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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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Proximal cells produce and activate more TGF-β than distal cells. (A) Heat-activated conditioned medium from proximal and distal cells (4 × 104 cells/24-well dish) was placed on TGF-β–responsive mink lung cells. The amount of total TGF-β was quantified by comparison with a standard curve. (B) Active TGF-β was measured directly by quantifying luciferase activity using a coculture assay in which either proximal or distal cells (4 × 103 cells/well) were combined with TGF-β–responsive mink lung cells (5 × 103 cells/well) in a 96-well plate. The presence of TGF-β in A and B was verified using TGF-β–neutralizing antibodies.
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fig2: Proximal cells produce and activate more TGF-β than distal cells. (A) Heat-activated conditioned medium from proximal and distal cells (4 × 104 cells/24-well dish) was placed on TGF-β–responsive mink lung cells. The amount of total TGF-β was quantified by comparison with a standard curve. (B) Active TGF-β was measured directly by quantifying luciferase activity using a coculture assay in which either proximal or distal cells (4 × 103 cells/well) were combined with TGF-β–responsive mink lung cells (5 × 103 cells/well) in a 96-well plate. The presence of TGF-β in A and B was verified using TGF-β–neutralizing antibodies.

Mentions: As we propose that stem cells in the proximal region are maintained in a quiescent state by TGF-β, we examined different ductal regions immunohistochemically to determine if regional differences in TGF-β levels were evident. We found that TGF-β is produced by both epithelial and stromal cells in all ductal regions (unpublished data). As TGF-β is secreted as a biologically inactive latent complex that is activated extracellularly (Massague et al., 1991; Abe et al., 1994; Munger et al., 1997) and as commercial antibodies that detect its histological presence do not distinguish between latent and active TGF-β, we isolated cells from proximal and distal regions and determined the levels of total (latent plus active) and active TGF-β produced by the cells of different ductal regions in vitro. Both proximal and distal cells produced latent TGF-β, with proximal cells producing more of the cytokine than distal cells (61.0 ± 3.1 and 52.8 ± 2.9 pg TGF-β/103 cells, respectively; P < 0.01; Fig. 2 A). In addition, a significantly larger fraction of the latent TGF-β was activated by proximal cells (19.7 ± 3.5 pg TGF-β /103 cells; 32.3% of the latent TGF-β) than by distal cells (2.3 ± 1.2 pg TGF-β /103 cells; 4.3% of the latent TGF-β; P < 0.001; Fig. 2 B). Thus, proximal cells both produce and activate significantly more TGF-β than do distal cells, suggesting that the quiescence of stem cells in the proximal prostate is maintained by autocrine synthesis and activation of TGF-β.


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)

Proximal cells produce and activate more TGF-β than distal cells. (A) Heat-activated conditioned medium from proximal and distal cells (4 × 104 cells/24-well dish) was placed on TGF-β–responsive mink lung cells. The amount of total TGF-β was quantified by comparison with a standard curve. (B) Active TGF-β was measured directly by quantifying luciferase activity using a coculture assay in which either proximal or distal cells (4 × 103 cells/well) were combined with TGF-β–responsive mink lung cells (5 × 103 cells/well) in a 96-well plate. The presence of TGF-β in A and B was verified using TGF-β–neutralizing antibodies.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171389&req=5

fig2: Proximal cells produce and activate more TGF-β than distal cells. (A) Heat-activated conditioned medium from proximal and distal cells (4 × 104 cells/24-well dish) was placed on TGF-β–responsive mink lung cells. The amount of total TGF-β was quantified by comparison with a standard curve. (B) Active TGF-β was measured directly by quantifying luciferase activity using a coculture assay in which either proximal or distal cells (4 × 103 cells/well) were combined with TGF-β–responsive mink lung cells (5 × 103 cells/well) in a 96-well plate. The presence of TGF-β in A and B was verified using TGF-β–neutralizing antibodies.
Mentions: As we propose that stem cells in the proximal region are maintained in a quiescent state by TGF-β, we examined different ductal regions immunohistochemically to determine if regional differences in TGF-β levels were evident. We found that TGF-β is produced by both epithelial and stromal cells in all ductal regions (unpublished data). As TGF-β is secreted as a biologically inactive latent complex that is activated extracellularly (Massague et al., 1991; Abe et al., 1994; Munger et al., 1997) and as commercial antibodies that detect its histological presence do not distinguish between latent and active TGF-β, we isolated cells from proximal and distal regions and determined the levels of total (latent plus active) and active TGF-β produced by the cells of different ductal regions in vitro. Both proximal and distal cells produced latent TGF-β, with proximal cells producing more of the cytokine than distal cells (61.0 ± 3.1 and 52.8 ± 2.9 pg TGF-β/103 cells, respectively; P < 0.01; Fig. 2 A). In addition, a significantly larger fraction of the latent TGF-β was activated by proximal cells (19.7 ± 3.5 pg TGF-β /103 cells; 32.3% of the latent TGF-β) than by distal cells (2.3 ± 1.2 pg TGF-β /103 cells; 4.3% of the latent TGF-β; P < 0.001; Fig. 2 B). Thus, proximal cells both produce and activate significantly more TGF-β than do distal cells, suggesting that the quiescence of stem cells in the proximal prostate is maintained by autocrine synthesis and activation of TGF-β.

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