Dietary energy balance modulation of Kras- and Ink4a/Arf+/--driven pancreatic cancer: the role of insulin-like growth factor-I.
Dietary energy balance modulation of Kras- and Ink4a/Arf+/--driven pancreatic cancer: the role of insulin-like growth factor-I.
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饮食能量平衡的调节kras和ink4a/arf+/ - 驱动胰腺癌：胰岛素样生长因子I的作用。
DOI：
10.1158/1940-6207.capr-13-0185
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Hursting SD
中科院分区：
文献类型：
--
作者：
Lashinger LM;Harrison LM;Rasmussen AJ;Logsdon CD;Fischer SM;McArthur MJ;Hursting SD
迫切需要新的分子靶点和干预策略来打破肥胖与胰腺癌的联系。使用相关的自发和原位移植的胰腺癌小鼠模型，我们测试了饮食能量平衡调节通过胰岛素样生长因子（IGF）-1依赖性机制影响胰腺癌发生和进展的假设。在LSL-KrasG 12 D/Pdx-1-Cre/Ink 4a/Arflox/+小鼠中，与超重或肥胖诱导饮食方案相比，热量限制降低了血清IGF-1、肿瘤Akt/哺乳动物雷帕霉素靶蛋白（mTOR）信号传导、胰腺结缔组织增生和胰腺导管腺癌（PDAC）进展;并增加了胰腺无肿瘤生存期。血清IGF-1，Akt/mTOR信号传导，原位移植PDAC生长在肝脏特异性IGF-1缺陷小鼠（与野生型小鼠相比），并与IGF-1输注挽救。因此，膳食能量平衡调节影响由突变型Kras和Ink 4a缺乏诱导的自发性胰腺肿瘤发生，这是人类胰腺癌中最常见的遗传改变。此外，IGF-1及其下游信号通路的组成部分是打破肥胖-胰腺癌联系的有希望的机制靶点。
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)-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. 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 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.