P124. 3-Polyunsaturated fatty acids may inhibit angiogenesis through suppression of ELR+ CXC chemokines expression and VEGF signaling in pancreatic cancer

Angiogenesis, the process of new blood vessel formation, is essential for tumor growth and metastasis. Although the protective role of ω3-PUFAs on cancer progression has been reported, the anti-angiogenic mechanisms remain to be further understood. The aim of this study is to investigate the anti-angiogenic mechanisms of ω3-PUFAs in pancreatic cancer. In angiogenesis protein array chip assay, only angiogenic ELR+ CXC chemokines expression, which activate endothelial cell migration and neutrophils recruitment, was significantly reduced by DHA treatment in SW1990 human pancreatic cancer cells. The reduced expression of ELR+ CXC chemokine was confirmed by RT-PCR. Chemotactic migration of HUVEC was significantly reduced in DHA-treated SW1990 conditioned medium (CM) compared to control CM. DHA also inhibited VEGF reporter activity in SW1990 cells. VEGF-induced endothelial cell proliferation and migration were markedly inhibited by DHA treatment. MMP-2 and MMP-9 promoter activities were reduced by DHA treatment, and ultimately attenuated the invasiveness of SW1990 cells as revealed by matrigel droplet assay. Moreover, NF-κB reporter activity, which is closely correlated with the expression of CXC chemokine, VEGF and MMPs, was reduced by DHA treatment. When mouse pancreatic cancer PANC02 cells were implanted into Fat-1 transgenic mice, tumor size and volume were dramatically reduced in Fat-1 mice compared to control mice. In immunohistochemical analysis of tumors of Fat-1 mice, apoptosis (TUNEL positive cells) was markedly increased and microvessel density (CD31 intensity) was significantly reduced in Fat-1 mice compared to control mice. In addition, VEGF-induced neovascularization to a subcutaneous matrigel plug was significantly inhibited in Fat-1 mice compared with control mice. Our finding suggests that ω3-PUFAs can suppress tumor angiogenesis through inhibition of ELR+ chemokines expression and VEGF signal in pancreatic cancer. Thus ω3-PUFAs supplementation may beneficial for chemoprevention and treatment of pancreatic cancer by anti-angiogenic effect. This work was supported by basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R13-2007-020-01000-0 and 2010-0016447), Korea.