docosapentaenoic-acid and Neoplasm-Metastasis

Epidemiological 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.

Topics: Animals; Carcinoma, Lewis Lung; Cell Movement; Cell Transformation, Neoplastic; Docosahexaenoic Acids; Dose-Response Relationship, Drug; Epoxide Hydrolases; Epoxy Compounds; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Microscopy; Neoplasm Metastasis; Neovascularization, Pathologic