Title

The Role of Prostate Specific Membrane Antigen in Prostate Cancer and Pathologic Angiogenesis in Vivo

Date of Completion

January 2012

Keywords

Biology, Cell

Degree

Ph.D.

Abstract

The Prostate Specific Membrane Antigen (PSMA) transmembrane peptidase is highly expressed on endothelial cells of tumor vasculature and on epithelial cells in advanced and metastatic prostate carcinoma where its expression correlates with tumor progression. While the expression pattern of PSMA makes it a potentially attractive target for therapeutic development, the precise function of PSMA in either tumor associated endothelium or prostate epithelial cells is not clear. ^ PSMA has been shown to be significantly and universally up-regulated on the vasculature of solid tumors, while it is absent in normal, quiescent vessels suggesting it may play a role in pathologic angiogenesis. Inhibiting the enzymatic activity of PSMA leads to a decrease in endothelial cell adhesion, invasion and migration in vitro, processes which are necessary for angiogenesis. Taken together, these findings suggest that PSMA may play a role in angiogenesis in vivo. We examined tumor initiation, growth and metastasis in a transgenic model of tumor progression in wild-type and PSMA-null animals. We also investigated the relative contribution of tumor vs. endothelial PSMA expression using PSMA positive tumor allografts into wild type or PSMA null mice, and show that PSMA expression on endothelial cells is necessary for tumor angiogenesis. We also showed that PSMA contribution to pathologic angiogenesis was not restricted to tumor angiogenesis, using a mouse model of retinopathy of prematurity to show that PSMA function changes outcome in this model. Understanding the contribution of PSMA to angiogenesis progression will further understanding of diseases involving pathologic blood vessel growth. ^ While angiogenesis occurs during normal development and in healing wounds, it is also involved in processes which involve the growth of new blood vessels, such as tumor growth and metastasis and the pathologic overgrowth of vessels into the eye which often results in blindness. Better understanding of the molecules regulating this process may lead to new therapies for tumor metastasis and for diseases involving detrimental angiogenesis. ^