High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model.
High-fat, high-calorie diet promotes early pancreatic neoplasia in the conditional KrasG12D mouse model.
复制标题
DOI：
10.1158/1940-6207.capr-13-0065
复制
发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Eibl G
中科院分区：
文献类型：
--
作者：
Dawson DW;Hertzer K;Moro A;Donald G;Chang HH;Go VL;Pandol SJ;Lugea A;Gukovskaya AS;Li G;Hines OJ;Rozengurt E;Eibl G
有流行病学证据表明，肥胖会增加患癌症的风险。一些潜在的机制，包括炎症和胰岛素抵抗，被提出。然而，胰腺癌的驱动机制尚不清楚。本研究的目标是在最先进的小鼠模型中建立饮食引起的肥胖和胰腺癌发展的模型，该模型类似于人类肥胖的重要临床特征，例如体重增加和代谢紊乱。Pdx-1-Cre和LSL-KrasG12D小鼠的后代被分配到高脂肪和高热量饮食（HFCD, ~4,535 kcal/kg， 40%的热量来自脂肪）或控制饮食（CD, ~3,725 kcal/kg， 12%的热量来自脂肪）3个月。与对照动物相比，喂食HFCD的小鼠体重明显增加，并出现高胰岛素血症、高血糖症、高瘦素血症和IGF-1水平升高。hfcd喂养动物的胰腺显示出明显的炎症迹象，浸润性炎症细胞（巨噬细胞和t细胞）数量增加，几种细胞因子和趋化因子水平升高，间质纤维化增加，PanIN病变更晚期。我们的研究结果表明，在条件KrasG12D小鼠模型中，高脂肪和高热量的饮食会导致与人类相似的肥胖和代谢紊乱，并加速早期胰腺肿瘤的形成。该模型和研究结果将为更有力的研究提供基础，这些研究试图揭示肥胖促癌特性的潜在机制，并评估针对肥胖相关胰腺癌发展的饮食和化学预防策略。
There is epidemiologic evidence that obesity increases the risk of cancers. Several underlying mechanisms, including inflammation and insulin resistance, are proposed. However, the driving mechanisms in pancreatic cancer are poorly understood. The goal of the present study was to develop 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 and LSL-KrasG12D mice 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 3 months. Compared to control animals, mice fed the HFCD significantly gained more weight and developed hyperinsulinemia, hyperglycemia, hyperleptinemia, and elevated levels of IGF-1. The pancreas of HFCD-fed animals showed robust signs of inflammation with increased numbers of infiltrating inflammatory cells (macrophages and T-cells), elevated levels of several cytokines and chemokines, increased stromal fibrosis, and more advanced PanIN lesions. Our 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. This model and findings will provide the basis for more robust studies attempting to unravel the mechanisms underlying the cancer-promoting properties of obesity as well as to evaluate dietary- and chemo-preventive strategies targeting obesity-associated pancreatic cancer development.