Most prostate cancer initially is androgen responsive. However, maximum androgen blockade, using antoandrogen and GnRH agonist treatment, only moderately increases progression-free survival or median length of survival; suggesting other growth promoters affect cancer cell proliferation. Our studies show that fibroblast-like (FGF-like) growth factors are principal mitogens produced by rat prostate cancer cells and that acidic, aFGF, and basic, bFGF, fibroblast growth factors enhance prostate cancer cell DNA synthesis. The objectives of this proposal are to understand androgen modulation of prostate cancer cell FGF-like mitogen production and FGF-like mitogen modulation of prostate cancer cell proliferation. We propose to address this issue by means of the following specific aims: The goal of aim 1 is to characterize rat prostate and prostate cancer cell FGF transcripts, including analysis for a rat bFGF antisense transcript comparable to that of X. laevis, and to define the relation between prostate cancer cell FGF-like mitogens produced in vitro and in vivo and prototypic aFGF and bFGF. The goal of aim 2 is to use plasmid pKK233-2 to construct expression vectors for generation of rat aFGF and bFGF in E. coli. These mitogens will be used to produce aFGF and bFGF antibodies in rabbits. Antibodies will be used for immunocytochemical localization of FGF-like mitogens in rat prostate cancer tumors, cultured prostate cancer cells, and normal prostate and for ELISA qantification of rat FGF-like mitogen production. Purified rat aFGF and bFGF will be used as standards for ELISA assays and in Western analyses. The goal of aim 3 is to define androgen modulation of prostate cancer cell FGF-like mitogen production in vitro and in vivo. The goal of aim 4 is to test the hypothesis that prostate cancer cell mitogens function in vivo as endocrine polypeptides. The goal of aim 5 is to determine what other mitogens, known to be expressed in prostate tissue, are expressed in rat prostate cancer cells. These studies will provide basic information detailing FGF-like growth factor function in normal and neoplastic prostate and new insight into the interactive roles of androgens and FGFs as modulators of prostate cancer cell proliferation.
