Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in
tumorigenesis. Endogenously produced
lipid autacoids, locally acting small-molecule mediators, play a central role in
inflammation and tissue homeostasis. These
lipid mediators, collectively referred to as
eicosanoids, have recently been implicated in
cancer. Although
eicosanoids, including
prostaglandins and
leukotrienes, are best known as products of
arachidonic acid metabolism by
cyclooxygenases and
lipoxygenases,
arachidonic acid is also a substrate for another enzymatic pathway, the
cytochrome P450 (CYP) system. This
eicosanoid pathway consists of two main branches: ω-
hydroxylases which converts
arachidonic acid to
hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic
acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate
inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble
epoxide hydrolase to less active dihydroxyeicosatrienoic
acids. EET signaling was originally studied in conjunction with inflammatory and
cardiovascular disease.
Arachidonic acid and its metabolites have recently stimulated great interest in
cancer biology. To date, most research on
eicosanoids in
cancer has focused on the COX and LOX pathways. In contrast, the role of
cytochrome P450-derived
eicosanoids, such as EETs and HETEs, in
cancer has received little attention. While CYP epoxygenases are expressed in human
cancers and promote human
cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in
cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis,
inflammation, and
cancer is discussed.