[HTML][HTML] Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis

J Chang, J Vacher, B Yao, X Fan, B Zhang, RC Harris… - Oncotarget, 2015 - ncbi.nlm.nih.gov
J Chang, J Vacher, B Yao, X Fan, B Zhang, RC Harris, MZ Zhang
Oncotarget, 2015ncbi.nlm.nih.gov
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 …
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/+ zmice. 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.
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