Appointment period: 4/14/2014 to 4/13/2016

Award: Judah Folkman Fellowship for Angiogenic Research

Project

Regulation of angiogenesis, tumor growth, and metastasis by the metabolism of epoxy omega-3 and -6 fatty acids

Metabolism of omega-6 arachidonic acid by cytochrome P450 (CYP) epoxygenases yields epoxy lipids including epoxyeicosatrienoic acids (EETs). These transformation products are pro-angiogenic and enhance tumor growth and metastasis by stimulation of tumor angiogenesis. By contrast, CYP epoxygenase metabolism of omega-3 dietary fatty acids, specifically decosahexaenoic acid, produces epoxydocosapentanoic acids (EDPs) which inhibit angiogenesis, decrease primary tumor growth, and slow cancer cell metastasis. The mechanisms by which omega-3 and omega-6 fatty acids affect angiogenesis and cancer are still not entirely understood. Preliminary evidence has suggested that EETs may be transformed by cylooxygenase (COX) enzymes to form products that are several times more angiogenic than EETs themselves. The ability of EDPs to react with COX is unknown.

This proposed study aims to further understand the opposing mechanisms of EETs and EDPs on angiogenesis and progression of cancer, by elucidating a novel lipid metabolism pathway controlled by CYP and COX enzymes. We firstly want to determine the relative affinities of EETs and EDPs as substrates for COX enzymes using a kinetic assay, and elucidate the primary products of this pathway using LC-ToF-MS and LC-MS/MS. Secondly, we aim to synthesize and evaluate the major COX transformation products to determine their influence on the stages of angiogenesis within human umbilical vein endothelial cells. Finally, the in vivo activity of the transformation products on tumor growth and metastasis will be determined using a breast cancer Met-1 tumor model and Lewis lung carcinoma model, respectively. Omega-3 fatty acids are increasingly being marketed as dietary supplements, therefore it is relevant and timely to further understand the cancer biology associated with these compounds.