When normal prostatic tissue is used to establish in vitro cultures, only the transit amplifying cells (i.e., intermediate cell type) continue to proliferate during the subsequent several passages (Liu and Peehl 2001). Low passage cultures of these transit amplifying cells have a high rate of proliferation (i.e., >50% proliferation per day) when grown in vitro in serum-free defined media (Chopra et al. 1996). Cells in such low passage cultures do not express AR and thus are not affected by adding androgen to the culture media. These cells are dependent, however, upon a critical mixture of peptide growth factor andromedins in the media for their survival and high rate of proliferation (Chopra et al. 1996). In contrast to the high proliferation rate in in vitro cultures, only 0.2% of the epithelial cells proliferate per day in normal prostatic tissue in vivo, even though these cells are exposed continuously to maximal physiological levels of andromedins present in non-androgen-ablated hosts (Berges etal. 1995). These observations raise the issue of how the in vivo proliferation of the transit amplifying cells becomes restricted to allow only homeostatic renewal and not net continuous prostatic epithelial growth, even though the level of the stromally produced andromedins remains constantly high in the presence of physiologic androgen levels.
One explanation is that AR signaling in the nuclei of the prostatic secretory lumi-nal cells and the subset of AR expressing transit amplifying cells actively inhibits proliferation of these cells even in the presence of continuous andromedin stimulation (Geck etal. 1997; Ling etal. 2001; Whitacre etal. 2002). This mechanism has been documented experimentally using both human (Ling et al. 2001) and rodent (Whitacre et al. 2002) prostate epithelial cells. These latter studies have demonstrated that when AR negative prostatic epithelial cells are transgenically induced to express AR, and are then exposed to physiological levels of androgen, their in vitro proliferation is profoundly inhibited even in the presence of andromedins with no effect upon cell survival (Ling et al. 2001; Whitacre et al. 2002). These results demonstrate that for non-malignant prostatic epithelial cells, the ligand-occupied AR functions as a growth suppressor via its ability to inhibit andromedin-induced proliferation. While functioning as a growth suppressor, such AR signaling also induces differentiation of these transit amplifying cells from an intermediate to a secretory luminal cell phenotype (Ling et al. 2001; Whitacre et al. 2002). This AR-mediated inhibition of andromedin-induced proliferation appears to be related to AR-induced upregulation of the p27Kip1 cyclin dependent kinase inhibition protein (Chen etal. 1996; Tsihlias et al. 2000; Waltregny et al. 2001). The mechanism for this upregulation in normal prostatic epithelial cells involves enhanced stability of the p27Kip1 protein secondary to AR-induced transcriptional repression of expression of the E3 ubiquitin ligase, Skp2 involved in p27Kip1 degradation (Lu etal. 2002; Waltregny etal. 2001).
In BPH, there is an increase in the cellular content of the transition zone of the prostate. This neoplastic growth could involve: 1) enhanced number of epithelial stem cell units, 2) enhanced number of proliferations by transit amplifying cells before these mature into non-proliferating luminal secretory cells, and/or 3) decreased ability of AR to limit the proliferation of luminal secretory cells. BPH characteristically is also associated with an enhanced number of stromal cells. Since at least a subset of these stromal cells express AR and thus andromedins, androgen regulation within these stromal cells may be abnormal, leading to enhanced andromedin production. Theoretically, in order to inhibit such enhanced andromedin production, androgen ablation could be utilized to treat BPH. Unfortunately, such systemic androgen ablation has other unacceptable side effects on bone density, muscle mass, and libido. For these reasons, BPH is often treated medically with 5a-reductase inhibitors like the 5a-reductase type II inhibitor, finasteride or the dual type I and II inhibitor, dutasteride (Foley and Kirby 2003). In this way, testosterone levels are not lowered even though prostatic DHT is lowered and the stromal andromedin production is also lowered but without the other side effects. Indeed, such 5a-reductase inhibition does reduce the size of the prostate by ^25%, even though systemic androgen levels are not decreased (Foley and Kirby 2003).
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