The escalation of prostate cancer(PCa) from a localized, largely treatable disease to an invasive, metastatic tumor with a nearly 70% mortality rate depends on factors affecting the progression, invasion and metastasis of the original tumor. Expression of the transmembrane peptidase Prostate Specific Membrane Antigen (PSMA) is markedly increased in more aggressive and metastatic prostate carcinomas where it correlates negatively with patient prognosis[1-3]. While this accelerating expression during progression of prostate tumors suggests this abundantly expressed prognostic marker contributes to PCa progression or metastasis, functional confirmation of such a role remains elusive. It has previously been shown that PSMA regulates neovessel formation in tumors and the retina by facilitating integrin 1-mediated endothelial adhesion to the extracellular matrix and resultant signal transduction mechanisms[4, 5]. More recently, PSMA expression on the prostate tumor epithelium promotes tumor progression in vivo, where tumors lacking PSMA are markedly less aggressive (unpublished data). Mechanistically, PSMA directly interferes with the PTEN tumor-suppressor pathway, alters activation of critical regulatory signaling pathways and modifies expression levels of cancer- controlling receptor tyrosine kinases as well as down regulating androgen receptor expression, thus driving a pro-tumorigenic, anti-apoptotic and hormone-refractory phenotype (unpublished data). Furthermore, adhesion and invasion of PCa cell lines is exquisitely PSMA dependent and tumors lacking PSMA show reduced rates of metastasis, suggesting its participation in metastasis to distant sites as well. Therefore, it is hypothesized that PSMA performs dual pivotal functions during prostate cancer tumorigenesis by: i) modulating critical tumor- promoting signal transduction pathways and receptor tyrosine kinase and androgen receptor expression and ii) regulating integrin adhesion of circulating tumor cells to bone marrow endothelial cells to promote metastasis.
This application uses mouse models of prostate cancer as well as archived human prostate cancer samples to establish PSMA as a major regulator of signal transduction pathway switching within critical cancer-promoting pathways during prostate cancer tumorigenesis and metastasis. This study has the potential to provide a novel paradigm for development of therapeutic strategies for prostate cancer treatment through prevention of the progression, metastasis and vascularization of prostate tumors opening up the potential for a new era of personalized management of metastatic prostate cancer.