Radial growth phase (RGP) primary melanomas are thin lesions which extend predominantly in the epidermis. They do not have competence for metastasis. Cultured RGP melanoma cells require several growth factors for continues proliferation, do not growth anchorage independently in soft agar, are no-invasive in skin reconstruction models, and are either non- tumorigenic in human skin grafted to immunodeficient mice or grow very slowly. By contrast, melanoma cells from the vertical growth phase (VGP) have metastatic competence, need maximally one growth factor for proliferation in culture, and express a variety of growth factors for autocrine stimulation and paracrine regulation of normal cells in the stroma. VGP melanomas readily form colonies in soft agar, grow invasively in skin reconstructs, and are invariably tumorigenic in immunodeficient mice. Our studies and others point to the central role of melanoma-derived growth factors in driving the expression of an increasingly aggressive phenotype during the progression of primary melanomas from RGP to VGP. Growth factors produced by VGP primary and metastatic melanoma cells stimulate not only self in autocrine circuit but also fibroblasts and endothelial cells in the stroma. In the first aim, we will test the hypothesis that bFGF, PDGF, and VEGF follow a hierarchical pattern of expression during melanoma development in which bFGF is the dominant 'stimulation factor' followed by PDGF as """"""""maintenance and survival factor,' whereas VEGF requires activation to become the 'expansion and invasion factor'. Each factor appears to have specific functions that complement the other in driving cells from a RGP-to a VGP-like phenotype. In the second aim, we will test for the positive feedback from the activated fibroblasts and endothelial cells. We propose that the stromal cells produce mitogens for melanoma cells that the malignant cells cannot synthesize but for which they express functional receptors. Specifically, we hypothesize that activated fibroblasts produce IGF-1 and endothelial cells produce endothelins for stimulation of melanoma cells. We will test our hypothesis with adenoviral vectors fro over-expression of growth factors and antisense constructs for inhibition of expression. To account for the complex environment in human skin, we will use a skin reconstruction model for in vitro studies and the human skin/SCID mouse chimera model for in vivo growth. We expect to find intricate and interdependent circuits for growth factors cross-link involving melanoma cells, fibroblasts, and endothelial cells which are essential for progression from non-tumorigenic RGP melanoma to tumorigenic VGP growth high potential for metastasis.
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