SEX HORMONE-INDUCED PROSTATIC CARCINOGENESIS IN THE NOBLE RAT - THE ROLE OF INSULIN-LIKE GROWTH-FACTOR-I (IGF-1) AND VASCULAR ENDOTHELIAL GROWTH-FACTOR (VEGF) IN THE DEVELOPMENT OF PROSTATE-CANCER

BACKGROUND. Despite extensive effort, the mechanisms of prostate carci nogenesis are still unknown. We report on a modified method which enab led us to induce a high incidence of prostate carcinogenesis in the No ble rat and examined the role of insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) and their receptors duri ng sex hormone-induced prostate carcinogenesis. METHODS. Noble rats we re implanted subcutaneously with a combination of testosterone and est radiol capsules for up to 12 months. Animals were sacrificed starting at 2 months after implantation, and the prostate gland was removed for histopathological and immunohistochemical studies. RESULTS. The resul ts showed that hyperplasia/dysplasia was detected as early as 2 months after treatment, while carcinoma in situ was induced in 4 months and adenocarcinoma in 7 months. Our data suggest that IGF-1, produced by s tromal cells in hyperplasia, exerted its effects, through a paracrine mode, or, epithelial cells which were IGF-1 receptor (IGF-1R)-positive . The production of IGF-1 appeared to switch to epithelial cells in ad enocarcinoma, through which it regulated tumor cell growth via autocri ne mode by binding to IGF-1R of carcinoma cells. On the other hand, VE GF was overexpressed in hyperplastic/dysplastic and carcinoma cells, w hile VEGF-R was detected in endothelial cells. The results suggest tha t overexpression of VEGF in deranged epithelia and arterial muscle cel ls may exert its influence on stromal angiogenesis and abnormal growth of prostate gland. CONCLUSIONS. A modified Noble rat model with;: hig h incidence of prostate carcinogenesis has been developed. Using this model, we have further established that IGF-1 and VEGF may be the crit ical regulators in mediating epithelial-stromal interactions in sex ho rmone-induced prostate carcinogenesis. (C) 1998 Wiley-Liss, Inc.