from the invasive but non-tumorigenic radial growth phase primary melanoma to the tumorigenic primary melanoma of the vertical growth phase, the step at which competence for metastasis is established. Project 1 will test the hypothesis that three growth factors, bFGF, PDGF, and VEGF, synergize to induce tumor formation by stimulation not only autocrine growth, but also the development of a tumor stroma with fibroblasts, blood vessels and extracellular matrix. Project 2 will use proteolytic enzymes to select those that define lesions with high risk for metastasis. These studies will reveal whether activation of common pathways for genes related to growth, invasion, and metastasis drive the progression to tumorigenicity. Projects 3 will focus on deregulated molecular checkpoints in melanoma, specifically examining how functional aberrations in the p53 pathways might lead to perturbation in cell growth, apoptosis, and/or response to radio- and chemotherapy in melanoma. P53 is in less than 90% of melanomas structurally investigate the mechanisms of deregulation of p53. The immunological investigations in Project 4 focus on the identification of new tumor antigens that elicit a specific humoral and cell-mediated response. Using clinical responders as donors for lymphocytes, we will test the hypothesis that antibodies and T helper cells identify unique epitopes on tumor antigens which are suitable for specific active immunotherapy and may have prognostic and diagnostic potential. This program project continues to explore fundamental issues in melanocytic tumor progression and its modulation. It also serves as a major impetus for progress in melanoma research in biology, molecular biology, and immunology.
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