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Brown-fat-mediated tumour suppression by cold-altered global metabolism
Nature ( IF 64.8 ) Pub Date : 2022-08-03 , DOI: 10.1038/s41586-022-05030-3
Takahiro Seki 1 , Yunlong Yang 1, 2 , Xiaoting Sun 1, 3 , Sharon Lim 1 , Sisi Xie 2, 4 , Ziheng Guo 5 , Wenjing Xiong 6 , Masashi Kuroda 7 , Hiroshi Sakaue 7 , Kayoko Hosaka 1 , Xu Jing 1, 8 , Masahito Yoshihara 9 , Lili Qu 6 , Xin Li 6 , Yuguo Chen 6 , Yihai Cao 1
Affiliation  

Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1,2,3,4,5,6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1—the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.



中文翻译:

通过冷改变的整体代谢抑制棕色脂肪介导的肿瘤

葡萄糖摄取对于癌症糖酵解至关重要,并且参与脂肪组织1,2,3,4,5,6的非颤抖性产热。大多数癌症利用糖酵解来利用能量实现其无限生长、侵袭和转移2,7,8。寒冷和药物激活棕色脂肪组织 (BAT) 中的产热代谢会促使脂肪细胞摄取血糖4,5,9. 然而,与 BAT 激活相关的整体代谢变化对肿瘤生长的功能影响尚不清楚。在这里,我们表明,将荷瘤小鼠暴露在寒冷条件下会显着抑制各种类型的实体瘤的生长,包括临床上无法治愈的癌症,如胰腺癌。从机制上讲,冷诱导的 BAT 激活会显着降低血糖并阻碍癌细胞中基于糖酵解的代谢。去除 BAT 并在冷暴露下以高糖饮食为食可恢复肿瘤生长,并且Ucp1基因缺失——BAT 产热的关键介质——消除了冷触发的抗癌作用。在一项人体试验性研究中,轻度寒冷暴露会激活健康人和癌症患者体内大量的 BAT,肿瘤组织中的葡萄糖摄取减少。这些发现为使用简单有效的方法的癌症治疗提供了以前未描述的概念和范例。我们预计通过任何其他方法(例如单独或与其他抗癌疗法联合使用药物和设备)冷暴露和激活 BAT 将为有效治疗各种癌症提供一种通用方法。

更新日期:2022-08-03
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