"Prostate Cancer Stem Cells"
To better prevent, diagnose and effectively treat prostate cancer we need to identify and characterize the cellular origins and molecular basis of the disease. Operating on the premise that prostate cancer represents the consequence of a transformed stem / progenitor cell and that the prostate stem cell (P-SC) and the prostate cancer stem cell (P-CSC) share similar properties, we propose to identify and characterize the both cellular populations using genetically engineered mouse models and in vitro cell sorting technologies. Specifically, we will exploit a transgenic line (11.5kb-GFP) in which the promoter for s-SHIP, believed to mark epithelial stem cells, drives expression of the green fluorescent protein reporter gene. Using these mice, s-SHIP was found to be expressed in ES cells in vitro and in stem / progenitor cells throughout embryonic development. To confirm that GFP+ cells in the normal mouse prostate are indeed stem/progenitor cells we will perform both in vivo prostate reconstitution assays and in vitro self-renewal assays. We will also test the possibility that s-SHIP marks prostate cancer stem cells after crossing the 11.5kb-GFP mice with the autochthonous TRAMP model of prostate cancer. We will also use these bigenics to determine whether castration selects for the emergence of a “stem-like” population by grafting sorted populations into immunocompromised mice and by cellular invasion assays. Finally, we propose to exploit microarray analysis to identify genes and pathways specifically deregulated in the tumorigenic P-CSC obtained from tumors of intact and castrate mice.
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