Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis
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Jian Chang1,4,5, Jean Vacher3, Bing Yao1, Xiaofeng Fan1, Bixiang Zhang4, Raymond C. Harris1,6 and Ming-Zhi Zhang1,2,7
1 Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
2 Cancer Biology, Vanderbilt University, Nashville, Tennessee, USA
3 Départment of Médecine, Clinical Research Institute of Montreal, Université de Montréal, 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
Ming-Zhi Zhang, email:
Keywords: cyclooxygenase-2, myeloid cells, polarization, tumor growth
Received: March 10, 2015 Accepted: August 23, 2015 Published: September 10, 2015
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.
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