Cellular Mechanisms Regulating Urokinase-Type Plasminogen Activator in Hormone Refractory Prostate Cancer: A Novel Therapeutic Target

摘要

This research had as its goal inhibiting the expression of two pathways critical to prostate cancer progression, one mediated by the tyrosine kinase receptor c-Met, and the second mediated by urokinase plasminogen activator (uPA). Each pathway has been demonstrated to be important to prostate tumor progression, and further, they may be related, i.e., increased c-Met expression leads directly to increased uPa expression. The purpose of this research was to determine the relationship between uPa and c-Met expression and prostate tumor progression. By using various strategies to inhibit these molecules, the second purpose was to determine if decreased tumor growth and/or tumor progression would result. Thus, the scope of the work utilized human prostate tumor cell lines, and examine in vitro and in vivo the effects of in habiting these pathways. We have demonstrated that inhibition of c-Met results in inhibition of growth at the primary tumor site and significantly, prevents development of lymph node metastases in an Orthotopic nude mouse model. Inhibition of uPaR also inhibits metastatic growth. UPaR expression increases in clinical specimens of more progressed disease. Thus, c-Met and UPAR contribute to CaP progression and further development of inhibitors for these enzymes is promising for CaP treatment.