Human cultured melanocytes from normal skin, common acquired and dysplastic nevi, early and late stages of primary melanoma and metastatic melanoma have characteristics similar to their in vivo counterparts. These cells and colorectal carcinoma cells representing tumors of different embryological origin will be used in a broad-based analysis of factors regulating growth of cells from different stages of tumor progression. Chemically defined media for continuous growth of cells from different stages will be developed to determine the minimal requirements for exogenous growth factors. The production and secretion of endogenous growth factors such as PDGF, alpha and beta TGF, and somatomedin C will be analyzed using biologic, immunologic and molecular techniques. These studies will also aid in the detection of any novel stimulatory and inhibitory factors produced by non-malignant and malignant cells in culture. Monoclonal antibodies (MAbs) have been developed that will be used in analyses of growth factor receptors and their functional role in growth control. Of the six MAbs that bind to the EGF receptor, MAb 425 inhibits growth of receptor-bearing tumor cells in vitro and in vivo. The non-effector cell- or complement-mediated mechanism of tumor growth inhibition by MAbs will be analyzed. MAb ME 20.4 to NGF receptor will aid in defining the biological role of this receptor which is expressed in culture on normal melanocytes, nevus, melanoma, and some carcinoma cells. Studies of the PDGF receptor with MAb 452 will focus on defining the growth regulatory role of PDGF in the human melanocytic system. In a different approach, studies will be conducted to determine the nuclear localization of growth factors and to characterize the acceptors on chromatin for the growth factor or growth factor/receptor complex in an effort to define the role of chromatin-binding in signal transduction for growth factor-induced cell proliferation.
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