Abstract 592: Dietary energy balance impacts spontaneous development of pancreatic ductal adenocarcinoma in the KrasG12D/INK4A transgenic model of pancreatic cancer

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. Obesity, which has increased dramatically over the past 40 years, has emerged as an important risk factor for pancreatic cancer, although the mechanisms underlying the obesity-pancreatic cancer association have not been fully identified. We have reported that calorie restriction (CR), a dietary strategy for preventing or reversing obesity, has significant anticancer effects in several mouse models of pancreatic and other cancers, including a model of pancreatitis-induced pancreatic dysplasia. However, it is unknown if energy balance modulation, including CR and diet-induced obesity (DIO) exerts anticancer effects in a transgenic mouse model of invasive pancreatic ductal adenocarcinoma induced by the most common genetic alterations associated with human pancreatic cancers (KrasG12D/INK4A). We hypothesized that KrasG12D/INK4A mice administered CR diet would develop fewer invasive tumors than mice on a control diet, while a DIO diet would enhance invasive tumors development. To test this, we placed 30 4-6 week old male KrasG12D/INK4A transgenic mice on one of three diets for 10 weeks (n=10 mice/group): CR diet (70% of weekly control intake; fed in daily aliquots), control diet (AIN-76A diet, fed ad libitum), or a DIO regimen (modified AIN-76A diet with 60kcal % fat; fed ad libitum). Mice were palpated daily and body composition was assessed by magnetic resonance imaging at week 8 to ensure effectiveness of diet regimens. Levels of energy balance-sensitive hormones were assayed using serum collected at study termination. CR mice had a significantly lower percent body fat (12.29% ± 0.03%; p<0.0001) and DIO mice had a significantly higher percent body fat (30.14% ± 0.07%; p<0.0001) than control mice (22.27% ± 0.06%). Circulating levels of insulin, leptin and IGF-1, were significantly lower in CR mice (p<0.05) and significantly higher in DIO mice (p<0.05) relative to control mice. Pancreatic tumor incidence was reduced in CR mice (2/10) and increased in DIO mice (7/10) as compared to control mice (5/10). Consistent with this trend, whole pancreas from CR mice weighed (0.22g ± 0.05g; p=0.03) significantly less on average than control mice (0.31g ± 0.11g), and pancreas from DIO mice weighed significantly more (0.54g ± 0.27g; p=0.001). Presence of liver macrometastases was also enhanced with the higher calorie diets (CR=1, control=3, and DIO=4). Using a mouse model of pancreatic cancer that closely mimics human histological disease progression, our findings indicate that dietary energy balance modulation can alter the development of pancreatic cancer. This could have direct implications for the prevention and control of pancreatic tumors due to obesity and obesity-related conditions such as diabetes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 592. doi:1538-7445.AM2012-592