title: Dietary energy balance modulation of Kras- and Ink4a/Arf+/--driven pancreatic cancer: the role of insulin-like growth factor-I.
abstract: New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-I-dependent mechanism. In LSL-Kras(G12D)/Pdx-1-Cre/Ink4a/Arf(lox/+) mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I-deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.
authors: Department of Nutritional Sciences, Dell Pediatric Research Institute, University of Texas at Austin, 1400 Barbara Jordan Blvd. Mail Code R1800, Austin, TX 78723. shursting@austin.utexas.edu.
authors: Laura M
authors: LM
authors: Lashinger
authors: Lauren M
authors: LM
authors: Harrison
authors: Audrey J
authors: AJ
authors: Rasmussen
authors: Craig D
authors: CD
authors: Logsdon
authors: Susan M
authors: SM
authors: Fischer
authors: Mark J
authors: MJ
authors: McArthur
authors: Stephen D
authors: SD
authors: Hursting
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D031204:Caloric Restriction; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D004734:Energy Metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009368:Neoplasm Transplantation; D009765:Obesity / Q000150:complications; D010190:Pancreatic Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C583557:IGF1 protein, human; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
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