HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Modulation of angiogenesis by -3 polyunsaturated fatty acids is mediated by cyclooxygenases

The potential role of dietary fats in cancer is attracting considerable interest within the community. Both epidemiologic and experimental findings suggest that omega-3 polyunsaturated fatty acids ( -3 PUFAs), which are almost absent from typical Western diets, exert protective effects against cancer progression, although the precise mechanism of this suppression remains unknown. One of the potential targets for -3 PUFAs in cancer suppression is angiogenesis, a process of new blood vessel formation within rapidly growing tumors. Here, we demonstrate that -6 PUFAs stimulate and -3 PUFAs inhibit major proangiogenic processes in human endothelial cells, including the induction of angiopoietin-2 (Ang2) and matrix metalloprotease-9, endothelial invasion, and tube formation, that are usually activated by the major -6 PUFA arachidonic acid. The cyclooxygenase (COX)– mediated conversion of PUFAs to prostanoid derivatives participated in modulation of the expression of Ang2. Thus, the -6 PUFA–derived prostaglandin E2 augmented, whereas the -3 PUFA–derived prostaglandin E3 suppressed the induction of Ang2 by growth factors. Our findings are consistent with the suggestion that PUFAs undergo biotransformation by COX-2 to lipid mediators that modulate tumor angiogenesis, which provides new insight into the beneficial effects of -3 PUFAs. (Blood. 2008;111:3514-3521)