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Mol Oncol. 2014 Mar;8(2):169-77. doi: 10.1016/j.molonc.2013.10.009. Epub 2013 Nov 8.

Targeted Cox2 gene deletion in intestinal epithelial cells decreases tumorigenesis in female, but not male, ApcMin/+ mice.

Author information

  • 1Department of Molecular and Medical Pharmacology and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 2Department of Medicine Statistics Core, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 3Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
  • 4Department 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.

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.

Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

APC; COX2; Cyclooxygenase 2; Gender-specific effect; Mouse intestinal tumors

PMID:
24268915
[PubMed - indexed for MEDLINE]
PMCID:
PMC3963510
Free PMC Article
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