Effects of N-3 Pufas on Endothelial Cell Migration and Angiogenesis Induced by Prostate Cancer Cells

Malignant carcinoma was the leading cause of death in 2009 and prostate cancer was the 7th cause of cancer-related death in Taiwan. Prostate cancer five-year survival rate drops to 33% with distant metastasis. Tumor-associated macrophages (TAMs) are the main leukocytes of intratumoral infiltration, and increased macrophage density correlates with poor prognosis. TAMs promote angiogenesis by secreting proangiogenic factors and facilitate invasion by releasing chemokines, cytokines and matrix-degrading enzymes. Epidemiologic data showed that the long-chain marine n-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were lower in plasma and prostate tissue of prostate cancer patients compared with cancer free men. Fish oil, rich in n-3 PUFAs, was proven to decrease lymphocytes proliferation, chemotaxis of monocytes and leukocytes as well as reducing the secretion of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. In vitro studies also showed that n-3 PUFAs could regulate inflammatory response by activation of peroxisome proliferators-activated receptor (PPAR)-γand downregulation of nuclear factor (NF)-κB activity. So far, there is no study investigating the effect of n-3 PUFAs on endothelial cell migration and angiogenesis induced by prostate cancer cells. Therefore, we plan to carry out this study in 3 consecutive years. In the first year, we plan to administer different n-3 PUFAs levels and PPAR-γ inhibitor GW9662 to PC-3 human prostate cancer cells to investigate the effect of n-3 PUFAs on the alteration of PPAR-γ activation and macrophages migration simulated by conditioned medium from lipopolysaccharide (LPS) activated THP-1. In the second year, the transwell assay will be used to observe the effect of n-3 PUFAs on endothelial cell migration and angiogenesis induced by prostate cancer cells. In the third year, we plan to figure out whether n-3 PUFAs intervention activate PPAR-γ and thus decrease NF-κB transcriptional activity and subsequently inhibit metastasis of prostate cancer cells in an orthotopic nude mice model. This study will provide useful information for clinical application in metastatic prostate cancer patients.