Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

Abstract

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

“…consistent with previous reports (26,28). Together, these results designate EDPs and EETs as unique mediators of an angiogenic switch to regulate tumorigenesis.…”

“…These results further argue that a replacement of EETs with EDPs upon omega-3 supplementation causes multiple beneficial effects. Previous studies showed that EETs stimulate angiogenesis via upregulation of VEGF (VEGF-A) in vitro and in vivo (25,28). Here we found that EDP had no effect on VEGF-A expression, whereas it potently inhibited the expression of VEGF-C in vitro (Fig.…”

“…3B). In comparison, our previous study in the same model showed that systematic administration of 14,15-EET (0.015 mg·kg −1 ·d −1 ) caused an approximately threefold increase of LLC metastasis (28), confirming the opposite effects of EDPs and EETs on tumor metastasis.…”

“…To test the effect of EDPs on metastasis in vivo, we used a well-established Lewis lung carcinoma (LLC) model, in which resection of the primary s.c. tumor consistently stimulates growth of dormant metastases (28,39). This spontaneous model of lung metastasis is believed to be triggered by reduced levels of circulating angiogenesis inhibitors that had been produced by the primary tumor (39) (Fig.…”

“…Cumulatively, these results imply that EDPs could mediate some of the health-promoting effects of DHA. In terms of angiogenesis and cancer, EETs are proangiogenic (25)(26)(27) and have been shown to accelerate tumor growth and metastasis by stimulation of tumor angiogenesis (28), whereas the roles of EDPs in angiogenesis and tumorigenesis have not been studied to date. To this end, we investigated the actions of EDPs on angiogenesis, tumor growth, and metastasis.…”