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Cancer Prevention Research
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Research Article

High-Fat, High-Calorie Diet Promotes Early Pancreatic Neoplasia in the Conditional KrasG12D Mouse Model

David W. Dawson, Kathleen Hertzer, Aune Moro, Graham Donald, Hui-Hua Chang, Vay Liang Go, Steven J. Pandol, Aurelia Lugea, Anna S. Gukovskaya, Gang Li, Oscar J. Hines, Enrique Rozengurt and Guido Eibl
David W. Dawson
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Kathleen Hertzer
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Aune Moro
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Graham Donald
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Hui-Hua Chang
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Vay Liang Go
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Steven J. Pandol
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Aurelia Lugea
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Anna S. Gukovskaya
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Gang Li
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Oscar J. Hines
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Enrique Rozengurt
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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Guido Eibl
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
Departments of 1Pathology and Laboratory Medicine, 2Surgery, and 3Medicine, UCLA Center for Excellence in Pancreatic Diseases, David Geffen School of Medicine at UCLA; 4Department of Biostatistics, School of Public Health at UCLA; 5UCLA Jonsson Comprehensive Cancer Center; 6Department of Medicine, Veterans Affairs Greater Los Angeles Health Care System; and 7Department of Internal Medicine, Cedars Sinai Medical Center, Los Angeles, California
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DOI: 10.1158/1940-6207.CAPR-13-0065 Published October 2013
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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. Cancer Prev Res; 6(10); 1064–73. ©2013 AACR.

  • Received February 25, 2013.
  • Revision received July 31, 2013.
  • Accepted August 5, 2013.
  • ©2013 American Association for Cancer Research.
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Cancer Prevention Research: 6 (10)
October 2013
Volume 6, Issue 10
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High-Fat, High-Calorie Diet Promotes Early Pancreatic Neoplasia in the Conditional KrasG12D Mouse Model
David W. Dawson, Kathleen Hertzer, Aune Moro, Graham Donald, Hui-Hua Chang, Vay Liang Go, Steven J. Pandol, Aurelia Lugea, Anna S. Gukovskaya, Gang Li, Oscar J. Hines, Enrique Rozengurt and Guido Eibl
Cancer Prev Res October 1 2013 (6) (10) 1064-1073; DOI: 10.1158/1940-6207.CAPR-13-0065

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High-Fat, High-Calorie Diet Promotes Early Pancreatic Neoplasia in the Conditional KrasG12D Mouse Model
David W. Dawson, Kathleen Hertzer, Aune Moro, Graham Donald, Hui-Hua Chang, Vay Liang Go, Steven J. Pandol, Aurelia Lugea, Anna S. Gukovskaya, Gang Li, Oscar J. Hines, Enrique Rozengurt and Guido Eibl
Cancer Prev Res October 1 2013 (6) (10) 1064-1073; DOI: 10.1158/1940-6207.CAPR-13-0065
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