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• W2005505909 abstract "The polycomb group transcriptional repressor Bmi-1 regulates both normal and cancer stem cells in multiple tissues. In this issue of Cell Stem Cell, Lukacs et al., 2010Lukacs R.U. Memarzadeh S. Wu H. Witte O.N. Cell Stem Cell. 2010; 7 (this issue): 682-693Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar report that Bmi-1 also regulates the self-renewal of at least one prostate stem cell population and is involved in prostate cancer initiation and progression. The polycomb group transcriptional repressor Bmi-1 regulates both normal and cancer stem cells in multiple tissues. In this issue of Cell Stem Cell, Lukacs et al., 2010Lukacs R.U. Memarzadeh S. Wu H. Witte O.N. Cell Stem Cell. 2010; 7 (this issue): 682-693Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar report that Bmi-1 also regulates the self-renewal of at least one prostate stem cell population and is involved in prostate cancer initiation and progression. Most adult tissues harbor self-renewing stem cells that are generally quiescent (Fuchs, 2009Fuchs E. Cell. 2009; 137: 811-819Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar). The prostate is a glandular organ whose development is driven by androgen. The ability of adult rodent prostate to repeatedly involute and regenerate as androgen is experimentally withdrawn and replaced suggests the presence of stem cells that weather androgen deprivation and repopulate the gland upon androgen restoration. Mouse prostate has four distinct lobes, i.e., anterior, ventral, dorsal, and lateral. Within each lobe are prostatic ducts that originate in the region proximal to the urethra and branch out into tree-like structures, terminating into distal tip regions physiologically distinct from the proximal and intermediate regions (Figure 1A ). Human prostate differs in that it does not contain anatomically distinct lobes. Mouse prostatic glands contain a single layer of luminal secretory epithelial cells surrounded by a layer of basal epithelial cells (Figure 1B). In vitro clonal assays and in vivo tissue regeneration using purified cell populations, in situ labeling, and lineage tracing studies have revealed at least four populations of prostate stem cells in basal and/or luminal compartments (Figure 1B). Early studies using a BrdU (bromodeoxyuridine) label-retaining approach to identify quiescent prostate stem cells revealed that the long-term label-retaining cells, or LRCs, are concentrated in the prostate tubules proximal to the urethra and distributed nearly equally in basal as well as luminal layers within the proximal region (Tsujimura et al., 2002Tsujimura A. Koikawa Y. Salm S. Takao T. Coetzee S. Moscatelli D. Shapiro E. Lepor H. Sun T.T. Wilson E.L. J. Cell Biol. 2002; 157: 1257-1265Crossref PubMed Scopus (257) Google Scholar), providing the first piece of in vivo evidence that prostate epithelial stem cells may exist in both basal and luminal cell compartments. The slow-cycling stem cells in proximal tubules (Figure 1A) were subsequently found to be enriched in the Sca-1+ cell population that also expresses high levels of integrin α6 (CD49f) (Burger et al., 2005Burger P.E. Xiong X. Coetzee S. Salm S.N. Moscatelli D. Goto K. Wilson E.L. Proc. Natl. Acad. Sci. USA. 2005; 102: 7180-7185Crossref PubMed Scopus (221) Google Scholar, Xin et al., 2005Xin L. Lawson D.A. Witte O.N. Proc. Natl. Acad. Sci. USA. 2005; 102: 6942-6947Crossref PubMed Scopus (367) Google Scholar). Further purifications using combinatorial markers have identified two stem cell populations mostly localized in the basal layer, i.e., Sca-1+CD49fhi(Trop2hi) (Goldstein et al., 2008Goldstein A.S. Lawson D.A. Cheng D. Sun W. Garraway I.P. Witte O.N. Proc. Natl. Acad. Sci. USA. 2008; 105: 20882-20887Crossref PubMed Scopus (243) Google Scholar) and Sca-1+CD133+CD44+CD117+ (Leong et al., 2008Leong K.G. Wang B.E. Johnson L. Gao W.Q. Nature. 2008; 456: 804-808Crossref PubMed Scopus (337) Google Scholar) (Figure 1B). Yet another population of stem cells, termed CARNs (for castration-resistant Nkx3.1-expressing cells), seems to localize exclusively in the luminal cell layer and manifests its stem cell properties only upon androgen deprivation (Wang et al., 2009Wang X. Kruithof-de Julio M. Economides K.D. Walker D. Yu H. Halili M.V. Hu Y.P. Price S.M. Abate-Shen C. Shen M.M. Nature. 2009; 461: 495-500Crossref PubMed Scopus (514) Google Scholar) (Figure 1B). The interrelationship between the Sca-1+CD49fhi(Trop2hi) and Sca-1+CD133+CD44+CD117+ basal stem cells is unclear, and the phenotype of the luminal CARNs remains to be defined. Most important, how the stem cell properties such as self-renewal of these various populations are regulated has not been characterized. In this issue of Cell Stem Cell, Lukacs and colleagues fill this critical gap in our knowledge and report that cells expressing the polycomb group protein Bmi-1 are enriched in the proximal region of the prostate, as well as in purified Sca-1+CD49fhi stem cells. Bmi-1 has been implicated in regulating hematopoietic, neural, and other stem cells, but its functional roles in prostate stem cell maintenance and prostate cancer are unknown. Using both shRNA knockdown and overexpression approaches, the authors demonstrate a significant functional contribution of Bmi-1 to self-renewal and maintenance of prostate stem cells, assessed by in vitro serial sphere assays and in vivo tissue regeneration using epithelial cells recombined with urogenital sinus mesenchyme. Consistent with the well-known role of Bmi-1 in regulating the Cdkn2a locus, the authors provide evidence that these effects on self-renewal are mediated at least in part through p16 and p19. Bmi-1 was also shown to be required for full manifestation of increased self-renewal initiated by constitutively active β-catenin, suggesting that Bmi-1 may be a mediator of Wnt/Frizzled signaling in normal prostate stem cells. The authors further show that Bmi-1 is required for normal prostate tubule formation in in vivo graft assays in SCID mice with Bmi-1-deficient tubules displaying signs of increased differentiation. Combined with the results of the serial sphere assays, these data provide convincing evidence that Bmi-1 plays a critical role in the self-renewal of at least some normal prostate stem cells. Thus, Bmi-1 joins p63 (Senoo et al., 2007Senoo M. Pinto F. Crum C.P. McKeon F. Cell. 2007; 129: 523-536Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar, Signoretti et al., 2005Signoretti S. Pires M.M. Lindauer M. Horner J.W. Grisanzio C. Dhar S. Majumder P. McKeon F. Kantoff P.W. Sellers W.R. Loda M. Proc. Natl. Acad. Sci. USA. 2005; 102: 11355-11360Crossref PubMed Scopus (126) Google Scholar) and Nkx3.1 (Wang et al., 2009Wang X. Kruithof-de Julio M. Economides K.D. Walker D. Yu H. Halili M.V. Hu Y.P. Price S.M. Abate-Shen C. Shen M.M. Nature. 2009; 461: 495-500Crossref PubMed Scopus (514) Google Scholar) on the short list of nuclear factors that have been shown to regulate prostate stem cells. An important question raised by the study of Lukacs et al. is whether Bmi-1 regulates the self-renewal properties of each of the reported prostate stem cell populations discussed above (Figure 1B). The slow-cycling LRCs are distributed equally in both basal and luminal layers of proximal prostate tubules (Tsujimura et al., 2002Tsujimura A. Koikawa Y. Salm S. Takao T. Coetzee S. Moscatelli D. Shapiro E. Lepor H. Sun T.T. Wilson E.L. J. Cell Biol. 2002; 157: 1257-1265Crossref PubMed Scopus (257) Google Scholar); in contrast, the Sca-1+CD49fhi(Trop2hi) (Goldstein et al., 2008Goldstein A.S. Lawson D.A. Cheng D. Sun W. Garraway I.P. Witte O.N. Proc. Natl. Acad. Sci. USA. 2008; 105: 20882-20887Crossref PubMed Scopus (243) Google Scholar) and Scal-1+CD133+CD44+CD117+ (Leong et al., 2008Leong K.G. Wang B.E. Johnson L. Gao W.Q. Nature. 2008; 456: 804-808Crossref PubMed Scopus (337) Google Scholar) cells localize preferentially to the basal layer, whereas CARNs seem to exist exclusively in the luminal layer (Wang et al., 2009Wang X. Kruithof-de Julio M. Economides K.D. Walker D. Yu H. Halili M.V. Hu Y.P. Price S.M. Abate-Shen C. Shen M.M. Nature. 2009; 461: 495-500Crossref PubMed Scopus (514) Google Scholar). It is tempting to speculate that the LRCs represent a large stem cell pool that encompasses all stem cell subsets found in both basal and luminal cell compartments. The Bmi-1+ cells resemble the LRCs and are also concentrated in the proximal region (Figure 1A), but the majority of Bmi-1+ cells appear to coexpress the basal cell marker cytokeratin 5 (Lukacs et al., 2010Lukacs R.U. Memarzadeh S. Wu H. Witte O.N. Cell Stem Cell. 2010; 7 (this issue): 682-693Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar), suggesting that Bmi-1 may preferentially regulate the basally localized prostate stem cells. Future endeavors that seek to uncover the detailed molecular mechanisms whereby Bmi-1 modulates prostate stem cell self-renewal will likely offer significant insight. Even more pressing, efforts are needed to elucidate the interrelationships between the seemingly disparate stem cell subpopulations. These and other questions might be addressed by generating new research tools, such as prostate-specific Bmi-1 knockout or knockin reporters and genetic models that allow the purification of live LRCs. Similar to its involvement in normal stem cells, Bmi-1 has also been implicated in regulating cancer stem cells in leukemia and several solid tumors. Furthermore, Bmi-1 is often upregulated in prostate cancer. The authors' demonstration of Bmi-1 function in normal prostate stem cell self-renewal suggests that Bmi-1 might also have a crucial role in the self-renewal of transformed prostate cells with stem cell-like properties. To investigate this possibility, the authors examined the effect of Bmi-1 depletion in an FGF10-driven hyperplasia system. Their results indicate that Bmi-1 is required for the development of hyperplasia, which might be interpreted as a form of PIN (prostate intraepithelial neoplasia). They also tested the effect of Bmi-1 knockdown on Pten null tumor grafts and found that Bmi-1 loss significantly reduced proliferation and increased tumor cell apoptosis. While the effect of Bmi-1 loss on specific prostate tumor cell subpopulations was not examined, these results point to a causal role for Bmi-1 in prostate cancer initiation and progression. The role Bmi-1 plays in specific prostate tumor-initiating subpopulations will be an important question to address in the future, and the answer may provide clues to the relationship between normal prostate stem cells and tumor-initiating cells as well as relapse and the emergence of castration-resistant disease. Much focus has been placed on determining which prostate stem cell population(s) may serve as the cell of origin for prostate cancer, but to date it is unknown which, if any, of these populations or their transformed progeny contribute to clinically relevant phenomena, such as therapeutic resistance, recurrence, and metastasis. Identifying the cell of origin for castration-resistant prostate cancer is an important complement to isolating the cell of origin for tumor development and will be crucial to developing therapeutics that can treat androgen-independent tumors. Bmi-1 Is a Crucial Regulator of Prostate Stem Cell Self-Renewal and Malignant TransformationLukacs et al.Cell Stem CellDecember 03, 2010In BriefThe Polycomb group transcriptional repressor Bmi-1 is often upregulated in prostate cancer, but its functional roles in prostate stem cell maintenance and prostate cancer are unclear. Loss- and gain-of-function analysis in a prostate sphere assay indicates that Bmi-1 expression is required for self-renewal activity and maintenance of p63+ stem cells. Loss of Bmi-1 blocks the self-renewal activity induced by heightened β-catenin signaling, suggesting that Bmi-1 is required for full activity of another self-renewal pathway. Full-Text PDF Open Archive" @default.
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• W2005505909 title "An Old Player on a New Playground: Bmi-1 as a Regulator of Prostate Stem Cells" @default.
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