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.

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferatoractivated receptor (PPAR)␣ deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPAR␣ would promote tumor growth. Surprisingly, the PPAR␣ agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPAR␣-deficient tumors were still susceptible to fenofibrate, absence of PPAR␣ in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPAR␣ as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPAR␣ agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPAR␣ agonists in cancer treatment, alone and in combination with other therapies. stroma ͉ inflammation ͉ fibrates ͉ microenvironment P eroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors comprising three isoforms, PPAR␣, PPAR␦, and PPAR␥, which act as ligand-activated transcriptional factors. PPARs play key roles in energy homeostasis by modulating glucose and lipid metabolism and transport (1). PPAR␣ is also critical in inflammation (2) and is the molecular target of the fibrate class of drugs, such as fenofibrate, which act as agonistic ligands of PPAR␣.Long-term administration of certain PPAR␣ agonists (clofibrate and WY14643) induces hepatocarcinogenesis in rodents but not in humans (3). Consequently, PPAR␣ has not been established as a molecular target for cancer therapy by its agonistic ligands. In contrast, PPAR␥ and PPAR␦ agonists have been extensively studied to evaluate their anticancer effects because of their antiproliferative, proapoptotic, antiapoptotic, and differentiation-promoting activity (4). However, recent studies have revealed the expression of PPAR␣ in tumor cells (5, 6), and PPAR␣ ligands suppress the growth of several cancer lines, including colon, breast, endometrial and skin, in vitro (7-10). PPAR␣ ligands also suppress the metastatic potential of melanoma cells in vitro and in vivo (11,12). Furthermore, PPAR␣ ligands decrease tumor development in murine colon carcinogenesis (7). Clofibric acid inhibits the growth of human ovarian cancer in mice (13). Most recently, the PPAR␣ agonist WY14643 suppresses tumorigenesis in a PPAR␣-dependent manner (14).Together, these data suggest that PPAR...

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