Abstract
BackgroundThe global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer.Methodology/Principal FindingsA distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-β has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg.Conclusions/SignificanceOur data indicate that adult prostate stem or progenitor 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.
Highlights
It is likely that the aberrant proliferation of prostate stem cells (PSC) and/or their progenitors contributes to prostate pathology
The most distinctive gene expression pattern was derived from the urogenital sinus epithelium (UGE) cell population, manifested by 1050 transcripts that were exclusively overexpressed in the UGEonly cluster (FPSC cluster)
Very few transcripts (5) were distinctively overexpressed in the more differentiated population (Sca-1Lo-only cluster). These results depict prominent stage-specific gene transcripts expressed during the maturation of prostate cells, starting from the most primitive fetal population (UGE), and progressing through the APSC population (Sca-1Hi), and its progeny, the transitamplifying cells (Sca-1Lo), and culminating with the most differentiated subset (Sca-1Neg)
Summary
It is likely that the aberrant proliferation of prostate stem cells (PSC) and/or their progenitors contributes to prostate pathology. We determined the gene expression signatures of fetal and adult PSC (FPSC and APSC) to gain insights into the signaling pathways that characterize these two normal stem cell (SC) populations and compared these profiles with those of prostate tumor cells. The first population, stem cells, has considerable growth potential, does not require androgen for survival, expresses high levels of Sca-1 and resides in the proximal region of ducts. The inner layer of epithelial cells of the murine urogenital sinus starts invading the outer layer of mesenchyme to form the ducts of the prostate gland after E16. Prior to this event, the urogenital sinus epithelium (UGE) containing primitive fetal prostate cells can be isolated from the urogenital sinus. The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer
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