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
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Growth factors are postulated to mediate stromal-epithelial interactions in the prostate to maintain normal tissue physiology. Transforming growth factor-β (TGFβ) has been shown to influence the prostate and probably mediate stromal-epithelial interactions. TGFβ1 messenger RNA (mRNA) expression is stimulated after castration and can be suppressed by in vivo treatment with androgens. The hypothesis tested is that TGFβ 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 TGFβ1, -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 TGFβ1, -2, and -3. TGFβ1 mRNA expression was constant during development of the prostate. TGFβ2 mRNA expression was elevated at birth, then declined and elevated again at 100 days of age. TGFβ3 mRNA expression was high during puberty and young adult ages then declined at 100 days of age. TGFβ2 and TGFβ3 expression are inversely related during prostate development. After castration of 60-day-old rats, both TGFβ1 and TGFβ2 mRNA were enhanced. Interestingly, TGFb3 mRNA was significantly suppressed after castration. Epidermal growth factor (EGF) stimulated TGFβ1 mRNA expression in stromal cells (6-fold increase), whereas keratinocyte growth factor stimulated TGFβ2 mRNA in epithelial cells. TGFβ inhibited both testosterone- and EGF-stimulated prostatic stromal and epithelial cell growth. EGF and TGFβ also inhibited prostatic ductal morphogenesis and growth in organ culture. Immunocytochemical localization of TGFβ in 20-day-old prostate demonstrated predominately stromal localization of the protein.
These results indicate that the isoforms of TGFβ2 and TGFβ3 are differentially regulated during prostate development, suggesting distinct regulatory mechanisms. Testosterone did not affect TGFβ expression in cultured prostatic cells. These observations suggest that the in vivo effects of castration on TGFβs 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 TGFβ1 expression. In summary, a network of growth factor-mediated stromal-epithelial interactions is needed to maintain prostate growth and development. TGFβ is postulated to have an important role in this process.