Developmental and hormonal regulation of transforming growth factor-β1 (TGFβ1), -2, and -3 gene expression in isolated prostatic epithelial and stromal cells:: Epidermal growth factor and TGFβ interactions

Growth factors are postulated to mediate stromal-epithelial interactions in the prostate to maintain normal tissue physiology. Transforming growth factor-beta (TGF beta) has been shown to influence the prostate and probably mediate stromal-epithelial interactions. TGF beta 1 messenger RNA (mRNA) expression is stimulated after castration and can be suppressed by in vivo treatment with androgens. The hypothesis tested is that TGF beta 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 TGF beta 1, -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 TGF beta 1, -2, and -3. TGF beta 1 mRNA expression was constant during development of the prostate. TGF beta 2 mRNA expression was elevated at birth, then declined and elevated again at 100 days of age. TGF beta 3 mRNA expression was high during puberty and young adult ages then declined at 100 days of age. TGF beta 2 and TGF beta 3 expression are inversely related during prostate development. After castration of 60-day-old rats, both TGF beta 1 and TGF beta 2 mRNA were enhanced. Interestingly, TGF beta 3 mRNA was significantly suppressed after castration. Epidermal growth factor (EGF) stimulated TGF beta 1 mRNA expression in stromal cells (6-fold increase), whereas keratinocyte growth factor stimulated TGF beta 2 mRNA in epithelial cells. TGF beta inhibited both testosterone-and EGF-stimulated prostatic stromal and epithelial cell growth. EGF and TGF beta also inhibited prostatic ductal morphogenesis and growth in organ culture. Immunocytochemical localization of TGF beta in 20-day-old prostate demonstrated predominately stromal localization of the protein. These results indicate that the isoforms of TGF beta 2 and TGF beta 3 are differentially regulated during prostate development, suggesting distinct regulatory mechanisms. Testosterone did not affect TGF beta expression in cultured prostatic cells. These observations suggest that the in vivo effects of castration on TGF beta s 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 TGF beta 1 expression. In summary, a network of growth factor-mediated stromal-epithelial interactions is needed to maintain prostate growth and development. TGF beta is postulated to have an important role in this process.