• Guodong Zhang, Dipak Panigrahy, Lisa M Mahakian, Jun Yang, Jun-Yan Liu, Stephen LeeKin SingKS, Hiromi I Wettersten, Arzu Ulu, Xiaowen Hu, Sarah Tam, Sung Hee Hwang, Elizabeth S Ingham, Mark W Kieran, Robert H Weiss, Katherine W Ferrara, and Bruce D Hammock.
• Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
• Proc. Natl. Acad. Sci. U.S.A. 2013 Apr 16; 110 (16): 6530-5.

AbstractEpidemiological and preclinical evidence supports that omega-3 dietary fatty acids (fish oil) reduce the risks of macular degeneration and cancers, but the mechanisms by which these omega-3 lipids inhibit angiogenesis and tumorigenesis are poorly understood. Here we show that epoxydocosapentaenoic acids (EDPs), which are lipid mediators produced by cytochrome P450 epoxygenases from omega-3 fatty acid docosahexaenoic acid, inhibit VEGF- and fibroblast growth factor 2-induced angiogenesis in vivo, and suppress endothelial cell migration and protease production in vitro via a VEGF receptor 2-dependent mechanism. When EDPs (0.05 mg · kg(-1) · d(-1)) are coadministered with a low-dose soluble epoxide hydrolase inhibitor, EDPs are stabilized in circulation, causing ~70% inhibition of primary tumor growth and metastasis. Contrary to the effects of EDPs, the corresponding metabolites derived from omega-6 arachidonic acid, epoxyeicosatrienoic acids, increase angiogenesis and tumor progression. These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers.

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