Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice.
Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice.
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DOI：
10.1371/journal.pone.0184455
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Eibl G
中科院分区：
文献类型：
--
作者：
Chang HH;Moro A;Takakura K;Su HY;Mo A;Nakanishi M;Waldron RT;French SW;Dawson DW;Hines OJ;Li G;Go VLW;Sinnett-Smith J;Pandol SJ;Lugea A;Gukovskaya AS;Duff MO;Rosenberg DW;Rozengurt E;Eibl G
流行病学数据已将肥胖与较高的胰腺癌风险联系在一起，但其潜在机制尚不清楚。为了能够在模拟饮食诱导的肥胖和胰腺癌的相关模型中进行详细的机制研究，给P48+/CRE；携带胰腺特异性致癌Kras突变的LSL-KrasG12D(KC)小鼠给予高脂肪、高热量饮食(HFCD)。这些小鼠被随机分配到HFCD或对照饮食(CD)。在3个月、6个月和9个月时处死队列，并采集组织进行进一步分析。与喂镉的小鼠相比，喂镉的小鼠体重增加了很多。重要的是，喂食HFCD的KC小鼠的癌症发病率显著增加，特别是在雄性KC小鼠中。此外，与年龄匹配的饲喂镉的KC小鼠相比，饲喂HFCD的KC小鼠表现出更广泛的炎症和纤维化，胰腺中的Panin病变也更严重。有趣的是，我们发现HFCD减少了KC小鼠Panin病变中的自噬通量。此外，对分离的小鼠Panin病变进行的外显子组测序发现了许多HFCD特有的遗传变异。这些数据强调了持续炎症和自噬失调在饮食诱导的胰腺癌发展中的作用，并表明饮食诱导的基因改变可能有助于这一过程。我们的发现有助于更好地理解男性和女性肥胖-癌症联系的潜在机制，并将促进针对肥胖相关胰腺癌的干预措施的发展。
Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.