Hepatocyte growth factor (HGF) has been proposed to be an autocrine/paracrine growth factor for carcinomas of various organs. We recently demonstrated that HGF produced by prostate-derived stromal cells was a paracrine growth factor that stimulated the growth of androgen-independent prostate cancer cells in vitro and in vivo. To assess possible involvement of HGF in prostate cancer, we examined the immunohistochemical expression and localization of HGF and c-Met/HGF receptor in benign and malignant human prostate tissues. In benign glands, columnar cells generally were negative for c-Met, but basal cells were stained uniformly at a high level. In high-grade prostatic intraepithelial neoplasia (PIN) and carcinoma, more than 50% of these foci were stained uniformly. There was no difference in the frequency of positively stained cells by Gleason score. The prostate stroma stained diffusely for HGF, and the staining intensity varied depending upon the amounts of smooth-muscle cells that were stained more intensely than the connective-tissue matrix. A great majority of benign columnar cells were negative for HGF whereas high-grade PIN and carcinoma foci stained focally for HGF. Hormonal ablation therapy prior to prostatectomy did not seem to alter the expression of HGF/c-Met in carcinoma cells. These results indicate that, as the degree of neoplasia progresses, epithelial cells begin to express c-Met protein, that PIN and carcinoma may have developed a c-Met-HGF paracrine loop with the stroma, and that in some carcinoma foci an autocrine loop may operate with HGF expressed by carcinoma cells themselves.

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