Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

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 & 11 others Kenneth B. Tomer, Jun Yang, Reto A. Schwendener, Bruce D. Hammock, J R Falck, Vijaya L. Manthati, Donald E. Ingber, Arja Kaipainen, Patricia A. D'Amore, Mark W. Kieran, Darryl C. Zeldin

Research output: Contribution to journalArticle

144 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)178-191
Number of pages14
JournalJournal of Clinical Investigation
Volume122
Issue number1
DOIs
StatePublished - Jan 3 2012

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Tumor Escape
Neoplasm Metastasis
Neoplasms
Growth
Pharmacology
Lipids
Epoxide Hydrolases
Pharmaceutical Preparations
Cytochrome P-450 Enzyme System
Endothelium
Blood Vessels
Carcinogenesis
Clinical Trials

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Panigrahy, D., Edin, M. L., Lee, C. R., Huang, S., Bielenberg, D. R., Butterfield, C. E., ... Zeldin, D. C. (2012). Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. Journal of Clinical Investigation, 122(1), 178-191. https://doi.org/10.1172/JCI58128

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

In: Journal of Clinical Investigation, Vol. 122, No. 1, 03.01.2012, p. 178-191.

Research output: Contribution to journalArticle

Panigrahy, D, Edin, ML, Lee, CR, Huang, S, Bielenberg, DR, Butterfield, CE, Barnés, CM, Mammoto, A, Mammoto, T, Luria, A, Benny, O, Chaponis, DM, Dudley, AC, Greene, ER, Vergilio, JA, Pietramaggiori, G, Scherer-Pietramaggiori, SS, Short, SM, Seth, M, Lih, FB, Tomer, KB, Yang, J, Schwendener, RA, Hammock, BD, Falck, JR, Manthati, VL, Ingber, DE, Kaipainen, A, D'Amore, PA, Kieran, MW & Zeldin, DC 2012, 'Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice', Journal of Clinical Investigation, vol. 122, no. 1, pp. 178-191. https://doi.org/10.1172/JCI58128
Panigrahy D, Edin ML, Lee CR, Huang S, Bielenberg DR, Butterfield CE et al. Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. Journal of Clinical Investigation. 2012 Jan 3;122(1):178-191. https://doi.org/10.1172/JCI58128
Panigrahy, Dipak ; Edin, Matthew L. ; Lee, Craig R. ; Huang, Sui ; Bielenberg, Diane R. ; Butterfield, Catherine E. ; Barnés, Carmen M. ; Mammoto, Akiko ; Mammoto, Tadanori ; Luria, Ayala ; Benny, Ofra ; Chaponis, Deviney M. ; Dudley, Andrew C. ; Greene, Emily R. ; Vergilio, Jo Anne ; Pietramaggiori, Giorgio ; Scherer-Pietramaggiori, Sandra S. ; Short, Sarah M. ; Seth, Meetu ; Lih, Fred B. ; Tomer, Kenneth B. ; Yang, Jun ; Schwendener, Reto A. ; Hammock, Bruce D. ; Falck, J R ; Manthati, Vijaya L. ; Ingber, Donald E. ; Kaipainen, Arja ; D'Amore, Patricia A. ; Kieran, Mark W. ; Zeldin, Darryl C. / Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 1. pp. 178-191.
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AU - Panigrahy, Dipak

AU - Edin, Matthew L.

AU - Lee, Craig R.

AU - Huang, Sui

AU - Bielenberg, Diane R.

AU - Butterfield, Catherine E.

AU - Barnés, Carmen M.

AU - Mammoto, Akiko

AU - Mammoto, Tadanori

AU - Luria, Ayala

AU - Benny, Ofra

AU - Chaponis, Deviney M.

AU - Dudley, Andrew C.

AU - Greene, Emily R.

AU - Vergilio, Jo Anne

AU - Pietramaggiori, Giorgio

AU - Scherer-Pietramaggiori, Sandra S.

AU - Short, Sarah M.

AU - Seth, Meetu

AU - Lih, Fred B.

AU - Tomer, Kenneth B.

AU - Yang, Jun

AU - Schwendener, Reto A.

AU - Hammock, Bruce D.

AU - Falck, J R

AU - Manthati, Vijaya L.

AU - Ingber, Donald E.

AU - Kaipainen, Arja

AU - D'Amore, Patricia A.

AU - Kieran, Mark W.

AU - Zeldin, Darryl C.

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