Identification of Markers of Human Vascular Dynamics Exposed in the Human Vasculature of Human Prostate Xenografts by Androgen Deprivation

摘要

The goals of this project are: (1) demonstration that androgen deprivation produces transient/permanent prostatic vascular damage; and (2) characterization of vascular targets for molecular treatment modalities that are induced/unmasked by androgen deprivation. Progress during the initial year has focused on immunohistochemical evaluation of the kinetics of changes induced in the prostate vasculature and surrounding tissue, and on demonstration of induction of a pro- coagulative state indicative of acute vascular damage. Characterization of change in markers of vascular stability, and endothelial, epithelial and stromal cell proliferation and death, demonstrates clearly that the vascular endothelial compartment is labilized maximally at two days post-androgen deprivation, and rebounds between 7-l4 days after androgen deprivation. Three- dimensional reconstruction of the prostatic vasculature from xenografts perfused with fluorescently labeled lectin demonstrates induction of areas of denuded vascular basement membrane is accompanied by leakage of lectin and fibrinogen into the interstitial tissue space and appearance of Tissue Factor on endothelial cell surfaces. Studies in year two will focus on verification of areas of vascular damage utilizing human platelets, and on characterization of new/unmasked targets by phage display. Induction of acute vascular damage suggests the opportunity for specific therapeutic targeting without risk of morbidity associated with long-term hormonal therapy.