Molecular Signatures of Fetal and Adult Prostate Stem Cells

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. A 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. Our 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. In order to identify molecules and pathways that are active in primitive prostate populations we determined the transcriptional profiles of four populations of cells: (i) fetal urogenital sinus epithelial cells, enriched in fetal prostate stem cells, (ii) Sca-1Hi, cells that express high levels of Sca-1, enriched in adult prostate stem cells, (iii) Sca-1Lo, cells that express medium to low levels of Sca-1 and are enriched in transit-amplifying cells, and (iv) Sca-1Neg, cells with no Sca expression, that represent the most mature population and have almost no in vivo regenerative potential.