Journal Article

Regulation of stromal cell <i>cyclooxygenase-2</i> in the <i>Apc<sup>Min/+</sup></i> mouse model of intestinal tumorigenesis

M.A. Hull, O.O. Faluyi, C.W.S. Ko, S. Holwell, D.J. Scott, R.J. Cuthbert, R. Poulsom, R. Goodlad, C. Bonifer, A.F. Markham and P.L. Coletta

in Carcinogenesis

Volume 27, issue 3, pages 382-391
Published in print March 2006 | ISSN: 0143-3334
Published online October 2005 | e-ISSN: 1460-2180 | DOI:
Regulation of stromal cell cyclooxygenase-2 in the ApcMin/+ mouse model of intestinal tumorigenesis

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Cyclooxygenase-2 (Cox-2) is expressed predominantly by stromal cells in intestinal adenomas from the ApcMin/+ mouse model of familial adenomatous polyposis. We investigated the mechanistic basis of stromal cell Cox-2 expression in ApcMin/+ mouse adenomas, as well as Cox-2 expression and activity in histologically normal (HN) ApcMin/+ mouse intestine, in order to gain further insights into regulation of Cox-2 as a potential chemoprevention target. Upregulation of Cox-2 in intestinal tumours is not an intrinsic feature of ApcMin/+ macrophages as bone marrow-derived ApcMin/+ macrophages did not exhibit an abnormality in Cox-2 expression or activity. Intestinal permeability to lactulose or mannitol was similar in ApcMin/+ mice and wild-type littermates, implying that macrophage activation by luminal antigen is unlikely to explain stromal cell Cox-2 induction. Moreover, stromal cells exhibited differential expression of Cox-2 and inducible nitric oxide synthase, suggesting ‘alternative’ (M2) rather than ‘classical’ (M1) macrophage activation. Flow cytometric sorting of isolated stromal mononuclear cells (SMNCs), on the basis of M-lysozyme and specific macrophage marker expression, demonstrated that macrophages, neutrophils and non-myelomonocytic cells all contributed to lamina propria prostaglandin (PG) E2 synthesis. However, the majority of PGE2 synthesis by macrophages was via a Cox-2-dependent pathway compared with predominant Cox-1-derived PGE2 production by non-myelomonocytic cells. SMNCs from HN ApcMin/+ intestinal mucosa exhibited similar levels of Cox-2 mRNA and protein, but produced more Cox-2-derived PGE2 than wild-type cells at 70 days of age. There was an age-dependent decline in PGE2 synthesis by ApcMin/+ SMNCs, despite tumour progression. These data suggest that other Cox-2-independent factors also control PGE2 levels during ApcMin/+ mouse intestinal tumorigenesis. Regulation of macrophage Cox-2 expression and other steps in PGE2 synthesis (e.g. PGE synthase) are valid targets for novel chemoprevention strategies that could minimize or avoid systemic COX-2 inhibition.

Keywords: BMDM, Bone marrow-derived macrophages; CRC, colorectal cancer; COX, cyclooxygenase; FAP, familial adenomatous polyposis; HN, histologically normal; Hprt, hypoxanthine-guanine phosphoribosyl transferase; IFN, interferon; Lys-EGFP-ki, M-lysozyme-enhanced green fluorescent protein knock-in mice; Nos2, nitric oxide synthase 2; PG, prostaglandin; SI, small intestine; SMNCs, stromal mononuclear cells

Journal Article.  6985 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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