Using Genetically Engineered Mice to Probe the Role of Bioactive Lipids in Prostate Carcinogenesis.

摘要

Prostate cancer (CaP) is the second most common cause of cancer death in North American men. CaP is characterized by stages that include aggressive forms that disseminate to other tissues. Tumors release factors that attract and activate cells of the immune system including macrophages. Exposure of macrophages to inflammatory stimuli results in the transcriptional activation of an anti-inflammatory phospholipase A2, platelet-activating factor acetylhydrolase (PAF-AH) that inactivates PAF and other bioactive phospholipids. PAF-AH expression is dramatically increased in CaP compared to normal prostate tissues. During the tenure of this Award we used in vivo and in vitro methodologies to investigate whether PAF and PAF-AH participate in the pathogenesis of CaP. We generated PAF-AH-deficient mice in a model of PCa (the TRAMP model) that recapitulates many aspects of human CaP. We established that deficiency of PAF-AH in mice decreases survival and increases disease severity. Secondly, we established that CaP cells respond to stimulation with PAF by increasing calcium transients, activating MAP kinases, and increasing cellular proliferation. These results identified a key role for PAF and PAF-AH in the pathogenesis of CaP and provide us with a framework on which we will build the next research phase which includes targeting this pathway to develop novel strategies to treat human CaP.