Abstract
The prostate is a highly heterogeneous organ, composed of different types of epithelial and stromal cells organized regionally along the ductal network. Although androgen-stimulated growth and maintenance of the prostate gland primarily involve epithelial cells, it is unclear whether all epithelial cells are androgen dependent. Moreover, the actions of androgens may not be direct; a number of polypeptide growth factors, including transforming growth factor-α (TGFα), are postulated to mediate androgen action in the rat prostate. In this investigation, using an immunohistochemical technique, we examined the cellular and regional expression of TGFα in the rat ventral prostate during postnatal development to adulthood. TGFα-immunopositive cells were located throughout the ductal epithelium from postnatal days 5–20. By day 45 and thereafter, regional variation in TGFα expression became apparent; epithelial cells in the proximal segment exhibited intense staining, whereas those in the distal segment exhibited negligible staining. These observations were coincident with increased serum testosterone concentrations at puberty. To understand the role of androgen in the expression of TGFα in the epithelial cells of the distal and proximal segments of the adult rat ventral prostate, androgen was withdrawn by castration, and testosterone subsequently was administered. Androgen receptor protein expression decreased after castration and reappeared after androgen replacement in both the distal and proximal segments. TGFα staining was negligible in epithelial cells of the distal segment of intact adult rats, became prominent by 7 days after castration, but then diminished after the administration of testosterone. Western blot analyses revealed the presence of a specific 30-kDa immunoreactive form of TGFα in rat ventral prostate, and its quantity reflected the staining intensities observed in the immunohistochemical studies. These results suggest that TGFα expression is negatively regulated by androgen in epithelial cells of the distal segment. In contrast, staining for TGFα in epithelial cells of the proximal segment did not change with castration or testosterone administration, suggesting that TGFα is not regulated by androgen in this region of the ventral prostate. In summary, TGFα expression is differentially regulated among epithelial cells localized in two different regions of the ventral prostate. We hypothesize that TGFα may function as a survival factor for epithelial cells which, as a consequence of its expression, become androgen independent and thus escape apoptotic cell death after androgen ablation.
Metalloproteinase-dependent Transforming Growth Factor-α Release Mediates Neurotensin-stimulated MAP Kinase Activation in Human Colonic Epithelial Cells
