Department of Developmental and Regenerative Biology, Annenberg 25-40, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, Box 1020, New York, NY 10029, USA.
Cell. 2013 Aug 1;154(3):664-75. doi: 10.1016/j.cell.2013.06.030.
The risk of specific cancers increases in patients with metabolic dysfunction, including obesity and diabetes. Here, we use Drosophila as a model to explore the effects of diet on tumor progression. Feeding Drosophila a diet high in carbohydrates was previously demonstrated to direct metabolic dysfunction, including hyperglycemia, hyperinsulinemia, and insulin resistance. We demonstrate that high dietary sugar also converts Ras/Src-transformed tissue from localized growths to aggressive tumors with emergent metastases. Whereas most tissues displayed insulin resistance, Ras/Src tumors retained insulin pathway sensitivity, increased the ability to import glucose, and resisted apoptosis. High dietary sugar increased canonical Wingless/Wnt pathway activity, which upregulated insulin receptor gene expression to promote insulin sensitivity. The result is a feed-forward circuit that amplified diet-mediated malignant phenotypes within Ras/Src-transformed tumors. By targeting multiple steps in this circuit with rationally applied drug combinations, we demonstrate the potential of combinatorial drug intervention to treat diet-enhanced malignant tumors.
代谢功能障碍（包括肥胖和糖尿病）患者的特定癌症风险会增加。在这里，我们使用果蝇作为模型来探索饮食对肿瘤进展的影响。先前的研究表明，给果蝇喂食高碳水化合物的饮食会导致代谢功能障碍，包括高血糖、高胰岛素血症和胰岛素抵抗。我们证明，高糖饮食还会将 Ras/Src 转化的组织从局部生长转化为具有侵袭性转移的侵袭性肿瘤。虽然大多数组织表现出胰岛素抵抗，但 Ras/Src 肿瘤仍然保留了胰岛素通路的敏感性，增加了葡萄糖摄取的能力，并抵抗细胞凋亡。高糖饮食增加了经典的 Wingless/Wnt 通路活性，从而上调胰岛素受体基因的表达以促进胰岛素敏感性。其结果是一个正反馈回路，放大了 Ras/Src 转化肿瘤中饮食介导的恶性表型。通过使用合理应用的药物组合靶向该回路中的多个步骤，我们证明了联合药物干预治疗饮食增强的恶性肿瘤的潜力。
