title: A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice.
abstract: OBJECTIVE
  Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but it is not clear how obesity contributes to pancreatic carcinogenesis. The oncogenic form of KRAS is expressed during early stages of PDAC development and is detected in almost all of these tumors. However, there is evidence that mutant KRAS requires an additional stimulus to activate its full oncogenic activity and that this stimulus involves the inflammatory response. We investigated whether the inflammation induced by a high-fat diet, and the accompanying up-regulation of cyclooxygenase-2 (COX2), increases Kras activity during pancreatic carcinogenesis in mice.
  
  
  METHODS
  We studied mice with acinar cell-specific expression of KrasG12D (LSL-Kras/Ela-CreERT mice) alone or crossed with COX2 conditional knockout mice (COXKO/LSL-Kras/Ela-CreERT). We also studied LSL-Kras/PDX1-Cre mice. All mice were fed isocaloric diets with different amounts of fat, and a COX2 inhibitor was administered to some LSL-Kras/Ela-CreERT mice. Pancreata were collected from mice and analyzed for Kras activity, levels of phosphorylated extracellular-regulated kinase, inflammation, fibrosis, pancreatic intraepithelial neoplasia (PanIN), and PDACs.
  
  
  RESULTS
  Pancreatic tissues from LSL-Kras/Ela-CreERT mice fed high-fat diets (HFDs) had increased Kras activity, fibrotic stroma, and numbers of PanINs and PDACs than LSL-Kras/Ela-CreERT mice fed control diets; the mice fed the HFDs also had shorter survival times than mice fed control diets. Administration of a COX2 inhibitor to LSL-Kras/Ela-CreERT mice prevented these effects of HFDs. We also observed a significant reduction in survival times of mice fed HFDs. COXKO/LSL-Kras/Ela-CreERT mice fed HFDs had no evidence for increased numbers of PanIN lesions, inflammation, or fibrosis, as opposed to the increases observed in LSL-Kras/Ela-CreERT mice fed HFDs.
  
  
  CONCLUSIONS
  In mice, an HFD can activate oncogenic Kras via COX2, leading to pancreatic inflammation and fibrosis and development of PanINs and PDAC. This mechanism might be involved in the association between risk for PDAC and HFDs.
authors: Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas.
authors: Bincy
authors: B
authors: Philip
authors: Christina L
authors: CL
authors: Roland
authors: Jaroslaw
authors: J
authors: Daniluk
authors: Yan
authors: Y
authors: Liu
authors: Deyali
authors: D
authors: Chatterjee
authors: Sobeyda B
authors: SB
authors: Gomez
authors: Baoan
authors: B
authors: Ji
authors: Haojie
authors: H
authors: Huang
authors: Huamin
authors: H
authors: Wang
authors: Jason B
authors: JB
authors: Fleming
authors: Craig D
authors: CD
authors: Logsdon
authors: Zobeida
authors: Z
authors: Cruz-Monserrate
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000503:physiopathology*; D050154:Adiposity / Q000502:physiology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D005355:Fibrosis; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*
chemical_list: D051546:Cyclooxygenase 2; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BAC; BW; CD; COX; ERK; Ela; GTP; HFD; IHC; KO; Oncogene; PBS; PDAC; PSC; PanIN; Pancreatic Cancer; Pdx; Prostaglandin; Signal Transduction; bacterial-artificial-chromosome; body weight; control diet; cyclooxygenase; elastase; extracellular signal-regulated kinase; guanosine triphosphate; high-fat diet; immunohistochemistry; knockout; pancreatic and duodenal homeobox 1; pancreatic ductal adenocarcinoma; pancreatic intraepithelial neoplasia; pancreatic stellate cell; phosphate-buffered saline; α-SMA; α-smooth muscle actin
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