Developmental and hormonal regulation of transforming growth factor-beta1 (TGFbeta1), -2, and -3 gene expression in isolated prostatic epithelial and stromal cells: epidermal growth factor and TGFbeta interactions.

Growth factors are postulated to mediate stromal-epithelial interactions in the prostate to maintain normal tissue physiology. Transforming growth factor-beta (TGFbeta) has been shown to influence the prostate and probably mediate stromal-epithelial interactions. TGFbeta1 messenger RNA (mRNA) expression is stimulated after castration and can be suppressed by in vivo treatment with androgens. The hypothesis tested is that TGFbeta is regulated not only by androgen, but also by a network of locally produced growth factors that influence prostatic growth and differentiation. Epithelial and stromal cells from 20-day-old rat ventral prostate were isolated and used to test this hypothesis. The expression of mRNA for TGFbeta1, -2, and -3 was analyzed by a quantitative RT-PCR procedure. Observations from this assay demonstrate that both epithelial and stromal cells express the mRNA for TGFbeta1, -2, and -3. TGFbeta1 mRNA expression was constant during development of the prostate. TGFbeta2 mRNA expression was elevated at birth, then declined and elevated again at 100 days of age. TGFbeta3 mRNA expression was high during puberty and young adult ages then declined at 100 days of age. TGFbeta2 and TGFbeta3 expression are inversely related during prostate development. After castration of 60-day-old rats, both TGFbeta1 and TGFbeta2 mRNA were enhanced. Interestingly, TGFbeta3 mRNA was significantly suppressed after castration. Epidermal growth factor (EGF) stimulated TGFbeta1 mRNA expression in stromal cells (6-fold increase), whereas keratinocyte growth factor stimulated TGFbeta2 mRNA in epithelial cells. TGFbeta inhibited both testosterone- and EGF-stimulated prostatic stromal and epithelial cell growth. EGF and TGFbeta also inhibited prostatic ductal morphogenesis and growth in organ culture. Immunocytochemical localization of TGFbeta in 20-day-old prostate demonstrated predominately stromal localization of the protein. These results indicate that the isoforms of TGFbeta2 and TGFbeta3 are differentially regulated during prostate development, suggesting distinct regulatory mechanisms. Testosterone did not affect TGFbeta expression in cultured prostatic cells. These observations suggest that the in vivo effects of castration on TGFbetas are regulated indirectly through a complex network of growth factors, not simply by direct androgen depletion. The ability of EGF to inhibit prostatic ductal morphogenesis and growth in organ culture is postulated to be in part mediated by the increase in TGFbeta1 expression. In summary, a network of growth factor-mediated stromal-epithelial interactions is needed to maintain prostate growth and development. TGFbeta is postulated to have an important role in this process.