New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant murine spontaneous and orthotopically transplanted models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF) 1—dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arflox/+ mice, calorie restriction, versus overweight- or obesity-inducing diet regimens, decreased serum IGF-1, tumoral Akt/mammalian target of rapamycin (mTOR) signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC); and increased pancreatic tumor-free survival by 50%. Serum IGF-1, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-1—deficient mice (versus wild-type mice), and rescued with IGF-1 infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a/Arf deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-1 and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.

Citation Format: Laura M. Lashinger, Lauren M. Harrison, Audrey J. Rasmussen, Craig D. Logsdon, Susan M. Fischer, Mark J. McArthur, Stephen D. Hursting. Dietary energy balance modulation of Kras- and Ink4a/Arf+/-driven pancreatic cancer: the role of insulin-like growth factor-1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-187. doi:10.1158/1538-7445.AM2013-LB-187

©2013 American Association for Cancer Research
2013