Paracrine cyclooxygenase-2 activity by macrophages drives colorectal adenoma progression in the Apc Min/+ mouse model of intestinal tumorigenesis

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 Apc Min/+ 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 Apc Min/+ mice was associated with significantly increased tumour size (P = 0.025) and multiplicity (P = 0.025), compared with control Apc Min/+ 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 Apc Min/+ 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.

Inhibition of Wound TGF Beta-1 by Celecoxib: A Possible Therapeutic Route for Scar Free Wound

“…The colocalization finding indicates that COX-2 produced by the infiltrating inflammatory cells at the wound site could induce TGF Beta-1 synthesis and production by the same cells through autocrine mechanism or the nearby cells through a paracrine mechanism or both. Paracrine/autocrine signalling between COX-2 and TGF Betahas been extensively studied in several in vitro models [71] and this COX-2 and TGF Beta-1 interregulation was shown in fibroblast [72], in macrophages and intestinal epithelial lining [73,74], in bronchial epithelium [75] in lung fibroblasts [76] and in keratinocytes [77]. Paracrine/autocrine regulation between COX-2 and TGF Beta and other growth factor has been a hot area of research in oncology as this inter-regulation was proposed to play a critical role in cancer invasion and metastasis [74][75][76][77][78].…”

Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

“…PGE 2 signalling has a direct trophic function in mouse models of colon cancer, for example, through activation of β-catenin [128]. Macrophage-derived PGE 2 also increases COX-2 expression in neoplastic cells, creating a positive feedback cycle, which greatly increases the local level of PGE 2 in the colon, driving tumourigenesis [208].…”

“…Secreted by neoplastic cells and macrophages in the colon [205][206][207][208]. Directly promotes PNC proliferation [7].…”

Microbial Sensing by Intestinal Myeloid Cells Controls Carcinogenesis and Epithelial Differentiation

“…It has been recognized for some time that macrophages are a principal source for increased COX-2 expression in intestinal adenomas ( Hull et al, 1999 ). Moreover, the same group previously showed that overexpression of COX-2 in the myeloid compartment (using the same Lys2 Cre driver utilized here) can lead to increased intestinal tumorigenesis ( Hull et al, 2017 ). However, in other studies, conditional Ptgs2 gene deletion only resulted in reduced intestinal polyp burden when the epithelial compartment was targeted in female mice, with no effects seen in males or after myeloid cell deletion of the gene ( Cherukuri et al, 2014 ).…”