Hormone-like, polypeptide growth factors, their receptors and the signal generated by growth factor-receptor coupling are now accepted as key elements in regulation of cell growth and differentiation. The proposed program brings together a group of investigators to understand the role of growth factor families in several facets of specific cancers. The underlying hypothesis to be tested is that alterations in regulation of different combinations of specific members (gene products) of polypeptide growth factor families, their receptors, and the signal transmitted by factor-receptor coupling is central to initiation, progression and maintenance of phenotypic properties of specific cancers. The role of the initiation stage on growth factor requirements of tumor cells will be investigated in a renal cell carcinogenesis model. Long-term goals are to understand the molecular targets for endogenous growth factor gene activation by specific carcinogens or the molecular basis for by-pass of essential signals generated by growth-receptor coupling. The mechanism of the promotion stage of tumors will be probed by elucidation of biochemical mechanisms by which alterations in protein kinase C cause attenuation of the phorbol ester (tumor promoter and PKC ligand) response of cultured cells. Long-term goals are then to determine whether the mechanism of desensitization accounts for by-pass of growth factor requirements for growth of specific tumors. The chemistry, molecular biology and regulation of the immunoregulatory factor, thymulin will be studied in a thymic epithelial cell system. The hypothesis that defects in regulation of or response to specific polypeptide growth factors, rather than androgen, account for the growth of the prostate tumors will be explored using transplantable rat prostate tumors and cultured cells derived from them. The mechanism underlying alterations in growth factor regulation that is associated with tumorigenicity will be explored in variants of teratoma cells. The hypothesis that, since growth factors directly support cancer cells, then therapies against growth factor receptors can be designed that block tumor growth in vivo. An in vitro system will be optimized for preparation of human monoclonal antibodies against human receptors for EGF, insulin and transferrin. Long-term goals are to apply this approach to block human tumor cell growth in vivo by monoclonal antibodies against human growth factor receptors that support specific cancers.
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