A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice

Gastroenterology. 2013 Dec;145(6):1449-58. doi: 10.1053/j.gastro.2013.08.018. Epub 2013 Aug 16.


Background & aims: 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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Adenocarcinoma / physiopathology*
  • Adiposity / physiology
  • Animals
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / physiopathology*
  • Cyclooxygenase 2 / deficiency
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / physiology*
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Fibrosis
  • Gene Expression Regulation, Neoplastic / physiology
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Pancreas / pathology
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / physiopathology*
  • Proto-Oncogene Proteins p21(ras) / physiology*


  • Cyclooxygenase 2
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)