ANGIOGENESIS AND PROSTATE-CANCER - IN-VIVO AND IN-VITRO EXPRESSION OFANGIOGENESIS FACTORS BY PROSTATE-CANCER CELLS

Objectives. Recently, it was confirmed that angiogenesis is important in the development and spread of a variety of human cancers, including prostate cancer (PCa). Tumor neovascularization is thought to be cont rolled by chemical signals, known as angiogenic factors (AF). To date, little is known regarding the existence and role of AF in PCa. We pre viously reported on vascular endothelial growth factor (VEGF) in PCa. Currently, we compare VEGF expression with that of interleukin-8 (IL-8 ), another putative regulator of angiogenesis. We evaluated the expres sion of these two important AF in PCa and explored the role of inflamm atory cytokines IL-l and tumor necrosis factor (TNF) in their regulati on. Methods. Ex vivo studies involved previously reported immunohistoc hemical analysis for VEGF and recent evaluation of IL-8 expression and distribution in archival tissue samples of PCa, benign prostatic hype rplasia (BPH), and normal prostate tissue. In vitro studies used PCa c ells (DU-145) grown in culture and stimulated with cytokines thought t o induce VEGF and IL-8 (ie, IL-l alpha, IL-l beta, TNF-alpha, and TNF- beta). After 24 hours, with or without cytokines, cell culture superna tants were analyzed by enzyme-linked immunosorbent assay or radioimmun oassay for VEGF or IL-8 levels. Results. Immunohistochemical studies o f prostate tissue showed that PCa cells stained positively for VEGF an d IL-8. Benign prostatic hyperplasia and normal prostate cells display ed little staining for either AF. Low levels of VEGF and IL-8 were pro duced by unstimulated DU-145 cells. Induction of DU-145 cells with cyt okines resulted in differential stimulation whereby TNF was the predom inant inducer of VEGF, whereas IL-I was the predominant inducer of IL- 8. Conclusions. Our results indicate that significant levels of VEGF a nd IL-8 are present in PCa, but not BPH or normal prostate cells in vi vo. In vitro studies suggest that differential regulation of AF expres sion occurs in PCa. Because IL-l and TNF are present in the PCa tumor microenvironment, it is likely that differential regulation of AF also occurs in human PCa and contributes to differential tumor growth and metastasis. (C) 1998, Elsevier Science Inc. All rights reserved.