Abstract B4: Calorie restriction prevents the development of pancreatic cancer in Kras; Pdx-1Cre mice

Abstract

Abstract Pancreatic cancer progresses over many years, which offers the opportunity for early detection and prevention. Studies have identified elevated body mass index as a risk factor for pancreatic cancer. Lowering body weight by calorie restriction has long been associated with extended life expectancy and reduced tumor incidence in laboratory animals. Chronic and intermittent calorie restriction has a powerful protective effect against tumor development. This proposal addresses the hypothesis that intermittent calorie restriction will prevent the development and delay the progression of preneoplastic to neoplastic pancreatic lesions. The Kras; Pdx-1Cre mouse model provides an opportunity to study the efficacy of calorie restriction during the preinvasive state. At 8 weeks of age Kras; Pdx-1Cre mice were (1) fed ad libitum a purified diet based on the AIN93M recommendations (control), or (2) a modified AIN 93M diet in which mice were fed in one-week intervals at 50% of ad libitum intake followed by one week of feeding at 100% of ad libitum intake (intermittent group), or fed a modified AIN 93M diet at 75% of ad libitum intake. Food intake was measured daily and body weights were recorded weekly. At 44 weeks of age, mice were sacrificed and blood was obtained to measure serum insulin-like growth factor (IGF-1) and adiponectin; the pancreases were evaluated histologically for PanIn lesions and pancreatic ductal adenocarcinoma (PDA). Control mice gained more weight than restricted groups (p<0.05). Food intake was greater in the control group compared to the restricted groups; there were no differences in food intake between intermittent and chronic calorie restricted mice. The incidences of PanIn 2 and PanIn 3 lesions were significantly reduced in calorie-restricted mice (n = 15) (p< 0.001) compared to ad libitium fed mice (n = 12). Intermittent calorie restriction suppressed PanIn 2 and PanIn 3 lesions to a greater extent than chronic calorie restriction (P<0.01). Seventy-three percent of the ad libitum fed mice had Pan-In 2 and PanIn 3 lesions, whereas 27% and 40 % of the intermittent and chronic calorie restricted mice, respectively, had PanIn 2 and PanIn 3 lesions. PDA was identified in 27% of the ad libitum fed mice but not in the calorie-restricted groups. Serum IGF-1 concentrations of the intermittent (523±35.9 pg/ml) and chronic calorie restricted mice (407.8±33.1 pg/ml) were significantly less (P<0.05) than the ad libitum fed mice (590.0±33.5 pg/ml). Chronic calorie restriction reduced serum IGF-1 levels to a greater extent than intermittent restriction (P<0.05). Serum adiponectin concentrations increased significantly in intermittent (4.94 ± 0.293 ng/nl) and chronic (4.86 ± 0.297 ng/ml) calorie restricted mice compared with the ad libitum fed mice (3.52±0.422 ng/ml). In summary, this is the first study to show that chronic and intermittent calorie restriction delays the progression of pancreatic precursor lesions to PDA and that intermittent calorie restriction has a greater beneficial effect than chronic restriction. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B4.