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dc.contributor.authorChing, M.M.
dc.contributor.authorReader, J.
dc.contributor.authorFulton, A.M.
dc.date.accessioned2020-06-24T20:50:59Z
dc.date.available2020-06-24T20:50:59Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85086433118&doi=10.3389%2ffphar.2020.00819&partnerID=40&md5=2ad7096133e80da496126beee652261b
dc.identifier.urihttp://hdl.handle.net/10713/13137
dc.description.abstractThe cyclooxygenase-2 (COX-2) enzyme is frequently overexpressed in epithelial malignancies including those of the breast, prostate, lung, kidney, ovary, and liver and elevated expression is associated with worse outcomes. COX-2 catalyzes the metabolism of arachidonic acid to prostaglandins. The COX-2 product prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors designated EP1-EP4. EP4 is commonly upregulated in cancer and supports cell proliferation, migration, invasion, and metastasis through activation of multiple signaling pathways including ERK, cAMP/PKA, PI3K/AKT, and NF-?B. EP4 antagonists inhibit metastasis in preclinical models. Cancer stem cells, that underlie therapy resistance and disease relapse, are driven by the expression of EP4. Resistance to several chemotherapies is reversed in the presence of EP4 antagonists. In addition to tumor cell-autonomous roles of EP4, many EP4-positive host cells play a role in tumor behavior. Endothelial cell-EP4 supports tumor angiogenesis and lymphangiogenesis. Natural Killer (NK) cells are critical to the mechanism by which systemically administered EP4 antagonists inhibit metastasis. PGE2 acts on EP4 expressed on the NK cell to inhibit tumor target cell killing, cytokine production, and chemotactic activity. Myeloid-derived suppressor cells (MDSCs), that inhibit the development of cytotoxic T cells, are induced by PGE2 acting on myeloid-expressed EP2 and EP4 receptors. Inhibition of MDSC-EP4 leads to maturation of effector T cells and suppresses the induction of T regulatory cells. A number of EP4 antagonists have proven useful in dissecting these mechanisms. There is growing evidence that EP4 antagonism, particularly in combination with either chemotherapy, endocrine therapy, or immune-based therapies, should be investigated further as a promising novel approach to cancer therapy. Several EP4 antagonists have now progressed to early phase clinical trials and we eagerly await the results of those studies. Copyright 2020 Ching, Reader and Fulton.en_US
dc.description.urihttps://doi.org/10.3389/fphar.2020.00819en_US
dc.language.isoen_USen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.ispartofFrontiers in Pharmacology
dc.subjectcanceren_US
dc.subjectEP4en_US
dc.subjectimmunotherapyen_US
dc.subjectmicroenvironmenten_US
dc.subjectprostaglandin E2en_US
dc.titleEicosanoids in Cancer: Prostaglandin E2 Receptor 4 in Cancer Therapeutics and Immunotherapyen_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fphar.2020.00819


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