Epoxyeicosatrienoic acids in cancer: a wake-up call

Lipidomics Gateway (25 January 2012) [doi:10.1038/lipidmaps.2012.3]

Increased levels of epoxyeicosatrienoic acids promote escape from tumour dormancy and multiorgan metastasis by inducing VEGF-stimulated angiogenesis.

Despite the knowledge that epoxyeicosatrienoic acids (EETs) promote angiogenesis, and that the enzymes that catalyse their generation from arachidonic acid are associated with cancer, surprisingly only now has a profound effect for EETs in stimulating metastasis and escape from tumour dormancy emerged. The findings are reported in The Journal of Clinical Investigation.

EETs are generated from arachidonic acid mainly in the endothelium by cytochrome P450 (CYP) epoxygenases, and metabolized by soluble epoxide hydrolase (sEH). In their study, Panigrahy et al. generated three transgenic mouse lines with high endothelial EET levels by expressing human CYP2C8 or human CYP2J2 (Tie2 promoter-driven; Tie2-CYP2C8-Tr or Tie2-CYP2J2-Tr) or by globally disrupting the gene encoding sEH (sEH-null); a fourth line with reduced endothelial EET levels was made by expressing human sEH (Tie2-sEH-Tr). All cases of increased EET expression, as well as the systemic administration of 14, 15-EET, profoundly increased tumour growth in a wide range of tumour models; conversely, tumour growth was suppressed in Tie2-sEH-Tr mice.

Panigrahy et al. ascertained that the increased EET levels promoted escape from dormancy — the transition from a microscopic dormant tumour to a macroscopic growing tumour — and were therefore required for normal tumour development when the tumour cell number was below a critical threshold. Suppression of angiogenesis maintains tumour dormancy and, consistent with increased EET levels accelerating escape, the authors observed an increase in the amount of endothelium in tumours from Tie2-CYP2C8-Tr, Tie2-CYP2J2-Tr and sEH-null mice, and a decrease in Tie2-sEH-Tr mice, compared with wild-type mice. The increased angiogenesis was a primary response to the increase in EET levels, rather than a consequence of increased tumour growth.

Next, the authors demonstrated that EETs — either endothelium-derived or systemic — stimulated spontaneous metastasis, and that the resulting macrometastatic lesions were independent of the tumour type. For example, EETs stimulated surface lung metastases and liver, kidney and distant lymph node metastasis after resection of a primary Lewis lung carcinoma tumour. Similar to exogenous EETs, pharmacological sEH inhibitors, which increase EET levels, stimulated primary tumour and metastatic growth, whereas a putative EET receptor antagonist reduced lung metastasis and inhibited distant metastasis induced by elevated EET levels.

Theoretically, EETs could influence the primary tumour or could act at the secondary site to stimulate metastasis. Through a series of parabiosis experiments in which tumour-bearing mice with high EET levels were conjoined to non-tumour-bearing mice with low EET levels, Panigrahy et al. established that high EET levels were required in the endothelium of the metastatic site. But what induces the rise in EET levels? The authors observed a considerable decrease in the expression levels of sEH, but no change in the expression of two CYP epoxygenases, in the endothelial cells of tumours compared to normal endothelial cells, indicating that elevated EET levels during tumour progression are the result of decreased degradation.

To assess the consequence of increased EET levels at the cellular level, Panigrahy et al. studied endothelial cell migration, which contributes to metastasis. Endothelial cells derived from Tie2-sEH-Tr mice or treated with a putative EET receptor antagonist migrated more slowly on collagen, whereas those derived from Tie2-CYP2C8-Tr or Tie2-CYP2J2-Tr migrated faster, compared with wild-type endothelial cells. The authors also found that vascular endothelial growth factor (VEGF), produced by the endothelium and other stromal cells, was required by EETs for tumour progression by demonstrating suppressed tumour growth following VEGF depletion. By contrast, high EET levels reduced the expression of thrombospondin-1, an inhibitor of angiogenesis.

This study outlines the dramatic metastatic potential of EETs on low-metastasizing tumours through an increase in the primary growth rate and escape from dormancy. It also highlights that decreasing the levels of sEH, either genetically or using pharmacological inhibitors, promotes tumour growth and metastasis, raising potential concerns regarding the use of sEH inhibitors currently in clinical trials for the treatment of hypertension. Conversely, however, inhibition of EET bioactivity might constitute a new therapeutic strategy for metastatic disease.

Katrin Legg