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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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A model for the regional regulation of prostatic homeostasis. A schematic diagram showing that in an androgen-replete prostate high levels of active TGF-β and TGF-β–mediated signaling in the proximal stem cell niche maintain the quiescence of stem cells in this region. In the distal region, low levels of active TGF-β and TGF-β–mediated signaling permit the division of transit-amplifying (TA) cells in this region. After castration, the decrease in androgen levels with concurrent increased levels of TGF-β and TGF-β–mediated signaling distally, lead to apoptosis of cells in this region, with the resulting involution of the prostate gland. Simultaneously, the decrease in TGF-β–mediated signaling in the proximal region sensitizes the cells in this region to mitogenic signals. When androgens are readministered these cells respond to androgen-induced mitogenic cytokines (GFs), thus contributing to prostatic regeneration. Simultaneously, as the distal TGF-β signaling activity declines, the transit-amplifying cells in this region also divide, resulting in regeneration of the gland.
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fig8: A model for the regional regulation of prostatic homeostasis. A schematic diagram showing that in an androgen-replete prostate high levels of active TGF-β and TGF-β–mediated signaling in the proximal stem cell niche maintain the quiescence of stem cells in this region. In the distal region, low levels of active TGF-β and TGF-β–mediated signaling permit the division of transit-amplifying (TA) cells in this region. After castration, the decrease in androgen levels with concurrent increased levels of TGF-β and TGF-β–mediated signaling distally, lead to apoptosis of cells in this region, with the resulting involution of the prostate gland. Simultaneously, the decrease in TGF-β–mediated signaling in the proximal region sensitizes the cells in this region to mitogenic signals. When androgens are readministered these cells respond to androgen-induced mitogenic cytokines (GFs), thus contributing to prostatic regeneration. Simultaneously, as the distal TGF-β signaling activity declines, the transit-amplifying cells in this region also divide, resulting in regeneration of the gland.

Mentions: These data are the first to show that TGF-β signaling in vivo is regulated by androgens in a differential manner along the proximal-distal prostatic ductal axis and that the inhibitory effects of TGF-β on proximal cells can be negated by several cytokines. We propose a model (Fig. 8) in which the stem cells, concentrated in the proximal niche, are maintained in a dormant state in the androgen-replete prostate by high levels of active TGF-β that are produced by the cells in this region. Lower levels of active TGF-β distally allow proliferation and differentiation of distal cells, thus accounting for the preferential location of dividing cells in this region (Sugimura et al., 1986a,b; Cunha and Donjacour, 1987; Tsujimura et al., 2002). Stem cells in the proximal region are protected from apoptosis by high Bcl-2 expression. After castration, the decrease in androgen levels with concurrent increased levels of TGF-β (Kyprianou and Isaacs, 1989) and TGF-β signaling distally lead to apoptosis of cells in this region, with the resulting involution of the prostate gland. Simultaneously, the decrease in TGF-β signaling (less pSMAD expression) in the proximal region may sensitize these cells to mitogenic signals. When androgens are readministered these sensitized cells respond to androgen-induced mitogenic cytokines, thus contributing to prostatic regeneration. As the distal TGF-β signaling activity declines in response to androgens, the transit-amplifying cells in this region, which are still capable of proliferation, also divide, resulting in regeneration of the gland.


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)

A model for the regional regulation of prostatic homeostasis. A schematic diagram showing that in an androgen-replete prostate high levels of active TGF-β and TGF-β–mediated signaling in the proximal stem cell niche maintain the quiescence of stem cells in this region. In the distal region, low levels of active TGF-β and TGF-β–mediated signaling permit the division of transit-amplifying (TA) cells in this region. After castration, the decrease in androgen levels with concurrent increased levels of TGF-β and TGF-β–mediated signaling distally, lead to apoptosis of cells in this region, with the resulting involution of the prostate gland. Simultaneously, the decrease in TGF-β–mediated signaling in the proximal region sensitizes the cells in this region to mitogenic signals. When androgens are readministered these cells respond to androgen-induced mitogenic cytokines (GFs), thus contributing to prostatic regeneration. Simultaneously, as the distal TGF-β signaling activity declines, the transit-amplifying cells in this region also divide, resulting in regeneration of the gland.
© Copyright Policy
Related In: Results  -  Collection

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

fig8: A model for the regional regulation of prostatic homeostasis. A schematic diagram showing that in an androgen-replete prostate high levels of active TGF-β and TGF-β–mediated signaling in the proximal stem cell niche maintain the quiescence of stem cells in this region. In the distal region, low levels of active TGF-β and TGF-β–mediated signaling permit the division of transit-amplifying (TA) cells in this region. After castration, the decrease in androgen levels with concurrent increased levels of TGF-β and TGF-β–mediated signaling distally, lead to apoptosis of cells in this region, with the resulting involution of the prostate gland. Simultaneously, the decrease in TGF-β–mediated signaling in the proximal region sensitizes the cells in this region to mitogenic signals. When androgens are readministered these cells respond to androgen-induced mitogenic cytokines (GFs), thus contributing to prostatic regeneration. Simultaneously, as the distal TGF-β signaling activity declines, the transit-amplifying cells in this region also divide, resulting in regeneration of the gland.
Mentions: These data are the first to show that TGF-β signaling in vivo is regulated by androgens in a differential manner along the proximal-distal prostatic ductal axis and that the inhibitory effects of TGF-β on proximal cells can be negated by several cytokines. We propose a model (Fig. 8) in which the stem cells, concentrated in the proximal niche, are maintained in a dormant state in the androgen-replete prostate by high levels of active TGF-β that are produced by the cells in this region. Lower levels of active TGF-β distally allow proliferation and differentiation of distal cells, thus accounting for the preferential location of dividing cells in this region (Sugimura et al., 1986a,b; Cunha and Donjacour, 1987; Tsujimura et al., 2002). Stem cells in the proximal region are protected from apoptosis by high Bcl-2 expression. After castration, the decrease in androgen levels with concurrent increased levels of TGF-β (Kyprianou and Isaacs, 1989) and TGF-β signaling distally lead to apoptosis of cells in this region, with the resulting involution of the prostate gland. Simultaneously, the decrease in TGF-β signaling (less pSMAD expression) in the proximal region may sensitize these cells to mitogenic signals. When androgens are readministered these sensitized cells respond to androgen-induced mitogenic cytokines, thus contributing to prostatic regeneration. As the distal TGF-β signaling activity declines in response to androgens, the transit-amplifying cells in this region, which are still capable of proliferation, also divide, resulting in regeneration of the gland.

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