Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

J Clin Invest. 2012 Jan;122(1):178-91. doi: 10.1172/JCI58128. Epub 2011 Dec 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Eicosanoids / metabolism*
  • Endothelium, Vascular / metabolism
  • Epoxy Compounds / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / physiopathology*
  • Neoplasms, Experimental / blood supply
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Cytochrome P-450 Enzyme Inhibitors
  • Eicosanoids
  • Epoxy Compounds
  • Recombinant Proteins
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • arachidonate epoxygenase