title: Targeted Cox2 gene deletion in intestinal epithelial cells decreases tumorigenesis in female, but not male, ApcMin/+ mice.
abstract: Mice heterozygous for mutations in the adenomatous polyposis coli gene (Apc(+/-) mice) develop intestinal neoplasia. Apc(+/-) tumor formation is thought to be dependent on cyclooxygenase 2 (COX2) expression; both pharmacologic COX2 inhibition and global Cox2 gene deletion reduce the number of intestinal tumors in Apc(+/-) mice. COX2 expression is reported in epithelial cells, fibroblasts, macrophages and endothelial cells of Apc(+/-) mouse polyps. However, the cell type(s) in which COX2 expression is required for Apc(+/-) tumor induction is not known. To address this question, we developed Apc(Min/+) mice in which the Cox2 gene is specifically deleted either in intestinal epithelial cells or in myeloid cells. There is no significant difference in intestinal polyp number between Apc(Min/+) mice with a targeted Cox2 gene deletion in myeloid cells and their control littermate Apc(Min/+) mice. In contrast, Apc(Min/+) mice with a targeted Cox2 deletion in intestinal epithelial cells have reduced intestinal tumorigenesis when compared to their littermate control Apc(Min/+) mice. However, two gender-specific effects are notable. First, female Apc(Min/+) mice developed more intestinal tumors than male Apc(Min/+) mice. Second, targeted intestinal epithelial cell Cox2 deletion decreased tumorigenesis in female, but not in male, Apc(Min/+) mice. Considered in the light of pharmacologic studies and studies with global Cox2 gene knockout mice, our data suggest that (i) intrinsic COX2 expression in intestinal epithelial cells plays a gender-specific role in tumor development in Apc(Min/+) mice, and (ii) COX2 expression in cell type(s) other than intestinal epithelial cells also modulates intestinal tumorigenesis in Apc(Min/+) mice, by a paracrine process.
authors.affiliation: Department of Molecular and Medical Pharmacology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Durga P
authors.initials: DP
authors.lastname: Cherukuri
authors.affiliation: Department of Molecular and Medical Pharmacology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Tomo-O
authors.initials: TO
authors.lastname: Ishikawa
authors.affiliation: Department of Molecular and Medical Pharmacology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chun
authors.affiliation: Department of Molecular and Medical Pharmacology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Art
authors.initials: A
authors.lastname: Catapang
authors.affiliation: Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.affiliation: Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Tristan R
authors.initials: TR
authors.lastname: Grogan
authors.affiliation: Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: James
authors.initials: J
authors.lastname: Bugni
authors.affiliation: Department of Molecular and Medical Pharmacology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address: hherschman@mednet.ucla.edu.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012727:Sex Characteristics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: APC; COX2; Cyclooxygenase 2; Gender-specific effect; Mouse intestinal tumors