Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras

• Published in: American journal of physiology: Gastrointestinal and liver physiology 2020-02, Vol.318 (2), p.G265-G276
• Main Authors: Asahina, Kinji, Balog, Steven, Hwang, Edward, Moon, Eugene, Wan, Emily, Skrypek, Kaitlin, Chen, Yibu, Fernandez, Jay, Romo, Janet, Yang, Qihong, Lai, Keane, French, Samuel W, Tsukamoto, Hidekazu
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Alcohol Drinking - adverse effects; Animals; Calcium-binding protein; Carcinogens - toxicity; Carcinoma, Pancreatic Ductal - chemically induced; Carcinoma, Pancreatic Ductal - pathology; Cell adhesion & migration; Cell adhesion molecules; Central Nervous System Depressants - toxicity; Ceruletide - pharmacology; Cholesterol; Cytokines - metabolism; Diet, Western; Drinking behavior; Ethanol - toxicity; Hepatocytes; Hepatocytes - metabolism; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Interleukin 6; K-Ras protein; Lipopolysaccharides; Liver Neoplasms - chemically induced; Mice; Mutants; Mutation; Nicotine; Nicotine - pharmacology; Pancreas; Pancreatic Neoplasms - chemically induced; Pancreatic Neoplasms - pathology; Pancreatitis; Proto-Oncogene Proteins p21(ras) - biosynthesis; Proto-Oncogene Proteins p21(ras) - genetics; Ribonucleic acid; Risk factors; RNA; Stromal cells; Tobacco smoking; Trans-Activators - biosynthesis; Trans-Activators - genetics; Transforming growth factor-b1; Tumor necrosis factor; Tumors; Vascular cell adhesion molecule 1
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/AJPGI.00218.2019

mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, the 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 and ;LSL- mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. 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 ;LSL- mice but not in the control mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in ;LSL- mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the ;LSL- mice, but its origin remained elusive due to leakiness of in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors ( , , , , and ), stroma ( , , and c), and cytokines ( and ) and decreases expression of and in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of nephronectin, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC. Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in ;LSL- mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC.