title: Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis.
abstract: Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. Although the factors underlying CRC development and progression are multifactorial, there is an important role for tumor-host interactions, especially interactions with myeloid cells. There is also increasing evidence that cyclooxygenase-derived prostaglandins are important mediators of CRC development and growth. Although prevention trials with either nonselective NSAIDs or COX-2 selective agents have shown promise, the gastrointestinal or cardiovascular side effects of these agents have limited their implementation. The predominant prostaglandin involved in CRC pathogenesis is PGE2. Since myeloid cells express high levels of the PGE2 receptor subtype, EP4, we selectively ablated EP4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, ApcMin/+ mice. ApcMin/+mice with selective myeloid cell deletion of EP4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE2-mediated EP4 signaling in myeloid cells promotes tumorigenesis, suggesting EP4 as a potentially attractive target for CRC chemoprevention or treatment.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.|Hepatobiliary Surgery Department, Wuhan No.1 Hospital, Wuhan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chang
authors.affiliation: Départment of Médecine, Clinical Research Institute of Montreal, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Vacher
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Bing
authors.initials: B
authors.lastname: Yao
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Fan
authors.affiliation: Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Bixiang
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.|Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA.|Jiangsu Center for The Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China.
authors.forename: Ming-Zhi
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D000067996:RAW 264.7 Cells; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058309:Receptors, Prostaglandin E, EP4 Subtype; D058570:TOR Serine-Threonine Kinases; C545651:Ptger4 protein, mouse; C077623:Ptgs2 protein, mouse; C546843:mTOR protein, mouse
keywords: cyclooxygenase-2; myeloid cells; polarization; tumor growth