Abstract IA18: Obesity, inflammation, and pancreatic cancer

There is epidemiologic evidence that obesity increases the risk of cancers including pancreatic cancer. Several underlying mechanisms, e.g. inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. We developed 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, e.g. weight gain and metabolic disturbances. Offspring of Pdx-1-Cre (or p48-cre) and LSL-KrasG12D crosses were allocated to either a diet high in fats and calories (HFCD; ~4,535 kcal/kg; 40% of calories from fats) or control diet (CD; ~3,725 kcal/kg; 12% of calories from fats) for various time periods. Compared to control animals, mice fed the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of IGF-1. Mice fed the HFCD had a substantial increase in visceral fat as measured by micro-CT. The white visceral adipose tissue in mice fed the HFCD showed signs of marked inflammation, which was more pronounced in the peri-pancreatic fat depot. In addition, the pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells. Detailed flow cytometry analysis showed a marked elevation of infiltrating natural killer cells, myeloid-derived suppressor cells, T-regulatory cells, and tumor-infiltrating macrophages into the pancreas of mice fed the HFCD. Multiplex analysis demonstrated a significant change in the pancreatic cytokine profile in HFCD-fed mice compared to CD-fed animals. Importantly, the HFCD led to an acceleration of PanIN development in conditional KrasG12D mice. These results demonstrate 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. Based on the notion that obesity is associated with an increase in inflammatory mediators and insulin-resistance and our previous finding that non-steroidal anti-inflammatory drugs inhibit the progression of PanIN lesions in the conditional KrasG12D mouse model, we investigated a potential crosstalk between the PGE2/EP/cAMP and IGF-1/Akt/mTORC1 signaling pathways in pancreatic cancer. In multiple cell lines PGE2 increased intracellular cAMP levels, indicating the activation of Gsα-coupled EP receptors (EP2 and/or EP4). PGE2 dose- and time-dependently increased the phosphorylation of S6 ribosomal protein downstream of mTORC1, suggesting a crosstalk between PGE2/cAMP and mTORC1. In addition, the effect of PGE2 on phospho-S6rp was mimicked by Forskolin, a pharmacological cAMP stimulator. Importantly, PGE2 enhanced the effect of IGF-1 on S6rp phosphorylation, supporting the existence of a positive reinforcement. Interestingly, PGE2 and forskolin had no effect on Akt phosphorylation, suggesting a link downstream of Akt. In the presence of the PKA inhibitor H89, baseline phosphorylation of S6rp and PGE2-activated S6rp phosphorylation were reduced, indicating a role of PKA in the crosstalk. In summary, these data provide evidence of a crosstalk between the PGE2/EP/cAMP and IGF-1/Akt/mTORC1 signaling pathways. Since both pathways are over-activated in obesity-associated cancers, this interaction may be of great importance in elucidating the tumor-promoting effects of obesity in pancreatic cancer. Citation Format: Guido Eibl. Obesity, inflammation, and pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA18.