PO.MCB09.06 · 分子与细胞生物学
研究饮食诱导的高胰岛素血症与突变型Kras对结直肠癌转移的协同影响
Investigating synergistic impact of diet-induced hyperinsulinemia and mutant Kras on colorectal cancer metastasis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：本研究考察慢性高脂高糖（HFS）饮食诱导的代谢功能障碍如何在体内的基因工程iKAP模型（诱导型Kras、Apc和p53）中影响癌症转移（Boutin等，Genes & Development，2017，31:370）。
方法：将8-10周龄小鼠随机分配至10%低脂低糖/LFS（健康饮食）或45%高脂高糖/HFS（西式饮食），以在肿瘤起始前诱导高胰岛素血症和代谢功能障碍。使用Echo-MRI监测体成分的改变、葡萄糖耐量试验（GTT）以及终点脂肪变性来监测代谢功能障碍的发展。肿瘤诱导后，测量肿瘤生长速率以比较肿瘤负荷与饮食及Kras突变状态的关系。使用micro-CT成像和终点组织病理学记录并比较微转移和宏转移。同时，一项使用一组同源结直肠癌细胞系的互补性体外研究正在进行，通过划痕试验和transwell试验以及Western blot下游信号分析，评估胰岛素介导的细胞迁移和侵袭的影响。
结果：我们的初步体内研究结果显示代谢功能障碍的信号，包括HFS喂养的iKAP小鼠体脂百分比升高、葡萄糖耐量降低以及肝脂肪变性的发展。与10%脂肪饮食组相比，45%高脂饮食组小鼠显示出更高的肝脏疾病评分。高脂组中肝细胞气球样变和炎症的表现明显增加。当前发现表明45% HFS小鼠相对于10%对照组存在饮食依赖性的肝脏脂肪变性增加。
结论：基于初步发现，HFS饮食可有效诱导iKAP体内模型的代谢功能障碍。这一背景可能支持研究高胰岛素血症与致癌Kras在CRC进展和转移中的相互作用。更多小鼠及基于性别的分析将进一步验证并加强这些发现。展望未来，慢性高胰岛素血症是否在突变型Kras存在下重编程代谢和细胞内信号传导以扩大肿瘤转移扩散，仍是一个有待解答的问题。
查看英文原文 English abstract
Purpose: This study examines how chronic high-fat-sugar (HFS) diet-induced metabolic dysfunction affects cancer metastasis in an in vivo, genetically engineered iKAP model (inducible Kras, Apc, and p53) (Boutin et al., Genes & Development, 2017, 31:370).
Methods: 8-10 weeks old mice are randomized to either a 10% low-fat-sugar/LFS (healthy diet) or a 45% high-fat-sugar/HFS (western-style diet) to induce hyperinsulinemia and metabolic dysfunction before tumor initiation. The development of metabolic dysfunction is monitored using Echo-MRI for alterations in body composition, a glucose tolerance test (GTT), and endpoint steatosis. Upon tumor induction, tumor growth rates are measured to compare tumor burden in relation to diet and Kras mutation status. Micro- and macro-metastases are being recorded and compared using micro-CT imaging and endpoint tissue histopathology. In parallel, a complementary in vitro study using a panel of isogenic colorectal cancer cell lines is underway to evaluate the effect of insulin-mediated cell migration and invasion through scratch and trans-well assays, as well as downstream signaling analyses by Western blot.
Result: Our preliminary in vivo findings demonstrate signals of metabolic dysfunctions, including higher body fat percentage, lower glucose tolerance, and the development of hepatic steatosis in HFS-fed iKAP mice. Mice on the 45% high-fat diet showed higher liver disease scores compared to those on the 10% fat diet. Inclusions of hepatocyte ballooning and inflammation were noticeably increased in the high-fat group. Current findings indicate a diet-dependent increase in liver steatosis in 45% HFS mice relative to the 10% control group.
Conclusion: Based on preliminary findings, an HFS diet effectively induces metabolic dysfunction in the iKAP in vivo model. This context may support investigating hyperinsulinemia-oncogenic Kras crosstalk in CRC progression and metastasis. Additional mice and sex-based analyses will further validate and strengthen these findings. Moving forward, chronic hyperinsulinemia reprograms metabolism and intracellular signaling in the presence of mutant Kras to expand tumor metastatic spread, is an open question.
利益披露 Disclosure
A. Mahanty, None..
C. Wallingford, None..
A. Magstadt, None..
R. Hammontree, None.