title: Calorie restriction delays the progression of lesions to pancreatic cancer in the LSL-KrasG12D; Pdx-1/Cre mouse model of pancreatic cancer.
abstract: Since pancreatic cancer is a lethal disease, developing prevention strategies is an important goal. We determined whether calorie restriction would prevent the development and delay progression of pancreatic intraepithelial neoplasms to pancreatic ductal adenocarcinoma (PDA) in LSL-KrasG12D/+; Pdx-1/Cre mice that develop all the precursor lesions that progress to PDA. Eight-week-old LSL-KrasG12D; Pdx-1/Cre mice were assigned to three groups: (1) ad libitum (AL) fed the AIN93M diet or (2) intermittently calorie restricted (ICR) a modified AIN93M at 50% of AL intake followed by one week intervals at 100% of AL intake, or (3) chronically calorie restricted (CCR) an AIN93M diet at 75% of AL intake. AL fed mice had a greater percentage of pancreatic ducts with PanIN-2 (13.6%) than did the ICR (1.0%) and CCR groups (1.6%), P < 0.0001. Calorie restriction (ICR [0%] and CCR [0.7%]) reduced the percentage of ducts with PanIN-3 lesions compared to the AL group (7.0%), P < 0.0001. The incidence of PanIN-2 or more lesions was significantly reduced in both ICR (27%; n = 16) and CCR (40%) mice (n = 15; P < 0.001) compared to AL (70%) fed mice (n = 11). The delayed progression of lesions in ICR and CCR mice was associated with reduced proliferation measured by proliferating cell nuclear antigen staining, reduced protein expression of Glut1, increased protein expression of Sirt1, increased serum adiponectin, and decreased serum leptin. CCR resulted in decreased phosphorylated mammalian target of rapamycin and decreased serum insulin-like growth factor-1. In summary, this is the first study to show in LSL-KrasG12D; Pdx-1/Cre mice that ICR and CCR delay the progression of lesions to PDA.
authors.affiliation: Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lanza-Jacoby
authors.forename: Guang
authors.initials: G
authors.lastname: Yan
authors.forename: Glenn
authors.initials: G
authors.lastname: Radice
authors.forename: Christopher
authors.initials: C
authors.lastname: LePhong
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baliff
authors.forename: Rachael
authors.initials: R
authors.lastname: Hess
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D031204:Caloric Restriction; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D018450:Disease Progression; D005247:Feeding Behavior; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D019426:Integrases / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010179:Pancreas / Q000473:pathology; D010183:Pancreatic Ducts / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D018398:Homeodomain Proteins; D020738:Leptin; D018809:Proliferating Cell Nuclear Antigen; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D007334:Insulin-Like Growth Factor I; C045073:Cre recombinase; D019426:Integrases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Glut1; LSL-KrasG12D; Pdx-1/Cre mice; calorie restriction; intermittent calorie restriction; mammalian target of rapamycin (mTOR); pancreatic cancer