Delayed Progression of Pancreatic Intraepithelial Neoplasia in a Conditional KrasG12D Mouse Model by a Selective Cyclooxygenase-2 Inhibitor
Open Access
- 1 August 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 67 (15), 7068-7071
- https://doi.org/10.1158/0008-5472.can-07-0970
Abstract
Pancreatic ductal adenocarcinomas are thought to arise from noninvasive, intraductal precursor lesions called pancreatic intraepithelial neoplasias (PanIN). The study of PanINs holds great promise for the identification of early detection markers and effective cancer-preventing strategies. Cyclooxygenase-2 (COX-2) represents an intriguing target for therapeutic and preventive approaches in various human malignancies. The aim of the present study was to evaluate the efficacy of a selective COX-2 inhibitor to prevent the progression of PanINs in a conditional KrasG12D mouse model. Offspring of LSL-KRASG12D x PDX-1-Cre intercrosses were randomly allocated to a diet supplemented with the selective COX-2 inhibitor nimesulide (400 ppm) or a control diet. After 10 months, animals were sacrificed. Successful recombination in the pancreas was evaluated by PCR. The pancreas of KRASG12D;PDX-1-Cre mice was analyzed for the presence of murine PanINs. Animals fed the COX-2 inhibitor had significantly fewer PanIN-2 and PanIN-3 lesions than control animals (P < 0.05). Ten percent of all pancreatic ducts in the nimesulide-fed animals showed PanIN-2 or PanIN-3 lesions, whereas 40% of the pancreatic ducts in the control animals had PanIN-2 or PanIN-3 lesions. Intrapancreatic prostaglandin E2 levels were reduced in nimesulide-fed animals. Immunohistochemistry confirmed COX-2 expression in early and late PanINs. In summary, we found that the selective COX-2 inhibitor nimesulide delays the progression of pancreatic cancer precursor lesions in a preclinical animal model. These data highlight the importance of COX-2 in the development of pancreatic cancer. Inhibition of COX-2 may represent an intriguing strategy to prevent pancreatic cancer in high-risk patients. [Cancer Res 2007;67(15):7068–71]Keywords
This publication has 15 references indexed in Scilit:
- Pancreatic cancer: a review of recent advancesExpert Opinion on Investigational Drugs, 2006
- Chemoprevention of Familial Adenomatous Polyposis by Low Doses of Atorvastatin and Celecoxib Given Individually and in Combination to APCMin MiceCancer Research, 2006
- Chemoprevention of spontaneous development of hepatocellular carcinomas in fatty liver Shionogi mice by a cyclooxygenase‐2 inhibitorCancer Science, 2006
- Preinvasive Duct-Derived Neoplasms in Pancreas of Keratin 5–Promoter Cyclooxygenase-2 Transgenic MiceGastroenterology, 2006
- Pathology of Genetically Engineered Mouse Models of Pancreatic Exocrine Cancer: Consensus Report and RecommendationsCancer Research, 2006
- Pancreatic Cancer in Mice and Man: The Penn Workshop 2004Cancer Research, 2006
- Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in miceCancer Cell, 2005
- Regression of Mouse Prostatic Intraepithelial Neoplasia by Nonsteroidal Anti-inflammatory Drugs in the Transgenic Adenocarcinoma Mouse Prostate ModelClinical Cancer Research, 2004
- Combined effects of cyclooxygenase‐1 and cyclooxygenase‐2 selective inhibitors on intestinal tumorigenesis in adenomatous polyposis coli gene knockout miceInternational Journal of Cancer, 2004
- Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinomaGenes & Development, 2003