Title: Eicosanoid regulation of debris-stimulated metastasis.
Authors: Deng, Jianjun; Yang, Haixia; Haak, Victoria M; Yang, Jun; Kipper, Franciele C; Barksdale, Chantal; Hwang, Sung Hee; Gartung, Allison; Bielenberg, Diane R; Subbian, Selvakumar; Ho, Koc-Kan; Ye, Xiang; Fan, Daidi; Sun, Yongkui; Hammock, Bruce D; Panigrahy, Dipak
Published In Proc Natl Acad Sci U S A, (2021 10 12)
Abstract: Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.
PubMed ID: 34607951
MeSH Terms: Animals; Antineoplastic Agents/adverse effects; Antineoplastic Agents/therapeutic use; Carcinoma, Hepatocellular/pathology; Cell Death/drug effects; Cell Line, Tumor; Cytokine Release Syndrome/immunology; Cytokine Release Syndrome/prevention & control; Cytokines/metabolism; Eicosanoids/metabolism*; Epoxide Hydrolases/biosynthesis*; Hep G2 Cells; Humans; Liver Neoplasms/drug therapy; Liver Neoplasms/pathology; Macrophages/immunology*; Male; Mice; Mice, Inbred C57BL; Neoplasm Metastasis/pathology*; Neoplasm Metastasis/prevention & control; Pancreatic Neoplasms/drug therapy; Pancreatic Neoplasms/pathology; Phagocytosis/immunology; RAW 264.7 Cells; Receptors, Prostaglandin E, EP4 Subtype/biosynthesis*