Diet-induced obesity promotes pancreatic tumor growth in mice. Free

A69

With 64% of the U.S. population being either overweight (BMI > 25 kg/m²) or obese (BMI >30 kg/m²) and epidemiological research suggesting that obesity is associated with an elevated risk of pancreatic cancer, the obesity epidemic represents a significant threat to public health and a target for cancer prevention. The purpose of this study was to determine if body weight/ adiposity alters the growth of pancreatic tumors in mice. The murine pancreatic tumor cell line, Panc02, shares many characteristics with human pancreatic tumors: 1) a ductal adenocarcinoma histology, 2) low cell surface MHC expression (<15%), a phenotype often associated with escape from immune recognition, and 3) production of the immunosuppressive cytokine, TGF-β, and the angiogenic factor, VEGF. To develop cohorts of mice with lean, overweight, and obese phenotypes prior to tumor injection, C57BL/6 mice were placed on one of three diets (N=8/group): 1) 30% calorie restriction, 2) 10 kcal% fat diet fed ad libitum, and 3) 60 kcal% fat diet fed ad libitum. Panc02 tumor cells were implanted subcutaneously in lean, overweight, and obese mice when body weights were 20.4 + 0.4 , 29.6 + 0.8, 53.2 + 2.3 grams, respectively. At week 7, tumor growth was significantly lower in lean versus overweight and obese mice with mean tumor volumes of 0.43 cm³, 1.17 cm³, 0.96 cm³, respectively (p<0.05). Survival was significantly greater in lean compared to overweight and obese mice (p<0.0001). Our laboratory has observed that diet-induced obesity is associated with impairments in innate and adaptive immune function in tumor-free mice. We sought to evaluate immune responses in tumor-bearing mice from each dietary group as a potential mechanism to explain our observations. Using 6-color flow cytometry, we characterized splenic and inguinal lymph node leukocytes from mice in each group. Splenomegaly with advancing tumor burden was observed in overweight and obese, but not lean mice. Obesity was associated with decreases in the percentage of T cells (CD3+ and CD3+/CD8+) and increases in the percentage of B cells (CD19+) and regulatory T cells (CD4+/CD25+/FoxP3+). These data suggest that adiposity promotes the growth of subcutaneously implanted pancreatic tumors in mice. Future research will evaluate whether diet-induced obesity alters innate and adaptive anti-tumor immune effector function in response to antigen-directed cancer vaccines.