Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.
Differential Effects of Dietary Macronutrients on the Development of Oncogenic KRAS-Mediated Pancreatic Ductal Adenocarcinoma.
复制标题
作者：
胰腺导管腺癌（PDAC）是一种高致死性疾病，致癌KRAS突变在PDAC患者中普遍存在。致癌性KRAS对于PDAC的发生和发展至关重要;然而，它本身不足以驱动胰腺癌。致癌性KRAS是代谢重编程（包括葡萄糖、谷氨酰胺和脂肪酸代谢）中的重要介质，用于癌细胞存活、增殖和侵袭。致癌性KRAS和慢性高脂饮食协同促进PDAC，表明饮食摄入在PDAC的发展中起关键作用。在这里，通过用高脂肪饮食、高碳水化合物饮食、高蛋白饮食或正常饮食喂养表达内源性致癌KRASG 12 D水平的小鼠，我们已经证明了不同的饮食宏量营养素对胰腺癌易感性的影响不同，与高脂肪饮食和高碳水化合物饮食相比，高蛋白饮食可能代表胰腺癌患者所需的有利饮食选择。此外，旨在阻止炎症的大量营养素摄入管理是携带致癌KRAS的患者的有希望的预防策略。KRAS突变在胰腺导管腺癌（PDAC）患者中普遍存在，并且部分通过异常重新连接葡萄糖，氨基酸和脂质代谢来促进肿瘤生长。肥胖是胰腺癌的一个可改变的危险因素。证实了这一流行病学观察结果，携带突变KRAS的小鼠非常容易受到致肥胖高脂饮食（HFD）的挑战，从而导致具有高肥胖率的PDAC的发展。然而，其他大量营养素饮食，如富含碳水化合物的饮食，被认为是比HFD更直接的燃料糖酵解的来源，以促进癌细胞存活和增殖，对胰腺肿瘤发生的贡献仍然不清楚。在这项研究中，我们比较了高碳水化合物饮食（HCD），HFD和高蛋白饮食（HPD）在PDAC发展中的差异效应，使用小鼠模型表达内源性水平的突变KRASG 12 D，特别是在胰腺腺泡细胞。我们的研究表明，尽管与慢性HFD相比，慢性HCD的致瘤能力较低，但与正常饮食（ND）相比，KrasG 12 D/+小鼠中慢性HCD促进了腺泡-导管化生（ADM）和胰腺上皮内瘤变（PanIN）病变，并增加了炎症，纤维化和细胞增殖。相比之下，慢性HPD与ND相比未显示出显著的不良反应。此外，KrasG 12 D/+小鼠胰腺腺泡细胞环氧合酶2（考克斯-2）的消融消除了HCD诱导的不良反应，表明饮食诱导的胰腺炎症对于促进致癌KRAS介导的肿瘤形成至关重要。这些结果表明，富含不同常量营养素的饮食对胰腺肿瘤发生具有不同的影响，其中随后的炎症加剧了该过程。因此，旨在阻止炎症的大量营养素摄入的管理是携带致癌KRAS的患者的重要预防策略。
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease and oncogenic KRAS mutations are prevalent in PDAC patients. Oncogenic KRAS is critical for the initiation and development of PDAC; however, it alone is insufficient to drive pancreatic cancer. Oncogenic KRAS is an important mediator in metabolic reprogramming, including glucose, glutamine, and fatty acid metabolisms, for cancer cell survival, proliferation, and invasion. Oncogenic KRAS and chronic high-fat diet synergize to promote PDAC, suggesting that dietary intake is critically involved in PDAC development. Here, by feeding mice expressing an endogenous level of oncogenic KRASG12D with a high-fat diet, high-carbohydrate diet, high-protein diet, or normal diet, we have demonstrated that different dietary macronutrients differentially impact pancreatic cancer susceptibility, and a high-protein diet may represent the desired, favorable dietary choice compared to high-fat diet and high-carbohydrate diet for pancreatic cancer patients. In addition, management of macronutrient intake aimed at thwarting inflammation is a promising preventive strategy for patients harboring oncogenic KRAS. KRAS mutations are prevalent in patients with pancreatic ductal adenocarcinoma (PDAC) and are critical to fostering tumor growth in part by aberrantly rewiring glucose, amino acid, and lipid metabolism. Obesity is a modifiable risk factor for pancreatic cancer. Corroborating this epidemiological observation, mice harboring mutant KRAS are highly vulnerable to obesogenic high-fat diet (HFD) challenges leading to the development of PDAC with high penetrance. However, the contributions of other macronutrient diets, such as diets rich in carbohydrates that are regarded as a more direct source to fuel glycolysis for cancer cell survival and proliferation than HFD, to pancreatic tumorigenesis remain unclear. In this study, we compared the differential effects of a high-carbohydrate diet (HCD), an HFD, and a high-protein diet (HPD) in PDAC development using a mouse model expressing an endogenous level of mutant KRASG12D specifically in pancreatic acinar cells. Our study showed that although with a lower tumorigenic capacity than chronic HFD, chronic HCD promoted acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions with increased inflammation, fibrosis, and cell proliferation compared to the normal diet (ND) in KrasG12D/+ mice. By contrast, chronic HPD showed no significant adverse effects compared to the ND. Furthermore, ablation of pancreatic acinar cell cyclooxygenase 2 (Cox-2) in KrasG12D/+ mice abrogated the adverse effects induced by HCD, suggesting that diet-induced pancreatic inflammation is critical for promoting oncogenic KRAS-mediated neoplasia. These results indicate that diets rich in different macronutrients have differential effects on pancreatic tumorigenesis in which the ensuing inflammation exacerbates the process. Management of macronutrient intake aimed at thwarting inflammation is thus an important preventive strategy for patients harboring oncogenic KRAS.
登录
查看更多内容
影响因子：
2.9
作者：
Basturk O;Singh R;Kaygusuz E;Balci S;Dursun N;Culhaci N;Adsay NV
通讯作者：
Adsay NV
DOI：
10.1158/1940-6207.capr-13-0065
发表时间：
2013-10
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
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
通讯作者：
Eibl G
DOI：
10.1038/nrc3106
发表时间：
2011-10-13
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
15.9
作者：
Collins, Meredith A.;Bednar, Filip;di Magliano, Marina Pasca
通讯作者：
di Magliano, Marina Pasca
影响因子：
5.6
作者：
Muyinda IJ;Park JG;Jang EJ;Yoo BC
通讯作者：
Yoo BC