Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice
Dipak Panigrahy, … , Mark W. Kieran, Darryl C. Zeldin
Dipak Panigrahy, … , Mark W. Kieran, Darryl C. Zeldin
Published December 19, 2011
Citation Information: J Clin Invest. 2012;122(1):178-191. https://doi.org/10.1172/JCI58128.
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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.

Authors

Dipak Panigrahy, Matthew L. Edin, Craig R. Lee, Sui Huang, Diane R. Bielenberg, Catherine E. Butterfield, Carmen M. Barnés, Akiko Mammoto, Tadanori Mammoto, Ayala Luria, Ofra Benny, Deviney M. Chaponis, Andrew C. Dudley, Emily R. Greene, Jo-Anne Vergilio, Giorgio Pietramaggiori, Sandra S. Scherer-Pietramaggiori, Sarah M. Short, Meetu Seth, Fred B. Lih, Kenneth B. Tomer, Jun Yang, Reto A. Schwendener, Bruce D. Hammock, John R. Falck, Vijaya L. Manthati, Donald E. Ingber, Arja Kaipainen, Patricia A. D’Amore, Mark W. Kieran, Darryl C. Zeldin

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Figure 2

EETs trigger spontaneous and multiorgan metastasis.

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EETs trigger spontaneous and multiorgan metastasis. (A) Spontaneous LLC ...
(A) Spontaneous LLC metastasis is increased in Tie2-CYP2C8-Tr and sEH-null mice relative to WT 10 days after primary tumor removal (LLC resection). Images show representative lung metastasis in transgenic and WT mice. n = 5 mice/group; *P = 0.011, **P = 0.004, ***P ≤ 0.001 versus WT. The experiment was performed 3 times, with similar results. Scale bars: 1 cm. (B) Spontaneous LLC metastasis is decreased in Tie2-sEH-Tr relative to WT 17 days after primary tumor removal. n = 6 mice/group; *P = 0.001, **P = 0.002. (C) Systemic administration of 14,15-EET (15 μg/kg/d) via osmotic minipump increases spontaneous LLC lung metastasis and distant axillary and inguinal lymph node metastasis 12 days after LLC resection. Dashed circles indicates metastatic and normal lung; arrows show inguinal lymph node metastasis (white arrow, 14,15-EET; black arrow, control); scale bars: 1 cm. GFP-labeled LLC tumor cells (green) demonstrate bilateral axillary and inguinal lymph node metastasis in mice treated with 14,15-EET 17 days after LLC-GFP tumor resection; scale bars: 500 μm (for GFP staining). n = 10 mice/group; *P = 0.001, **P ≤ 0.001. (D) 14,15-EET (15 μg/kg/d) reduces survival and stimulates multiorgan lung, liver, and kidney metastasis of B16F10-GFP melanoma cells injected intravenously. Dashed circles indicate (top to bottom) representative lung, liver, and kidney metastasis 19 days after injection; scale bar: 1 cm. GFP-labeled melanoma tumor cells (green) confirm lung, liver, and kidney metastasis in mice treated with 14,15-EET; scale bar: 500 μm (for GFP staining). n = 7–9 mice/group; *P = 0.021. (E) 14,15-EET (15 μg/kg/d) stimulates liver metastasis in an orthotopic human prostate cancer (PC3M-LN4) model. H&E-stained section of liver metastasis of mice treated with 14,15-EET; arrows indicate nodules of tumor within hepatic parenchyma; scale bar: 100 μm. Black circles indicate representative orthotopic prostate tumors; scale bars: 1 cm. n = 5–6 mice/group.