Sonic Hedgehog Signaling in Normal Prostate Stem Cells And Prostate Cancer Stem Cells

摘要

As an approach to identify potential Shh-responding stem cells in the mouse prostate, we used Genetic Inducible Fate Mapping (GIFM) to follow the fate of Shh-responding cells both during prostate development and during androgen-mediated regeneration of the gland in the adult, two processes that are driven by stem or progenitor cell expansion. As Gli1 expression is a sensitive readout of Shh signaling, we used a Gli1CreER allele and Rosa26 reporter to fate map Shhresponding cells. We show that Shh-responding cells do not expand over time in the normal homoeostatic prostate, but these same cells do expand massively after androgen-mediated regeneration, indicating that Shh- responding cells are normally quiescent, but retain the ability to expand in the adult prostate. The expansion of cells is confined to stromal fibroblasts and smooth muscle cells; no glandular epithelial cells are marked. These results indicate that Gli1 either specifically marks stromal stem cells that expand during regeneration to give rise to the two stromal cell types, or that fibroblasts and smooth muscle cells in general have a high capacity for proliferation even in the adult prostate. To determine whether the marked Shh- responding cells have the capacity for selfrenewal, we subjected Gli1CreER ; Rosa26 mice to eight cycles of prostate involution and regeneration. Cells marked before castration expand after 8 cycles of involution/regeneration, indicating that the initially marked Shh-responding cells are self-renewing.