Abstract
Genetic deletion or pharmacological inhibition of cyclooxygenase (COX)-2 abrogates intestinal adenoma development at early stages of colorectal carcinogenesis. COX-2 is localised to stromal cells (predominantly macrophages) in human and mouse intestinal adenomas. Therefore, we tested the hypothesis that paracrine Cox-2-mediated signalling from macrophages drives adenoma growth and progression in vivo in the ApcMin/+ mouse model of intestinal tumorigenesis. Using a transgenic C57Bl/6 mouse model of Cox-2 over-expression driven by the chicken lysozyme locus (cLys-Cox-2), which directs integration site-independent, copy number-dependent transgene expression restricted to macrophages, we demonstrated that stromal macrophage Cox-2 in colorectal (but not small intestinal) adenomas from cLys-Cox-2 x ApcMin/+ mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control ApcMin/+ mice. Transgenic macrophage Cox-2 expression was associated with increased dysplasia, epithelial cell Cox-2 expression and submucosal tumour invasion, as well as increased nuclear β-catenin translocation in dysplastic epithelial cells. In vitro studies confirmed that paracrine macrophage Cox-2 signalling drives catenin-related transcription in intestinal epithelial cells. Paracrine macrophage Cox-2 activity drives growth and progression of ApcMin/+ mouse colonic adenomas, linked to increased epithelial cell β-catenin dysregulation. Stromal cell (macrophage) gene regulation and signalling represent valid targets for chemoprevention of colorectal cancer.
Highlights
There is incontrovertible genetic and pharmacological evidence from rodent models that the inducible isoform of prostaglandin (PG) G/H synthase (PTGS2), known as cyclooxygenase (COX), COX-2 plays an important role in the early stages of intestinal tumorigenesis during adenoma development[1,2,3]
Whole genome DNA sequencing of a homozygous B6 G25 chicken lysozyme (cLys)-Cox-2 mouse revealed that there were 5 possible transgene insertion sites, four of which were flanked by major satellite (MaSat) repeats in large, transcriptionally silent intergenic regions[25], and one of which was located in the centre of the first (360 kb) intron of the MAM domain containing glycosylphosphatidylinositol anchor 2 gene
We have previously reported that the presence of stromal Cox-2-positive macrophages in human colorectal adenomas is associated with an increased microvessel density (MVD) indicative of increased angiogenesis, which could account for accelerated intestinal tumorigenesis in cLys-Cox-2 x ApcMin/+ mice[11, 27]
Summary
There is incontrovertible genetic and pharmacological evidence from rodent models that the inducible isoform of prostaglandin (PG) G/H synthase (PTGS2), known as cyclooxygenase (COX), COX-2 plays an important role in the early stages of intestinal tumorigenesis during adenoma (or polyp) development[1,2,3]. These pre-clinical studies led to investigation of the chemopreventative efficacy of selective COX-2 inhibitors in randomized, placebo-controlled colorectal polyp prevention trials in humans[4]. We tested the hypothesis that increased expression of Cox-2 by macrophages promotes ApcMin/+ mouse intestinal tumorigenesis using a transgenic model of macrophage-specific Cox-2 over-expression
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