Tumor invasion in human prostate cancer involves a series of coordinated events, including cell adhesion, secretion of specific proteases, degradation of extracellular matrix (ECM) structures and finally movement of tumor cells through the basal lamina and out of the prostate gland. Carcinogenesis in the prostate also involves proliferation of epithelial cells. The prostate is high in polyamine content and polyamines are known to be essential for optimal proliferation of pro- and eukaryotic cells. Recent studies indicate that polyamine levels may affect the expression of genes involved in tumor invasion, including genes involved in prostate tumor invasion. These data provide the rationale for depletion of tissue polyamine contents as a possible strategy for prostate cancer chemoprevention. The major hypothesis to be tested in this project is that alpha-difluoromethylornithine (DFMO), and inhibitor of polyamine synthesis, an suppress polyamine contents in prostate tissue in men from families with histories of early onset prostate cancer and, consequently, suppress the expression of specific genes known to be dependent on cellular polyamine levels and also associated with either growth or tumor invasion. Suppression of tissue polyamine pools and/or expression of polyamine-dependent genes may then inhibit prostate carcinogenesis by either direct or indirect mechanisms. In order to test this hypothesis, the specific aims of this proposal are to conduct pathological analysis of prostate biopsies obtained in this study, to measure surrogate endpoint biomarkers (SEBs) associated with prostate cancer proliferation and invasion and then, determine the effects of DFMO treatment on these SEBs and prostate tissue polyamine contents. The overall objective of this project is to determine if DFMO doses used in the clinical trial, described in Project 1, are sufficient to reduce polyamine contents in prostates of this high risk cohort, and then, if this treatment suppresses the expression of genes, or affects genetic changes, associated with progression of prostate cancer. The long term goal of this project is to determine if suppression of prostate polyamine contents is an effective strategy for prevention of prostate cancer in human males.
