Functional Angiogenic Mediators in Prostate Cancer
Annual rept. 1 Aug 1999-31 Jul 2000
NORTHWESTERN UNIV CHICAGO IL MEDICAL SCHOOL
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In normal adults, the tissue vasculature is quiescent due to the predominance of angiogenesis inhibitors over that of inducers secreted into the tissue matrix. During tumor progression, this balance shifts to favor angiogenesis. Our goal is to characterize this transition in the prostate by 1 identifying the key angiogenic mediators, 2 investigating the clinical significance of mediator levels in prostatic fluid, and 3 designing anti- angiogenic therapies utilizing these mediators. We have found that normal prostate epithelial cells inhibit angiogenesis through secretion of thrombospondin-l TSP-l, a potent angiogenesis inhibitor, with only low levels of inducers present. In the transition to a pro-angiogenic state, in BPH and PCa, TSP-i expression is downregulated or lost, and both BPH and PCa, secrete increased levels of angiogenic inducers vascular endothelial growth factor VEGF andor fibroblast growth factor-2 FGF-2. Analysis of prostatic fluids from normal controls and prostatitis, BPH and PCa patients revealed no correlations between overall angiogenic activity or VEGF levels and patient group, and neither FGF-2 or TSP was detectable in these samples suggesting that angiogenic mediators are not a useful measure of disease in prostatic fluids. We have also initiated anti- angiogenic treatment studies in mouse models using TSP-l and anti-VEGF approaches.
- Anatomy and Physiology
- Medicine and Medical Research