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

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Final rept. 15 Dec 2004-14 Jun 2006

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Prostate cancer PCa is the most common malignancy in North American men and represents the second most common cause of cancer death. PCa is characterized by many different stages including very aggressive forms that disseminates to bone, lymph nodes, and other tissues. Tumors release factors that attract and activate cells of the immune system including macrophages. In some tumors, macrophages can both stimulate and inhibit cancer growth and proliferation. One of the changes that take place when macrophages are exposed to specific stimuli is the transcriptional activation of a gene encoding a phospholipase A2, platelet-activating factor acetylhydrolase PAF-AH that has anti-inflammatory properties owing to its ability to hydrolyze a large group of bioactive lipids. The levels of PAF-AH are dramatically increased in PCa compared to normal prostate tissues the source is likely macrophages recruited to PCa sites. We are testing the hypothesis is that elevated PAF-AH derived from macrophages recruited to PCa sites alters the rate of PCa progression using both in vivo and in vitro methodologies. We have successfully generated PAF-AH-deficient mice in a model of PCa the TRAMP transgenic model that recapitulates many salient aspects of human PCa. We are analyzing how deficiency of PAF-AH modulates PCa progression in vivo. In addition, we have used cellular approaches to establish that members of the PAF signaling axis promote growth of PCa cells and that overexpression of PAF-AH decreases cellular proliferation either by inhibiting cell division or by promoting apoptosis.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology

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