Delayed Progression of Pancreatic Intraepithelial Neoplasia in a Conditional KrasG12D Mouse Model by a Selective Cyclooxygenase-2 Inhibitor

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 Kras G12D mouse model. Offspring of LSL-KRAS G12D 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 KRAS G12D ; 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 nimesulidefed 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 E 2 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]

Inhibition of Tumor-Derived Prostaglandin-E2 Blocks the Induction of Myeloid-Derived Suppressor Cells and Recovers Natural Killer Cell Activity

“…Even though tumor-derived PGE2 was not evaluated in that study, a number of reports have demonstrated the overexpression of COX-2 or PGE2, and their tumor-promoting roles in spontaneous pancreatic cancer model (44), or human pancreatic cancer tissues (45,46). Thus, it is likely that GM-CSF, PGE2, as well as other tumor-derived inflammatory mediators, collaborate in promoting the induction of MDSCs in cancers.…”

An NF-κB pathway–mediated positive feedback loop amplifies Ras activity to pathological levels in mice

“…Taken together, these data support that activation of NF-κB and its target gene Cox-2 mediate amplification of Ras signaling when oncogenic Ras is present (Figure 8). Further support for a role for Cox-2 in Ras-mediated pathologies comes from previous studies that indicated high levels of Cox-2 expression in human PanIN lesions (39) and reported that Cox-2 inhibitors reduced the development of pancreatic cancer in oncogenic Ras-based mouse models (40). The current study indicates that targeting NF-κB and Cox-2 pathways would be likely to reduce Ras activity in cells that bear this mutation and therefore may be clinically useful to prevent oncogenic Ras-induced diseases.…”

PGE2 regulates pancreatic stellate cell activity via the EP4 receptor

“…Previous studies have shown that inhibiting the COX-2 pathway suppresses the development of many cancers including pancreatic cancer (32). Also, COX-2 gene expression and its primary metabolite prostaglandin E2 (PGE 2 ) were highly expressed in 90% of pancreatic tumors (7).…”