Fang Jian-Hong, Chen Jie-Ying, Zheng Jia-Lin, Zeng Hui-Xian, Chen Jun-Guang, Wu Chen-Hui, Cai Jia-Li, Wang Zhi-Yong, Zhuang Shi-Mei
Key Laboratory of Gene Function and Regulation, School of Life Sciences, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, P.R. China.
MOE Key Laboratory for Polymeric Composite & Functional Materials, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, P.R. China.
Cancer Res. 2023 Apr 14;83(8):1249-1263. doi: 10.1158/0008-5472.CAN-22-1844.
Angiogenesis is vital for tumor growth and metastasis. Emerging evidence suggests that metabolic reprogramming in endothelial cells (EC) may affect angiogenesis. Here, we showed that multiple regulators in the fructose metabolism pathway, especially fructose transporter SLC2A5 and fructose-metabolizing enzyme ketohexokinase (KHK), were upregulated in tumor endothelial cells from hepatocellular carcinoma (HCC). In mouse models with hepatoma xenografts or with Myc/sgp53-induced liver cancer, dietary fructose enhanced tumor angiogenesis, tumor growth, and metastasis, which could be attenuated by treatment with an inhibitor of SLC2A5. Furthermore, vessel growth was substantially increased in fructose-containing Matrigel compared with PBS-Matrigel. Inhibiting fructose metabolism in EC cells in vivo using EC-targeted nanoparticles loaded with siRNA against KHK significantly abolished fructose-induced tumor angiogenesis. Fructose treatment promoted the proliferation, migration, and tube formation of ECs and stimulated mitochondrial respiration and ATP production. Elevated fructose metabolism activated AMPK to fuel mitochondrial respiration, resulting in enhanced EC migration. Fructose metabolism was increased under hypoxic conditions as a result of HIF1α-mediated upregulation of multiple genes in the fructose metabolism pathway. These findings highlight the significance of fructose metabolism in ECs for promoting tumor angiogenesis. Restricting fructose intake or targeting fructose metabolism is a potential strategy to reduce angiogenesis and suppress tumor growth.
Fructose metabolism in endothelial cells fuels mitochondrial respiration to stimulate tumor angiogenesis, revealing fructose metabolism as a therapeutic target and fructose restriction as a dietary intervention for treating cancer.
血管生成对肿瘤生长和转移至关重要。新出现的证据表明，内皮细胞（EC）中的代谢重编程可能影响血管生成。在此，我们发现果糖代谢途径中的多个调节因子，尤其是果糖转运蛋白SLC2A5和果糖代谢酶酮己糖激酶（KHK），在肝细胞癌（HCC）的肿瘤内皮细胞中上调。在肝癌异种移植或Myc/sgp53诱导的肝癌小鼠模型中，饮食中的果糖增强了肿瘤血管生成、肿瘤生长和转移，而用SLC2A5抑制剂治疗可减弱这些作用。此外，与PBS-基质胶相比，含果糖的基质胶中血管生长显著增加。使用负载针对KHK的siRNA的内皮细胞靶向纳米颗粒在体内抑制内皮细胞中的果糖代谢，可显著消除果糖诱导的肿瘤血管生成。果糖处理促进了内皮细胞的增殖、迁移和管腔形成，并刺激了线粒体呼吸和ATP产生。果糖代谢升高激活了AMPK以促进线粒体呼吸，从而增强了内皮细胞迁移。由于HIF1α介导的果糖代谢途径中多个基因的上调，低氧条件下果糖代谢增加。这些发现突出了内皮细胞中果糖代谢对促进肿瘤血管生成的重要性。限制果糖摄入或靶向果糖代谢是减少血管生成和抑制肿瘤生长的潜在策略。
内皮细胞中的果糖代谢为线粒体呼吸提供能量以刺激肿瘤血管生成，揭示果糖代谢作为治疗靶点以及果糖限制作为治疗癌症的饮食干预措施。
