Role of Linoleic Acid-Derived Oxylipins in Cancer

In recent decades, dietary guidance has advocated reducing the intake of total and saturated fats, elimination of trans fats, and replacement with polyunsaturated fats. Increasing intake of the essential fatty acid linoleic acid (LA) lowers low-density lipoprotein cholesterol and also lowers the risk of hypertension¹. Thus, LA is considered a “cardiovascular-friendly” essential dietary fatty acid and American consumption of LA containing vegetable oils has increased significantly over the past century². However, dietary LA intake is controversial, as increasing LA consumption fails to protect against cardiovascular diseases or reduce all-cause mortality². In addition, the effects of increased LA consumption on other diseases is less well studied. While LA consumption has been promoted by some to protect against cardiovascular disease, recent data suggests that cytochrome P450-mediated metabolism of LA to pro-inflammatory and pro-angiogenic oxylipins may have deleterious effects on tumor growth and metastasis.

Cytochromes P450 of the CYP2C and CYP2J subfamilies can oxidize polyunsaturated fatty acids to form bioactive epoxy fatty acid (EpFAs). The most widely studied EpFAs are the arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which have potent cardioprotective effects. The effects of EETs are diminished by microsomal and soluble epoxide hydrolases (mEH and sEH, respectively), which hydrolyze EET to less-active diols (dihydroxyeicosatrienoic acids, DHETs)^3,4. The vasodilatory, anti-inflammatory, anti-apoptotic and cardioprotective effects of EETs suggest that sEH inhibitors (sEHi) may be beneficial for the treatment of cardiovascular diseases; however, EET-induced cellular proliferation, migration and angiogenesis may promote tumor growth and metastasis⁵. In humans, dietary LA is the precursor of AA formation. CYP2C and CYP2J enzymes can also metabolize LA to EpFAs termed epoxyoctadecamonoenoic acids (EpOMES) which are hydrolyzed to corresponding diols dihyroxyoctadecamonoenoic acids (DiHOMEs). EpOMEs and DiHOMEs are produced by many cell types and are far more abundant in tissues and plasma than EETs and DHETs. EpOMEs and DiHOMEs are routinely used as surrogate markers for CYP or epoxide hydrolase activity in vivo⁶; however, these LA-derived oxylipins have a distinct profile of biological effects. In opposition to the effects of EETs, EpOMEs and/or DiHOMEs are vasoconstrictive, cardiodepressive, cytotoxic and pro-inflammatory^3,7.

LA-derived oxylipins are less well studied than AA-derived eicosanoids, although they may have important biological effects. We recently measured serum oxylipins in subjects during screening for prostate, lung, colorectal and ovarian cancers. Our results suggested a positive correlation between 5 oxylipins (8-HETE, 12,13-DiHOME, 13-HODE, 9-HODE and 9,12,13-TriHOME) and ovarian cancer. Although LA metabolites comprise only 6 of >50 oxylipins in our LC/MS/MS panel, 3 of the 5 metabolites that correlated with ovarian cancer are LA-derived⁸. This data suggests that increased LA consumption, or increased LA oxidation, may have significant deleterious effects.

To more closely examine the role of CYPs and LA-derived oxylipins in cancer, we used a well-established azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced murine colon cancer model. We observed that Cyp2c gene expression, EpOME levels and inflammatory cytokines are upregulated in this model. To examine the specific role of the Cyp2c genes and EpOMEs in AOM/DSS-induced colon tumorigenesis, we compared wild-type (WT) to Cyp2c heterozygous mice (Cyp2c^+/−), which have reduced expression of 14 of the 15 murine Cyp2c genes. Cyp2c^+/− mice had decreased EpOMEs in colon tissue and developed fewer/smaller tumors than WT controls. Moreover, treatment with 12,13-EpOME exacerbated AOM/DSS-induced colon tumorigenesis in vivo. In vitro studies revealed that 12,13-EpOME increased JNK activation and activated inflammatory signaling pathways to promote tumor initiation⁹. Together these experiments revealed a previously unrecognized role for CYP2C enzymes in colon tumor progression and suggested a new therapeutic target for patients with colon cancer.

While LA-derived oxylipins are emerging as potent signaling molecules in cardiovascular diseases and cancer, numerous questions remain. Dietary LA is well documented to exacerbate murine colon cancer in the AOM/DSS model; however, it is unknown whether this is due to LA-derived EpFAs⁷. While EpOME treatments increase colon tumorigenesis, it remains unclear whether these effects are directly mediated by EpOMEs or occur after sEH-mediated conversion to DiHOMEs. While genetic deletion or inhibition of sEH promotes tumors in some animal models⁵, it may have either pro- or anti-tumor effects in colon cancer. Indeed, previous studies have shown that inhibition or genetic disruption of sEH attenuates colonic inflammation and colon cancer^10–12. The specific roles of EpOMEs and/or DiHOMEs in increasing tumor burden are also unclear; they likely promote tumors by exacerbating inflammation but may also have roles in cell proliferation or migration that can increase tumor burden and/or metastasis. While many oxylipins signal through G-protein-coupled receptors, no such receptor has been identified for either EpOMEs or DiHOMEs. Identification of these receptors and/or the use of selective receptor antagonists will be critical steps in precisely defining the cell-specific physiological roles of these oxylipins in cancer. In conclusion, LA-derived oxylipins are emerging as important mediators in colon cancer; a better understanding their physiological functions may lead to improved recommendations for dietary or pharmacological interventions for the treatment of colon or other cancers.

“MARGIN QUOTE”.

“While LA consumption has been promoted by some to protect against cardiovascular disease, recent data suggests that cytochrome P450-mediated metabolism of LA to pro-inflammatory and pro-angiogenic oxylipins may have deleterious effects on tumor growth and metastasis.”