MOLECULAR REGULATION OF HUMAN MELANOMA METASTASIS

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The major goal of our research is to define the mechanism(s) that regulate the process of metastasis, and use this knowledge to design innovative hypothesis-based therapies. Metastasis is a highly selective process that is regulated by multiple interrelated mechanisms whose outcome is dependent upon both the intrinsic properties of tumor cells and the host response. Signals from autocrine or paracrine pathways, alone or in combination, may regulate tumor growth and metastasis with the eventual outcome dependent on a balance of stimulatory and inhibitory factors. Recent data from our laboratory demonstrate that the organ microenvironment can modulate gene expression of growth and angiogenic factors in tumor cells in an organ site specific manner. Our analyses of different human metastatic melanoma cell variants demonstrated a direct correlation between the levels of interleukin-8 (IL-8) mRNA expression and protein secretion with metastatic phenotype in nude mice. Preliminary data from our laboratory and others suggest that IL-8 is an obligate autocrine growth, motility and angiogenic factor for melanoma cells. In this application we propose to test the hypothesis that autocrine production of IL-8 and its receptors and their regulation by organ specific cytokines are important determinant in melanoma growth and metastasis. Three specific aims will be pursued: First, we will determine the functional significance of the autocrine production of IL-8 and its receptors on the expression of cellular phenotypes associated with melanoma growth and metastasis. Second, we will analyze whether the organ microenivronments can differentially modulate the expression of IL-8 and its receptors in metastatic melanoma cells. Third, we will determine whether the expression of IL-8 correlates with the clinical grade of human melanoma tumor specimens. The knowledge gained from this research will extend our basic and clinical understanding of the mechanism(s) regulating the process of melanoma tumor growth and metastasis.