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High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model.
- Source :
-
Cancer prevention research (Philadelphia, Pa.) [Cancer Prev Res (Phila)] 2013 Oct; Vol. 6 (10), pp. 1064-73. Date of Electronic Publication: 2013 Aug 13. - Publication Year :
- 2013
-
Abstract
- There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. The goal of the present study was to develop a model of diet-induced obesity and pancreatic cancer development in a state-of-the-art mouse model, which resembles important clinical features of human obesity, for example, weight gain and metabolic disturbances. Offspring of Pdx-1-Cre and LSL-KrasG12D mice were allocated to either a high-fat, high-calorie diet (HFCD; ∼4,535 kcal/kg; 40% of calories from fats) or control diet (∼3,725 kcal/kg; 12% of calories from fats) for 3 months. Compared with control animals, mice fed with the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of insulin-like growth factor I (IGF-I). The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our results show that a diet high in fats and calories leads to obesity and metabolic disturbances similar to humans and accelerates early pancreatic neoplasia in the conditional KrasG12D mouse model. This model and findings will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity, as well as to evaluate dietary- and chemopreventive strategies targeting obesity-associated pancreatic cancer development.
- Subjects :
- Actins metabolism
Animals
Body Weight
Carcinoma, Pancreatic Ductal metabolism
Chemokines metabolism
Cytokines metabolism
Disease Models, Animal
Energy Intake
Female
Fibronectins metabolism
Genotype
Immunohistochemistry
Inflammation
Insulin Resistance
Male
Mice
Mice, Inbred C57BL
Obesity metabolism
Pancreatic Neoplasms metabolism
Carcinoma, Pancreatic Ductal genetics
Diet, High-Fat adverse effects
Genes, ras
Pancreatic Neoplasms genetics
ras Proteins genetics
ras Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1940-6215
- Volume :
- 6
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer prevention research (Philadelphia, Pa.)
- Publication Type :
- Academic Journal
- Accession number :
- 23943783
- Full Text :
- https://doi.org/10.1158/1940-6207.CAPR-13-0065