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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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Bcl-2 is highly expressed by cells from the proximal region of prostatic ducts. (A) More cells in the proximal region of prostatic ducts express Bcl-2 than those from the remaining regions of ducts (P < 0.00001). (B) Cells in the proximal region express higher levels of Bcl-2 per cell, as is indicated by a higher mean fluorescence intensity (MFI) (P < 0.00001). (C) A representative histogram of Bcl-2 expression by cells from the proximal region (thick solid line; MFI = 599) and the remaining ductal regions (gray filled area; MFI = 157). The marker M1 is set such that <1% of control cells are included within this marker. The marker M2 delineates Bcl-2high cells with MFI > 800. (D) Cells expressing high levels of Bcl-2 (MFI > 800) are 7.1-fold enriched in the proximal region of ducts compared with those in the remaining ductal regions (P < 0.00001).
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fig7: Bcl-2 is highly expressed by cells from the proximal region of prostatic ducts. (A) More cells in the proximal region of prostatic ducts express Bcl-2 than those from the remaining regions of ducts (P < 0.00001). (B) Cells in the proximal region express higher levels of Bcl-2 per cell, as is indicated by a higher mean fluorescence intensity (MFI) (P < 0.00001). (C) A representative histogram of Bcl-2 expression by cells from the proximal region (thick solid line; MFI = 599) and the remaining ductal regions (gray filled area; MFI = 157). The marker M1 is set such that <1% of control cells are included within this marker. The marker M2 delineates Bcl-2high cells with MFI > 800. (D) Cells expressing high levels of Bcl-2 (MFI > 800) are 7.1-fold enriched in the proximal region of ducts compared with those in the remaining ductal regions (P < 0.00001).

Mentions: More Bcl-2–expressing cells were found in the proximal region (42.1 ± 6.9%) than in the remaining regions of the prostate (27.5 ± 8.2%; P < 0.0001; Fig. 7 A). Proximal cells also expressed 2.2-fold more Bcl-2 per cell than cells from the remaining regions (P < 0.0001) as evidenced by an increase in the mean fluorescence intensity (MFI) of these cells (Fig. 7 B). A representative histogram (Fig. 7 C) shows the increase in both intensity of Bcl-2 expression (MFI) and the numbers of cells expressing this antigen in the proximal region (MFI = 599; Bcl-2–expressing cells =36%) compared with the cells in the remaining regions (MFI = 157, Bcl-2–expressing cells = 18%). Furthermore, examination of cells expressing high levels of Bcl-2 (cells with a MFI >800) indicates that the cells from the proximal region contain 7.1-fold more Bcl-2high cells than those in the remaining regions (7.2 ± 2.7 and 1.0 ± 1.0%, respectively; P < 0.00001; Fig. 7 D). Thus, cells with the highest Bcl-2 levels are almost exclusively located in the proximal region. The high levels of Bcl-2 in this region may protect proximal cells from the apoptotic events initiated during involution of the gland after androgen deprivation.


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)

Bcl-2 is highly expressed by cells from the proximal region of prostatic ducts. (A) More cells in the proximal region of prostatic ducts express Bcl-2 than those from the remaining regions of ducts (P < 0.00001). (B) Cells in the proximal region express higher levels of Bcl-2 per cell, as is indicated by a higher mean fluorescence intensity (MFI) (P < 0.00001). (C) A representative histogram of Bcl-2 expression by cells from the proximal region (thick solid line; MFI = 599) and the remaining ductal regions (gray filled area; MFI = 157). The marker M1 is set such that <1% of control cells are included within this marker. The marker M2 delineates Bcl-2high cells with MFI > 800. (D) Cells expressing high levels of Bcl-2 (MFI > 800) are 7.1-fold enriched in the proximal region of ducts compared with those in the remaining ductal regions (P < 0.00001).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171389&req=5

fig7: Bcl-2 is highly expressed by cells from the proximal region of prostatic ducts. (A) More cells in the proximal region of prostatic ducts express Bcl-2 than those from the remaining regions of ducts (P < 0.00001). (B) Cells in the proximal region express higher levels of Bcl-2 per cell, as is indicated by a higher mean fluorescence intensity (MFI) (P < 0.00001). (C) A representative histogram of Bcl-2 expression by cells from the proximal region (thick solid line; MFI = 599) and the remaining ductal regions (gray filled area; MFI = 157). The marker M1 is set such that <1% of control cells are included within this marker. The marker M2 delineates Bcl-2high cells with MFI > 800. (D) Cells expressing high levels of Bcl-2 (MFI > 800) are 7.1-fold enriched in the proximal region of ducts compared with those in the remaining ductal regions (P < 0.00001).
Mentions: More Bcl-2–expressing cells were found in the proximal region (42.1 ± 6.9%) than in the remaining regions of the prostate (27.5 ± 8.2%; P < 0.0001; Fig. 7 A). Proximal cells also expressed 2.2-fold more Bcl-2 per cell than cells from the remaining regions (P < 0.0001) as evidenced by an increase in the mean fluorescence intensity (MFI) of these cells (Fig. 7 B). A representative histogram (Fig. 7 C) shows the increase in both intensity of Bcl-2 expression (MFI) and the numbers of cells expressing this antigen in the proximal region (MFI = 599; Bcl-2–expressing cells =36%) compared with the cells in the remaining regions (MFI = 157, Bcl-2–expressing cells = 18%). Furthermore, examination of cells expressing high levels of Bcl-2 (cells with a MFI >800) indicates that the cells from the proximal region contain 7.1-fold more Bcl-2high cells than those in the remaining regions (7.2 ± 2.7 and 1.0 ± 1.0%, respectively; P < 0.00001; Fig. 7 D). Thus, cells with the highest Bcl-2 levels are almost exclusively located in the proximal region. The high levels of Bcl-2 in this region may protect proximal cells from the apoptotic events initiated during involution of the gland after androgen deprivation.

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