"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 use these bigenics to determine if s-SHIP expression selects for a cancer stem-cell population by grafting sorted populations into immunocompromised mice and evaluating tumor formation and growth. Additionally, I will evaluate s-SHIP expression in samples of advanced human prostate cancer, before and after chemotherapy, to determine if there is an enrichment for s-SHIP-expressing cells in keeping with the stem-cell hypothesis whereby cells with a stem-cell phenotype are more resistant to cytotoxic chemotherapy. Finally, we propose to exploit microarray analysis to identify genes and pathways specifically deregulated in the tumorigenic P-CSC obtained from tumors of bigenic mice and human tumor samples.