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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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pSMAD 2 and 3 expression are differentially regulated by androgens in proximal and distal cells. (A–F) Paraffin sections of the proximal (A, C, and E) and distal (B, D, and F) regions of ducts examined immunohistochemically for pSMAD2/3-expressing cells in tissues removed from androgen-replete animals (A and B), and after androgen deprivation for 1 d (D1, no androgen; C and D) and 8 d (D8, no androgen; E and F). Bars, 100 μm. (G) Quantification of the number of nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. (H) Quantification of the number of basal and luminal nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. White bars, basal cells; black bars, luminal cells.
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fig3: pSMAD 2 and 3 expression are differentially regulated by androgens in proximal and distal cells. (A–F) Paraffin sections of the proximal (A, C, and E) and distal (B, D, and F) regions of ducts examined immunohistochemically for pSMAD2/3-expressing cells in tissues removed from androgen-replete animals (A and B), and after androgen deprivation for 1 d (D1, no androgen; C and D) and 8 d (D8, no androgen; E and F). Bars, 100 μm. (G) Quantification of the number of nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. (H) Quantification of the number of basal and luminal nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. White bars, basal cells; black bars, luminal cells.

Mentions: Immunohistochemistry was used to detect the presence of pSMAD2/3 in prostate tissue sections. In the intact androgen-replete prostate (Fig. 3, T0), pSMAD2/3 was present mainly in the proximal region of the prostatic ducts, with little expression in the distal region (62.3 ± 6.8% positive nuclei in the proximal region compared with 15.5 ± 1.6% in the distal region; P < 0.001; Fig. 3, A, B, and G). However, 1 d after castration, pSMAD2/3 expression increased markedly in the distal region of the ducts (from 15.5 ± 1.6 to 38.9 ± 4.5% positive nuclei; P < 0.01), but remained similar in the proximal region (from 62.3 ± 6.8 to 61.3 ± 5.3% positive nuclei; Fig. 3, C, D, and G). By 8 d after castration, pSMAD2/3 was lower proximally than distally (43.9 ± 1.9 vs. 65.4 ± 7.1% positive nuclei, respectively; P < 0.01; Fig. 3, E–G). The number of pSMAD-expressing cells did not change significantly between 8 and 14 d after castration (unpublished data). When androgens were replaced by means of a slow-release subcutaneous androgen pellet (Tsujimura et al., 2002), the levels of pSMAD2/3 returned to the levels detected in the intact prostate within 8 d (65.3 ± 2.8% positive nuclei proximally and 17.1 ± 5.5% distally; P < 0.001; Fig. 3 G). A similar pattern of results was obtained when the expression of pSMAD was verified by Western blotting using extracts of prostates and antibodies to this protein (unpublished data).


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)

pSMAD 2 and 3 expression are differentially regulated by androgens in proximal and distal cells. (A–F) Paraffin sections of the proximal (A, C, and E) and distal (B, D, and F) regions of ducts examined immunohistochemically for pSMAD2/3-expressing cells in tissues removed from androgen-replete animals (A and B), and after androgen deprivation for 1 d (D1, no androgen; C and D) and 8 d (D8, no androgen; E and F). Bars, 100 μm. (G) Quantification of the number of nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. (H) Quantification of the number of basal and luminal nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. White bars, basal cells; black bars, luminal cells.
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fig3: pSMAD 2 and 3 expression are differentially regulated by androgens in proximal and distal cells. (A–F) Paraffin sections of the proximal (A, C, and E) and distal (B, D, and F) regions of ducts examined immunohistochemically for pSMAD2/3-expressing cells in tissues removed from androgen-replete animals (A and B), and after androgen deprivation for 1 d (D1, no androgen; C and D) and 8 d (D8, no androgen; E and F). Bars, 100 μm. (G) Quantification of the number of nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. (H) Quantification of the number of basal and luminal nuclei positive for pSMAD2/3 expression in proximal and distal cells in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates. White bars, basal cells; black bars, luminal cells.
Mentions: Immunohistochemistry was used to detect the presence of pSMAD2/3 in prostate tissue sections. In the intact androgen-replete prostate (Fig. 3, T0), pSMAD2/3 was present mainly in the proximal region of the prostatic ducts, with little expression in the distal region (62.3 ± 6.8% positive nuclei in the proximal region compared with 15.5 ± 1.6% in the distal region; P < 0.001; Fig. 3, A, B, and G). However, 1 d after castration, pSMAD2/3 expression increased markedly in the distal region of the ducts (from 15.5 ± 1.6 to 38.9 ± 4.5% positive nuclei; P < 0.01), but remained similar in the proximal region (from 62.3 ± 6.8 to 61.3 ± 5.3% positive nuclei; Fig. 3, C, D, and G). By 8 d after castration, pSMAD2/3 was lower proximally than distally (43.9 ± 1.9 vs. 65.4 ± 7.1% positive nuclei, respectively; P < 0.01; Fig. 3, E–G). The number of pSMAD-expressing cells did not change significantly between 8 and 14 d after castration (unpublished data). When androgens were replaced by means of a slow-release subcutaneous androgen pellet (Tsujimura et al., 2002), the levels of pSMAD2/3 returned to the levels detected in the intact prostate within 8 d (65.3 ± 2.8% positive nuclei proximally and 17.1 ± 5.5% distally; P < 0.001; Fig. 3 G). A similar pattern of results was obtained when the expression of pSMAD was verified by Western blotting using extracts of prostates and antibodies to this protein (unpublished data).

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