Abstract
Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.
Highlights
Pancreatic cancer, of which pancreatic ductal adenocarcinoma (PDAC) represents the vast majority, is a remarkably aggressive and lethal disease with an overall 5-year survival rate of only about 8% [1]
We described for the first time genetic variants in advanced PanIN lesions that are unique to the HFCD and HFCD-induced obesity, suggesting that diet-induced genetic alterations may underlie and/or contribute to the acceleration of PDAC development by the HFCD
We have shown previously that 3-month-old mice fed the HFCD in comparison with control diet (CD)-fed animals displayed higher levels of insulin, leptin, and glucose in plasma, but there was no significant difference in plasma cholesterol and triglyceride levels between the two diet groups [20]
Summary
Pancreatic cancer, of which pancreatic ductal adenocarcinoma (PDAC) represents the vast majority, is a remarkably aggressive and lethal disease with an overall 5-year survival rate of only about 8% [1]. The incidence of this disease in the US is estimated to increase to 53,670 new cases in 2017 and it is currently the fourth leading cause of cancer mortality in both men and women [1]. Despite advances in understanding the tumor biology of pancreatic cancer development, molecularly targeted therapy has not been translated into substantially improved prognosis of this deadly disease. Novel targets and agents for chemo- and/or dietary prevention are urgently needed and will most likely arise from the identification of modifiable risk factors, and from a more detailed understanding of the molecular mechanisms stimulating the promotion and progression of PDAC
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