Mouse models of pancreatic cancer induced by chronic pancreatitis and smoking.

Abstract

229 Background: Chronic pancreatitis (CP) and smoking are two major risk factors for pancreatic cancer (PaCa). Here we developed mouse models of PaCa by exposing mice to CP and/or smoking. Methods: Wild type (WT) and Pdx1-Cre;LSL-Kras transgenic mice were subjected to 7-hourly cerulein injections (50µg/kg) twice a week for 3 weeks to induce CP. Another group of mice was exposed to tobacco smoke (80mg/m3) in chambers for 5days/week during 6 weeks. A third group was exposed to both treatments. Mice were then sacrificed and pancreatic tissue analyzed. Pancreatic lesions, proliferation, fibrosis, inflammation, EMT and stem cell markers were analyzed by immunohistochemistry and Western. Results: CP significantly increased the number and stage of pancreatic neoplastic (PanIN) lesions with fibrosis, stellate cell activation and inflammation in transgenic mice. These changes were significantly less in WT mice. EMT markers (decrease in E-Cadherin and increase in vimentin protein levels) were stimulated by CP in both WT and transgenic mice. Similarly, smoking stimulated PanIN lesion formation, fibrosis and inflammation in transgenic mice, but to a lesser extent than CP model. Expression of EMT and stem cell markers was greater in the smoking model compared to CP. Combination of CP and smoking induced greater stimulation of PanIN lesion formation, fibrosis and inflammation compared to either treatment alone in transgenic mice. Conclusions: The results indicate that both CP and tobacco smoke promote PaCa progression in transgenic mice. The combination of CP and smoking has greater effects than either treatment alone. EMT and stem cell markers developed in WT as well as in transgenic mice with smoking suggesting that smoking has effects independent of Kras on cell transformation.