E Lynette Wilson, PhD
Professor of Cell Biology and Urology
PhD 1971 University of Cape Town, South Africa
Prostate Stem Cells
It is likely that the aberrant proliferation of prostate stem cells and/or their progenitors contributes to prostate pathology. Our work focuses on the isolation and characterization of the stem and progenitor cell populations of the adult and the fetal prostate. In particular, we have shown that the proximal region of murine prostatic ducts is enriched in stem cells that express high levels of Sca-1, are quiescent and have high proliferative potential in vitro and in vivo. In addition, single proximal cells give rise to branched ductal structures that contain both basal and luminal cells. Cells from this region have significant regenerative capacity when assayed in an in vivo prostate reconstitution assay in which combinations of prostate cells and embryonic urogenital sinus mesenchyme (inductive mesenchyme for prostatic tissue) are inserted under the renal capsule of recipient animals. Proximal cells also withstand prolonged androgen deprivation, another characteristic of stem cells. Sca-1high prostate regenerating cells also express other antigens characteristic of stem cells such as alpha 6 integrin, aldehyde dehydrogenase and Bcl-2. High levels of TGF-beta in the proximal region maintain the quiescence of the proximal stem cell niche. We find that the stem cell compartment can be transformed by activated Akt resulting in malignant tumors in vivo whereas the transit-amplifying and the mature cell compartments are refractory to transformation by Akt lentiviral constructs. This indicates that adult prostate stem cells are uniquely susceptible to malignant transformation. We have also determined that cells from murine bone marrow can contribute to the epithelial and mesenchymal compartments of the normal adult prostate. The global gene expression profiles of adult and fetal prostate stem cells indicate that adult stem cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors. We have defined a unique murine stem cell gene signature that predicts prognosis of individuals with prostate cancer. Currently limited guidelines exist for post-operative treatment for prostate cancer patients with intermediate 6/7 Gleason scores and patients post-surgery continue to worry about relapses. We are able to stratify this group of patients into those individuals who have a 10 year disease-free prognosis from those patients who relapse based on expression of genes indentified in murine prostate stem cells. Our approach indicates that we are able to distinguish between cancer patients that need to be treated aggressively and those that can be assured of cure. A number of the molecules that predict for good prognosis maintain quiescence in adult prostate stem cells. The knockdown of these molecules during Akt-mediated malignant transformation of adult prostate stem cells results in larger and more invasive prostate tumors. Our current experiments are aimed to determine the roles of these predictive molecules in normal prostate stem cell biology and the manner by which they influence malignant transformation.
Research is supported by the National Institutes of Health, Amgen Inc.
C Ontiveros, S Salm and E L Wilson. 2008. Axin2 expression identifies progenitor cells in the murine prostate. The Prostate, 68; 1263-1272. PMID: 18563716
Roy Blum, Rashmi Gupta, Patricia E. Burger, Christopher S. Ontiveros, Sarah N. Salm, Xiaozhong Xiong, Alexander Kamb, Holger Wesche, Lisa Marshall, Gene Cutler, Sean Wang, Jiri Zavadil, David Moscatelli and E. Lynette Wilson. 2009. Molecular Signatures of Prostate Stem Cells Reveal Novel Signaling Pathways and Provide Insights into Prostate Cancer. PLoS One 4(5); e5722. PMID: 19478945
Patricia E. Burger , Rashmi Gupta , Xiaozhong Xiong , Christopher S. Ontiveros, Sarah N. Salm , David Moscatelli and E. Lynette Wilson. 2009. High ALDH activity: A novel functional marker of murine prostate stem/progenitor cells. Stem Cells 27: 2220-2228. PMID: 19544409
Roy Blum, Rashmi Gupta, Patricia E. Burger, Christopher S. Ontiveros, Sarah N. Salm, Xiaozhong Xiong, Alexander Kamb, Holger Wesche, Lisa Marshall, Gene Cutler, Sean Wang, Jiri Zavadil, David Moscatelli and E. Lynette Wilson. 2010. Molecular signatures of the primitive prostate stem cell niche reveal novel mesenchymal-epithelial signaling pathways. PLoS ONE 5; e13024. PMID: 20941365
David Moscatelli and E Lynette Wilson. 2010. PINing down the origin of prostate cancer. Science Translational Medicine 2: 43ps38. PMID: 20686176
S. N. Salm, P. E. Burger and E. L. Wilson. 2012. TGF-ß and stem cell factor regulate cell proliferation in the proximal stem cell niche. The Prostate 72; 998-1005. PMID: 22024978
David Moscatelli, and E Lynette Wilson. 2013. The Prostate Stem Cell Niche in Stem Cells and Prostate Cancer, Ed: Scott D Cramer, pp 91-109, Springer New York.