Moderate Alcohol Intake Promotes Pancreatic Ductal Adenocarcinoma Development in Mice Expressing Oncogenic Kras.

Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1 Cre and Pdx1 Cre ;LSL- Kras G12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 months. In addition, mice were treated with cerulein, for induction of pancreatitis, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the Pdx1 Cre ;LSL- Kras G12D mice, but not in the control Pdx1 Cre mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in Pdx1 Cre ;LSL- Kras G12D mice compared to mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the Pdx1 Cre ;LSL- Kras G12D mice, but its origin remained elusive due to leakiness of Pdx1 Cre in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors ( Epcam , Krt19 , Prom1 , Wt1 , Wwtr1 ), stroma ( Dcn , Fn1 , Tn c), and cytokines ( Tgfb1 , Tnf ) and decreases expression of Fgf21 and Il6 in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of NPNT, S100A6, and VCAM1 in pancreatic tumors surrounded by PDPN+ stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC.