title: Regulation of stromal cell cyclooxygenase-2 in the ApcMin/+ mouse model of intestinal tumorigenesis.
abstract: Cyclooxygenase-2 (Cox-2) is expressed predominantly by stromal cells in intestinal adenomas from the Apc(Min/+) mouse model of familial adenomatous polyposis. We investigated the mechanistic basis of stromal cell Cox-2 expression in Apc(Min/+) mouse adenomas, as well as Cox-2 expression and activity in histologically normal (HN) Apc(Min/+) 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 Apc(Min/+) macrophages as bone marrow-derived Apc(Min/+) macrophages did not exhibit an abnormality in Cox-2 expression or activity. Intestinal permeability to lactulose or mannitol was similar in Apc(Min/+) 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) E(2) synthesis. However, the majority of PGE(2) synthesis by macrophages was via a Cox-2-dependent pathway compared with predominant Cox-1-derived PGE(2) production by non-myelomonocytic cells. SMNCs from HN Apc(Min/+) intestinal mucosa exhibited similar levels of Cox-2 mRNA and protein, but produced more Cox-2-derived PGE(2) than wild-type cells at 70 days of age. There was an age-dependent decline in PGE(2) synthesis by Apc(Min/+) SMNCs, despite tumour progression. These data suggest that other Cox-2-independent factors also control PGE(2) levels during Apc(Min/+) mouse intestinal tumorigenesis. Regulation of macrophage Cox-2 expression and other steps in PGE(2) synthesis (e.g. PGE synthase) are valid targets for novel chemoprevention strategies that could minimize or avoid systemic COX-2 inhibition.
authors.affiliation: Molecular Medicine Unit, University of Leeds, Leeds LS9 7TF, UK. M.A.Hull@leeds.ac.uk
authors.forename: M A
authors.initials: MA
authors.lastname: Hull
authors.forename: O O
authors.initials: OO
authors.lastname: Faluyi
authors.forename: C W S
authors.initials: CW
authors.lastname: Ko
authors.forename: S
authors.initials: S
authors.lastname: Holwell
authors.forename: D J
authors.initials: DJ
authors.lastname: Scott
authors.forename: R J
authors.initials: RJ
authors.lastname: Cuthbert
authors.forename: R
authors.initials: R
authors.lastname: Poulsom
authors.forename: R
authors.initials: R
authors.lastname: Goodlad
authors.forename: C
authors.initials: C
authors.lastname: Bonifer
authors.forename: A F
authors.initials: AF
authors.lastname: Markham
authors.forename: P L
authors.initials: PL
authors.lastname: Coletta
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000503:physiopathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000503:physiopathology; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D017154:Stromal Cells / Q000201:enzymology
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051546:Cyclooxygenase 2; D015232:Dinoprostone