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.
Highlights
Colorectal cancer (CRC) is one of the most preventable cancers; it is still the leading cause of cancer death
Both selective COX-2 inhibitors and global COX2 deletion have been shown to effectively suppress adenoma development and growth [5, 25, 26], and COX2 is highly expressed in myeloid cells in both human sporadic colorectal adenomas and intestinal adenomas in ApcMin/+ mice [13, 14]
Double immunofluorescent staining indicated that COX-2expressing macrophages/dendritic cells make up only about half of the COX-2-expressing cells in the adenoma stroma
Summary
Colorectal cancer (CRC) is one of the most preventable cancers; it is still the leading cause of cancer death. Myeloid cells have been proposed to promote tumor initiation, tumor growth, metastasis and immunomodulation In both human sporadic colorectal adenomas and intestinal adenomas in ApcMin/+ mice, COX-2 is highly expressed in macrophages [13, 14]. Either genetic or pharmacologic inhibition of EP4 receptors led to inhibition of ERK and mTOR pathways in adenomas in association with decreased M2 and increased M1 phenotypic macrophages. These findings suggest an important role for myeloid cell EP4 receptors in regulation of colorectal tumorigenesis and identify EP4 receptor as a possible target for prevention and/or therapy for colorectal cancer
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