Eicosanoid regulation of debris-stimulated metastasis
Jianjun Deng, Haixia Yang, Victoria M. Haak, Jun Yang, Franciele Kipper, Chantal Barksdale, Sung Hee Hwang, Allison Gartung, Diane R. Bielenberg, Selvakumar Subbian, Koc-Kan Ho, Xiang Ye, Daidi Fan, Yongkui Sun, Bruce D. Hammock, Dipak Panigrahy
Abstract
Significance Cancer therapy, such as chemotherapy, induces tumor cell death (“debris”), which can stimulate metastasis. Chemotherapy-generated debris upregulates soluble epoxide hydrolase (sEH) and the prostaglandin E 2 receptor 4 (EP4), which triggers a macrophage-derived storm of proinflammatory and proangiogenic lipid autacoid and cytokine mediators. Although sEH inhibitors and EP4 antagonists are in clinical development for multiple inflammatory diseases, their combined role in cancer is unknown. Here, we show that the synergistic antitumor activity of sEH and EP4 inhibition suppresses hepato-pancreatic tumor growth, without overt toxicity, via macrophage phagocytosis of debris and counterregulation of a debris-stimulated cytokine storm. Thus, stimulating the resolution of inflammation via combined inhibition of sEH and EP4 may be an approach for preventing metastatic progression driven by cancer therapy.