title: Characterization of Mouse Models of Early Pancreatic Lesions Induced by Alcohol and Chronic Pancreatitis.
abstract: OBJECTIVE
  We describe the first mouse model of pancreatic intraepithelial neoplasia (PanIN) lesions induced by alcohol in the presence and absence of chronic pancreatitis.
  
  
  METHODS
  Pdx1-Cre;LSL-K-ras mice were exposed to Lieber-DeCarli alcohol diet for 6 weeks with cerulein injections. The PanIN lesions and markers of fibrosis, inflammation, histone deacetylation, epithelial-to-mesenchymal transition (EMT), and cancer stemness were measured by immunohistochemistry and Western.
  
  
  RESULTS
  Exposure of Pdx1-Cre;LSL-K-ras mice to an alcohol diet significantly stimulated fibrosis and slightly but not significantly increased the level of PanIN lesions associated with an increase in tumor-promoting M2 macrophages. Importantly, the alcohol diet did not increase activation of stellate cells. Alcohol diet and cerulein injections resulted in synergistic and additive effects on PanIN lesion and M2 macrophage phenotype induction, respectively. Cerulein pancreatitis caused stellate cell activation, EMT, and cancer stemness in the pancreas. Pancreatitis caused histone deacetylation, which was promoted by the alcohol diet. Pancreatitis increased EMT and cancer stemness markers, which were not further affected by the alcohol diet.
  
  
  CONCLUSIONS
  The results suggest that alcohol has independent effects on promotion of PDAC associated with fibrosis formed through a stellate cell-independent mechanism and that it further promotes early PDAC and M2 macrophage induction in the context of chronic pancreatitis.
authors.affiliation: From the *Veterans Affairs Greater Los Angeles Healthcare System, University of California at Los Angeles, Los Angeles, CA; †Department of Gastroenterology, Nanlou Division, The PLA General Hospital, Beijing, China; ‡Departments of Medicine and Biological Sciences, Cedars-Sinai Medical Center, Los Angeles, CA; §Faculty of Sciences Dhar el Mehraz, University Mohamed Ben Abdellah, Fez, Morocco; ∥Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University; ¶Department of Medicine, University of Illinois-Chicago, Chicago, IL; and #Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine University of Southern California, Los Angeles, CA.
authors.forename: Shiping
authors.initials: S
authors.lastname: Xu
authors.forename: Chintan
authors.initials: C
authors.lastname: Chheda
authors.forename: Yassine
authors.initials: Y
authors.lastname: Ouhaddi
authors.forename: Hajar
authors.initials: H
authors.lastname: Benhaddou
authors.forename: Mouloud
authors.initials: M
authors.lastname: Bourhim
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Grippo
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Principe
authors.forename: Emman
authors.initials: E
authors.lastname: Mascariñas
authors.forename: Brian
authors.initials: B
authors.lastname: DeCant
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.forename: Mouad
authors.initials: M
authors.lastname: Edderkaoui
mesh_terms: D000107:Acetylation; D000208:Acute Disease; D000818:Animals; D002278:Carcinoma in Situ / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002108:Ceruletide; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D000431:Ethanol; D005355:Fibrosis; D006657:Histones / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019512:Pancreatitis, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
chemical_list: D006657:Histones; D000431:Ethanol; D002108:Ceruletide