TY - JOUR
T1 - Dietary energy balance modulation of Kras- and Ink4a/Arf +/--driven pancreatic cancer
T2 - The role of insulin-like growth factor-I
AU - Lashinger, Laura M.
AU - Harrison, Lauren M.
AU - Rasmussen, Audrey J.
AU - Logsdon, Craig D.
AU - Fischer, Susan M.
AU - McArthur, Mark J.
AU - Hursting, Stephen D.
PY - 2013/10
Y1 - 2013/10
N2 - New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine 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)-I-dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arf lox/+ mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I-deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.
AB - New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine 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)-I-dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arf lox/+ mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I-deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.
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U2 - 10.1158/1940-6207.CAPR-13-0185
DO - 10.1158/1940-6207.CAPR-13-0185
M3 - Article
C2 - 23980075
AN - SCOPUS:84887949665
SN - 1940-6207
VL - 6
SP - 1046
EP - 1055
JO - Cancer Prevention Research
JF - Cancer Prevention Research
IS - 10
ER -