Paracrine androgen axis in the normal prostate

In contrast to the regulation of transcription of the prostate differentiation marker proteins, AR in the nuclei of the secretory luminal cells does not directly regulate the survival of these cells nor does it positively regulate the proliferation and survival of the prostatic epithelial stem and transit amplifying cells. Instead, survival of the secretory luminal cells and the proliferation of the transit amplifying cells requires the androgen-dependent production of peptide growth factors by the prostatic stromal cells (Cunha etal. 1987; Hayward etal. 1992; Kurita etal. 2001). These processes are initiated by testosterone diffusing from the capillary bed in the stromal compartment of the normal prostate across the basement membrane (BM) to enter the basal epithelial cells. These basal cells express 5a-reductase type I and II proteins which enzymatically convert testosterone to 5a-dihydrotestosterone (Bonkhoff etal. 1996). Once formed, DHT diffuses both into the secretory luminal cells in the epithelial compartment and also back across the BM to the smooth muscle cells and fibroblasts in the stromal compartment. Secretory luminal cells also express 5a-reductase type I activity (Bonkhoff et al. 1996), thus further increasing their cellular level of DHT above that provided by the basal cells. Within these secretory luminal epithelial cell nuclei, this enhanced level of DHT binds to the AR and directly transcriptionally upregulates the expression of the prostate-specific differentiation markers (PSAP, PSA, hKh2, PSCA, NKX3.1 and PSMA) (Jain etal. 2002; Mitchell et al. 2000; Ornstein et al. 2001; Schuur et al. 1996; Watabe et al. 2002; Watt etal. 2001; Zelivianski etal. 2002) and indirectly also vascular endothelial growth factor (VEGF) (Joseph et al. 1997). These secretory luminal cells also express transforming growth factor ßi (TGFBi) (Gerdes etal. 1998). These growth factors diffuse across the BM to affect stromal cells. Specifically, VEGF effects the survival of the stromal endothelial cells (Joseph et al. 1997) and TGF-ß1 inhibits stromal cell proliferation and induces smooth muscle differentiation and neuronal trophism (Peehl etal. 1997; Yang etal. 1997).

Binding of DHT to the AR within the nuclei of these stromal smooth muscle cells inhibits their expression of certain cytokines such as TGFß1 (Kyprianou and Isaacs 1989; Wikstrom et al. 1999) while enhancing their secretion of "andromedins" i.e., androgen-induced stromal peptide growth factors (Lu etal. 1999; Planz etal. 1999). These andromedins diffuse back across the BM into the epithelial compartment where they interact with their specific cognate plasma membrane receptors of the secretory luminal cells generating intracellular signaling e.g., downregulation of TGß receptors needed to repress the apoptotic death pathway in the secretory luminal cells (Martikainen etal. 1990). Binding of the andromedins to the plasma membrane receptors of the transit amplifying epithelial cells can recruit them into the cell cycle. If a sufficient systemic androgen level is not chronically maintained (e.g., following androgen ablation), then the level of DHT-occupied AR within prostatic stromal cells decreases to a level unable to maintain adequate expression of the stromally derived "andromedins" and unable to repress expression of TGFß1 (Kyprianou and Isaacs 1989; Wikstrom et al. 1999). Without adequate "andromedins," prostatic transit amplifying epithelial cells remain proliferatively quiescent in Go and do not enter the cell cycle, while in the prostatic secretory luminal epithelial cells, lack of sufficient andromedins results in the upregula-tion of expression of type I and II TGFß1 receptors (Wikstrom et al. 1999). The enhanced levels of TGFß1 receptors in these secretory luminal cells are activated by the enhanced levels of TGFß 1 ligand produced by stromal cells following androgen ablation (Kyprianou and Isaacs 1989; Wikstrom et al. 1999). This enhanced TGFß 1 receptor signaling activates the energy-dependent apoptotic cascade within the secretory luminal cells, inducing their death (Denmeade etal. 1996; Kyprianou and Isaacs 1989; Martikainen etal. 1990). This apoptotic cascade involves changes in the intracellular free calcium level, caspase and nuclease activation, and degradation of the secretory luminal cells into apoptotic fragments (Denmeade et al. 1996; Kyprianou and Isaacs 1988; Kyprianou etal. 1988). Since secretory luminal cells are the source of VEGF production in the prostate, their death results in a lowering of the prostatic VEGF levels (Joseph etal. 1997).ThisloweringofthetissueVEGFlevel results in the activation of the apoptotic death of a subset of stromal endothelial cells, reducing tissue blood flow (Lissbrant etal. 2001).

While secretory luminal cells undergo apoptosis following androgen ablation, the basal stem and transit amplifying cells do not (English et al. 1987). A possible explanation for this observation is that prostatic stromal cells express hepatocyte growth factor (HGF) (Gmyrek et al. 2001). HGF expression by these stromal cells is not regulated by androgen occupancy of the AR in these stromal cells (Kasai et al. 1996). Basal stem and transit amplifying cells constitutively express c-MET, the plasma membrane cognate receptor for HGF, while secretory luminal cells do not (Gmyrek et al. 2001). Such c-MET signaling is inhibitory for basal cell apoptosis and proliferation (Gmyrek etal. 2001). Thus, following androgen ablation, the prostatic stromal cells continue to supply adequate levels of HGF to bind to and induce signaling by the basal cells' c-MET receptors, thus blocking both activation of apoptosis and inhibiting proliferation of these basal cells (Gmyrek etal. 2001).

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