The focus of this NIH Proposal is an improved understanding of the factors responsible for the growth of human germ cell cancer, a curable solid tumor. The experimental objective is to examine the contribution of two growth factors, TGF-alpha and Hst-1/kFGF, to the growth or differentiation of human germ cell cancer cell lines and tumors. Preliminary data from the NTera-2 clone Dl (NT2/Dl) human teratocarcinoma cell line demonstrate that the expression of these growth factors inversely correlate with the tumor cell's differentiation state. Human germ cell cancer cell lines that are responsive or refractory to the effects of the differentiation agents retinoic acid (RA) and hexamethylene bisacetamide (HMBA) will be studied. The NT2/Dl cell is responsive to both agents. After RA treatment, this multipotential cell differentiates into a neuronal phenotype and other cell lineages. HMBA induces a distinct pathway based on cellular and biochemical markers. Using cellular, biochemical, immunologic, pathologic, and recombinant DNA techniques, the goals of this Proposal are to: (1) contrast the regulated expression of TGF-alpha and Hst-1/kFGF in the induced NT2/Dl cell and correlate this with expressed differentiation markers and the tumorigenic potential of the cell; (2) stably transfect these factors into NT2/Dl cells; (3) select RA and/or HMBA refractory NT2/Dl cells; (4) analyze the expression of these important growth-regulated genes in other established germ cell cancer cell lines; and (5) explore the pattern of expression of these genes within tumors and correlate this with the tumor diagnosis and clinical outcome. From these studies, a better knowledge of the role of growth factors in the growth or differentiation of germ cell cancers will be gained. Applications of the findings may lead to improvements in the diagnosis and treatment of this solid tumor based on biologic and genetic properties.
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