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TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts.

Salm SN, Burger PE, Coetzee S, Goto K, Moscatelli D, Wilson EL - J. Cell Biol. (2005)

Bottom Line: This conclusion is supported by the observations showing that high levels of TGF-beta 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.A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
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)-beta than the distal ductal region and that under physiological conditions androgens and TGF-beta are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-beta 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-beta signaling gradient, leading to an increase in TGF-beta signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-beta-mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

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Related in: MedlinePlus

Microdissected prostatic ducts. A segment from a microdissected mouse dorsal prostate showing the distal, intermediate, and proximal regions of prostatic ducts. Bar, 1 mm.
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fig1: Microdissected prostatic ducts. A segment from a microdissected mouse dorsal prostate showing the distal, intermediate, and proximal regions of prostatic ducts. Bar, 1 mm.

Mentions: The mouse prostate can be divided into ventral, dorsal, and lateral lobes with each lobe consisting of a branched ductal network that opens into the urethra. Each duct consists of a proximal region (adjacent to the urethra), an intermediate region, and a distal region (Fig. 1). We recently demonstrated that the proximal region of murine prostatic ducts contains a population of cells exhibiting features of stem cells, namely slow-cycling cells with high proliferative potential capable of reconstituting branched glandular ductal structures from a single cell (Tsujimura et al., 2002). We propose that the stem cell population in the proximal region of the prostate is kept in a quiescent state in its niche by a balance between TGF-β, which inhibits proliferation of the stem cells, and other mitogenic cytokines that promote proliferation. In this paper, we show that cells in the proximal and distal regions of prostatic ducts respond differentially to TGF-β. In the intact prostate, active TGF-β in the proximal region maintains the stem cells in a quiescent state. During castration-induced involution, TGF-β signaling increases distally. The increased signaling distally results in the apoptosis of cells in this region, leading to involution of the prostate. At the same time, TGF-β signaling decreases proximally, thus “priming” stem cells in this region to respond to mitogenic growth factors. With androgen replacement, the reduced levels of TGF-β signaling in the proximal region, in conjunction with expression of various stimulatory cytokines, facilitates division of the stem cells. Once the prostate has regenerated, TGF-β signaling in the proximal region increases and is again significantly higher than that of the distal region, thereby maintaining quiescence of the stem cells in the proximal region. Our data indicate that Bcl-2 levels are significantly higher in cells in the proximal compared with the remaining regions, thus insuring that these cells are protected from apoptosis after androgen withdrawal and are therefore available to regenerate the gland after subsequent androgen addition.


TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts.

Salm SN, Burger PE, Coetzee S, Goto K, Moscatelli D, Wilson EL - J. Cell Biol. (2005)

Microdissected prostatic ducts. A segment from a microdissected mouse dorsal prostate showing the distal, intermediate, and proximal regions of prostatic ducts. Bar, 1 mm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171389&req=5

fig1: Microdissected prostatic ducts. A segment from a microdissected mouse dorsal prostate showing the distal, intermediate, and proximal regions of prostatic ducts. Bar, 1 mm.
Mentions: The mouse prostate can be divided into ventral, dorsal, and lateral lobes with each lobe consisting of a branched ductal network that opens into the urethra. Each duct consists of a proximal region (adjacent to the urethra), an intermediate region, and a distal region (Fig. 1). We recently demonstrated that the proximal region of murine prostatic ducts contains a population of cells exhibiting features of stem cells, namely slow-cycling cells with high proliferative potential capable of reconstituting branched glandular ductal structures from a single cell (Tsujimura et al., 2002). We propose that the stem cell population in the proximal region of the prostate is kept in a quiescent state in its niche by a balance between TGF-β, which inhibits proliferation of the stem cells, and other mitogenic cytokines that promote proliferation. In this paper, we show that cells in the proximal and distal regions of prostatic ducts respond differentially to TGF-β. In the intact prostate, active TGF-β in the proximal region maintains the stem cells in a quiescent state. During castration-induced involution, TGF-β signaling increases distally. The increased signaling distally results in the apoptosis of cells in this region, leading to involution of the prostate. At the same time, TGF-β signaling decreases proximally, thus “priming” stem cells in this region to respond to mitogenic growth factors. With androgen replacement, the reduced levels of TGF-β signaling in the proximal region, in conjunction with expression of various stimulatory cytokines, facilitates division of the stem cells. Once the prostate has regenerated, TGF-β signaling in the proximal region increases and is again significantly higher than that of the distal region, thereby maintaining quiescence of the stem cells in the proximal region. Our data indicate that Bcl-2 levels are significantly higher in cells in the proximal compared with the remaining regions, thus insuring that these cells are protected from apoptosis after androgen withdrawal and are therefore available to regenerate the gland after subsequent androgen addition.

Bottom Line: This conclusion is supported by the observations showing that high levels of TGF-beta 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.A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
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)-beta than the distal ductal region and that under physiological conditions androgens and TGF-beta are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-beta 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-beta signaling gradient, leading to an increase in TGF-beta signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-beta-mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

Show MeSH
Related in: MedlinePlus