Angiogenesis and prostate cancer: Identification of a molecular progression switch

To elucidate the sequence of molecular events intricate with angiogenesis a nd the initiation and progression prostate cancer, the temporal and spatial expression patterns of platelet endothelial cell adhesion molecule-1 (PECA M-1/CD31), hypoxia-induced factor-1 alpha (HIF-1 alpha), vascular endotheli al growth factor (VEGF), and the cognate receptors VEGFR1 and VEGFR2 were c haracterized. Immunohistochemical and ill situ analyses of prostate tissue specimens derived from the spontaneous autochthonous transgenic adenocarcin oma of the mouse prostate (TRAMP) model identified a distinct early angioge nic switch; consistent with the expression of PECAM-1, HIF-1 alpha, and VEG FR1 and the recruitment of new vasculature to lesions representative of hig h-grade prostatic epithelial neoplasia (PIN). During progression of prostat e cancer, the intraductal microvessel density (IMVD) was also observed to i ncrease as a function of tumor grade. Immunoblot and in situ analyses furth er demonstrated a distinct late angiogenic snitch consistent with decreased expression of VEGFR1, increased expression of VEGFR2, and the transition f rom a differentiated adenocarcinoma to a more poorly differentiated state. Analysis of clinical prostate cancer specimens validated the predictions of the TRAMP model. This resolution of prostate cancer-associated angiogenesi s into distinct early and late molecular events establishes the basis for a "progression-switch" model to explain how the targets of antiangiogenic th erapy might change as a function of tumor progression.