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Brown-fat-mediated tumour suppression by cold-altered global metabolism

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机构: [1]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden. [2]Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China. [3]Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vison and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China. [4]Longyan First Hospital Affiliated to Fujian Medical University, Longyan, China. [5]Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China. [6]Department Nuclear Medicine, Department of Emergency Medicine, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China. [7]Department of Nutrition and Metabolism, Tokushima University Graduate School, Tokushima, Japan. [8]Department of Head and Neck Surgery, Center of Otolaryngology-Head and Neck Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China. [9]Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
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Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1-6. 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.© 2022. The Author(s).

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第一作者机构: [1]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Sweden.
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