TGF-β maintains dormancy of prostatic stem cells in the proximal region of ducts

We have previously shown that prostatic stem cells are located in the proximal region of mouse prostatic ducts. Here, we show that this region responds differently to transforming growth factor (TGF)-β than the distal ductal region and that under physiological conditions androgens and TGF-β are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-β signaling are present in the quiescent proximal region of ducts in an androgen-replete animal and that cells in this region overexpress Bcl-2, which protects them from apoptosis. Moreover, androgen ablation reverses the proximal-distal TGF-β signaling gradient, leading to an increase in TGF-β signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-β–mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-β signaling gradient (high proximally and low distally) and its functional correlates are restored after androgen replenishment. In addition to highlighting the regulatory role of androgens and TGF-β, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.