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 cancers. 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 test the hypothesis that PSA may have antiangiogenic properties, we evaluated the effects of PSA on endothelial cell proliferation, migration, and invasion, which are key steps in angiogenesis, the process by which tumors develop a blood supply.


METHODS
To assess the antiproliferative effects of PSA, we treated bovine endothelial cells and human endothelial cell lines (HUVEC and HMVEC-d) with purified human PSA (0.1-10 microM) and then stimulated them with 10 ng/mL fibroblast growth factor-2 (FGF-2). Effects on FGF-2- or vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration, invasion, and tube formation were measured by use of one cell line only (HUVEC). PSA was administered to mice at 9 microM for 11 consecutive days after intravenous inoculation of B16BL6 melanoma cells to assess its ability to inhibit the formation of lung colonies (i.e., metastatic tumors).


RESULTS
PSA inhibited endothelial cell proliferation, migration, and invasion at IC(50) (i. e., the concentration at which inhibition was 50%) values ranging from 0.3-5 microM. In addition, PSA inhibited endothelial cell responses to both angiogenic stimulators tested, FGF-2 and VEGF. In a mouse model of metastatic disease, daily PSA treatment resulted in a 40% reduction in the mean number of lung tumor nodules compared with phosphate-buffered saline treatment (two-sided P =.003).


CONCLUSIONS
To our knowledge, this is the first report that PSA may function in tumors as an endogenous antiangiogenic protein. This function may explain, in part, the naturally slow progression of prostate cancer. Our findings call into question various strategies to inhibit the expression of PSA in the treatment of prostate cancer.
Fortier
A H
AH
EntreMed, Inc., Rockville, MD 20850, USA.
Nelson
B J
BJ
Grella
D K
DK
Holaday
J W
JW
D020533:Angiogenesis Inhibitors; D000818:Animals; D002417:Cattle; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000517:prevention & control*; D008546:Melanoma, Experimental; D051379:Mice; D009389:Neovascularization, Pathologic; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D014471:Umbilical Veins
D020533:Angiogenesis Inhibitors; D017430:Prostate-Specific Antigen