Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis

// Jian Chang 1,4,5 , Jean Vacher 3 , Bing Yao 1 , Xiaofeng Fan 1 , Bixiang Zhang 4 , Raymond C. Harris 1,6 and Ming-Zhi Zhang 1,2,7 1 Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA 2 Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA 3 Department of Medecine, Clinical Research Institute of Montreal, Universite de Montreal, Montreal, Quebec, Canada 4 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China 5 Hepatobiliary Surgery Department, Wuhan No.1 Hospital, Wuhan, China 6 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA 7 Jiangsu Center for The Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, China Correspondence to: Ming-Zhi Zhang, email: // Keywords : cyclooxygenase-2, myeloid cells, polarization, tumor growth Received : March 10, 2015 Accepted : August 23, 2015 Published : September 10, 2015 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 PGE 2 . Since myeloid cells express high levels of the PGE 2 receptor subtype, EP 4 , we selectively ablated EP 4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, Apc Min/+ mice. Apc Min/+ mice with selective myeloid cell deletion of EP 4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP 4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE 2 -mediated EP 4 signaling in myeloid cells promotes tumorigenesis, suggesting EP 4 as a potentially attractive target for CRC chemoprevention or treatment.