Antiangiogenic activity of prostate-specific antigen

Background: Measurement of serum levels of prostate-specific antigen (PSA) is widely used as a screening tool for prostate cancer. However, PSA is not prostate specific, having been detected in breast, lung, and uterine cance rs. In one study, patients whose breast tumors had higher levels of PSA had a better prognosis than patients whose tumors had lower PSA levels, To tes t the hypothesis that PSA may have antiangiogenic properties, we evaluated the effects of PSA on endothelial cell proliferation, migration, and invasi on, which are key steps in angiogenesis, the process by which tumors develo p a blood supply. Methods: To assess the antiproliferative effects of PSII, we treated bovine endothelial cells and human endothelial cell lines (HUVE C and HMVEC-d) with purified human PSA (0.1-10 mu M) and then stimulated th em with 10 ng/mL, fibroblast growth factor-2 (FGF-2), Effects on FGF-2- or vascular endothelial growth factor (VEGF)-stimulated endothelial cell migra tion, invasion, and tube formation were measured by use of one cell line on ly (HUVEC), PSA. was administered to mice at 9 mu M for 11 consecutive days after intravenous inoculation of B16BL6 melanoma cells to assess its abili ty to inhibit the formation of lung colonies (i.e., metastatic tumors). Res ults: PSA inhibited endothelial cell proliferation, migration, and invasion at IC,, (i.e., the concentration at which inhibition was 50%) values rangi ng from 0.3-5 mu M. In addition, PSA inhibited endothelial cell responses t o both angiogenic stimulators tested, FGF-2 and VEGF. In a mouse model of m etastatic disease, daily PSA treatment resulted in a 40% reduction in the m ean number of lung tumor nodules compared with phosphate-buffered saline tr eatment (two-sided P =.003). Conclusion: To our knowledge, this is the firs t report that PSA may function in tumors as an endogenous antiangiogenic pr otein. This function may explain, in part, the naturally slow progression o f prostate cancer. Our findings call into question various strategies to in hibit the expression of PSA in the treatment of prostate cancer.