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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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The inhibitory effect of TGF-β on cell growth is opposed by EGF, FGF-2, and SCF. Cells from the proximal or distal region were seeded (5 × 103 cells/well) on collagen and overlaid with medium containing TGF-β (0.5, 1, or 10 ng/ml; A) and either TGF-β alone (0.5 ng/ml) or TGF-β together with either EGF (10 ng/ml), FGF-2 (10 ng/ml), SCF (100 ng/ml), or IGF-1 (10 ng/ml) (B). Control wells received EGF, FGF-2, SCF, IGF-1, or none of these factors in the absence of TGF-β. Wells were cultured for 10 d, after which cells were enumerated. The y axis in A is normalized to cells that were not treated with TGF-β. The histograms of the proximal and distal cells in B cannot be directly compared with each other because of their differential responses to TGF-β. The comparisons should be made between the control (No GF) and experimental samples within each of the two histograms.
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fig5: The inhibitory effect of TGF-β on cell growth is opposed by EGF, FGF-2, and SCF. Cells from the proximal or distal region were seeded (5 × 103 cells/well) on collagen and overlaid with medium containing TGF-β (0.5, 1, or 10 ng/ml; A) and either TGF-β alone (0.5 ng/ml) or TGF-β together with either EGF (10 ng/ml), FGF-2 (10 ng/ml), SCF (100 ng/ml), or IGF-1 (10 ng/ml) (B). Control wells received EGF, FGF-2, SCF, IGF-1, or none of these factors in the absence of TGF-β. Wells were cultured for 10 d, after which cells were enumerated. The y axis in A is normalized to cells that were not treated with TGF-β. The histograms of the proximal and distal cells in B cannot be directly compared with each other because of their differential responses to TGF-β. The comparisons should be made between the control (No GF) and experimental samples within each of the two histograms.

Mentions: TGF-β inhibited the proliferation of both proximal and distal cells. Low levels of TGF-β (0.5 ng/ml) inhibited the growth of proximal prostate cells by 24.4% and distal cells by 34.5% (P < 0.01). At a concentration of 1.0 ng/ml, TGF-β inhibited proximal and distal growth by 57.5 and 85.6% (P < 0.001), whereas 10.0 ng/ml TGF-β inhibited proximal and distal growth by 85.6 and 99.3% (P < 0.001), respectively (Fig. 5 A). Thus, distal cells were more sensitive to TGF-β inhibition than were proximal cells (P < 0.01 at all concentrations of TGF-β). We determined whether the inhibitory effect of TGF-β on proximal prostate cells could be negated by SCF, EGF, FGF-2, FGF-7, or IGF-1, all of which induce proliferation in several stem cell types (Isfort et al., 1997; Mitsunari et al., 1999; Santa-Olalla and Covarrubias, 1999; Deasy et al., 2002). TGF-β–mediated inhibition of proximal cells was abrogated by the simultaneous addition of EGF, FGF-2, or SCF. Growth of proximal cells in wells receiving EGF (10 ng/ml), FGF-2 (10 ng/ml), or SCF (100 ng/ml) along with TGF-β (0.5 ng/ml) was not significantly different from growth in wells that received the same mitogens but no TGF-β (P < 0.1; Fig. 5 B). In contrast, EGF, FGF-2, or SCF only partially reversed the inhibition of growth caused by administration of TGF-β to distal cells (P < 0.01; Fig. 5 B). FGF-7 and IGF-1 did not counteract the inhibitory effect of TGF-β on either proximal or distal cells.


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)

The inhibitory effect of TGF-β on cell growth is opposed by EGF, FGF-2, and SCF. Cells from the proximal or distal region were seeded (5 × 103 cells/well) on collagen and overlaid with medium containing TGF-β (0.5, 1, or 10 ng/ml; A) and either TGF-β alone (0.5 ng/ml) or TGF-β together with either EGF (10 ng/ml), FGF-2 (10 ng/ml), SCF (100 ng/ml), or IGF-1 (10 ng/ml) (B). Control wells received EGF, FGF-2, SCF, IGF-1, or none of these factors in the absence of TGF-β. Wells were cultured for 10 d, after which cells were enumerated. The y axis in A is normalized to cells that were not treated with TGF-β. The histograms of the proximal and distal cells in B cannot be directly compared with each other because of their differential responses to TGF-β. The comparisons should be made between the control (No GF) and experimental samples within each of the two histograms.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171389&req=5

fig5: The inhibitory effect of TGF-β on cell growth is opposed by EGF, FGF-2, and SCF. Cells from the proximal or distal region were seeded (5 × 103 cells/well) on collagen and overlaid with medium containing TGF-β (0.5, 1, or 10 ng/ml; A) and either TGF-β alone (0.5 ng/ml) or TGF-β together with either EGF (10 ng/ml), FGF-2 (10 ng/ml), SCF (100 ng/ml), or IGF-1 (10 ng/ml) (B). Control wells received EGF, FGF-2, SCF, IGF-1, or none of these factors in the absence of TGF-β. Wells were cultured for 10 d, after which cells were enumerated. The y axis in A is normalized to cells that were not treated with TGF-β. The histograms of the proximal and distal cells in B cannot be directly compared with each other because of their differential responses to TGF-β. The comparisons should be made between the control (No GF) and experimental samples within each of the two histograms.
Mentions: TGF-β inhibited the proliferation of both proximal and distal cells. Low levels of TGF-β (0.5 ng/ml) inhibited the growth of proximal prostate cells by 24.4% and distal cells by 34.5% (P < 0.01). At a concentration of 1.0 ng/ml, TGF-β inhibited proximal and distal growth by 57.5 and 85.6% (P < 0.001), whereas 10.0 ng/ml TGF-β inhibited proximal and distal growth by 85.6 and 99.3% (P < 0.001), respectively (Fig. 5 A). Thus, distal cells were more sensitive to TGF-β inhibition than were proximal cells (P < 0.01 at all concentrations of TGF-β). We determined whether the inhibitory effect of TGF-β on proximal prostate cells could be negated by SCF, EGF, FGF-2, FGF-7, or IGF-1, all of which induce proliferation in several stem cell types (Isfort et al., 1997; Mitsunari et al., 1999; Santa-Olalla and Covarrubias, 1999; Deasy et al., 2002). TGF-β–mediated inhibition of proximal cells was abrogated by the simultaneous addition of EGF, FGF-2, or SCF. Growth of proximal cells in wells receiving EGF (10 ng/ml), FGF-2 (10 ng/ml), or SCF (100 ng/ml) along with TGF-β (0.5 ng/ml) was not significantly different from growth in wells that received the same mitogens but no TGF-β (P < 0.1; Fig. 5 B). In contrast, EGF, FGF-2, or SCF only partially reversed the inhibition of growth caused by administration of TGF-β to distal cells (P < 0.01; Fig. 5 B). FGF-7 and IGF-1 did not counteract the inhibitory effect of TGF-β on either proximal or distal cells.

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