Carcinogenesis Advance Access originally published online on October 11, 2005
Carcinogenesis 2006 27(3):382-391; doi:10.1093/carcin/bgi236
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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.
Regulation of stromal cell cyclooxygenase-2 in the ApcMin/+ mouse model of intestinal tumorigenesis
Molecular Medicine Unit, University of Leeds, Leeds LS9 7TF, UK and 1 Cancer Research UK, Lincoln's Inn Fields, London WC2A 3PX, UK
* To whom correspondence should be addressed at: Molecular Medicine Unit, University of Leeds, Clinical Sciences Building, St James's University Hospital, Leeds LS9 7TF, UK. Tel: +44 113 206 5251; Fax: +44 113 242 9722; Email: M.A.Hull{at}leeds.ac.uk
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.
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