科學家揭示代謝如何促進腫瘤轉移
作者：
小柯機器人發布時間：2019/8/26 14:21:52
近日，英國弗朗西斯克裡克研究所Karen H. Vousden課題組發現，細胞聚集通過促進代謝轉換來支持腫瘤轉移定植。相關論文於2019年8月22日在線發表於國際學術期刊《細胞—代謝》雜誌上。
據了解，癌症轉移依賴於細胞外基質附著的喪失和循環傳播後的細胞存活。脫離癌細胞的聚集和抗氧化防禦的增加可以增強轉移性擴散。
通過描繪細胞聚集如何限制活性氧（ROS），研究人員將這些反應聯繫了起來。附著喪失導致線粒體波動和ROS產生的增加。細胞聚集的形成引起缺氧環境，其驅動缺氧誘導因子1-α（Hif1α）介導的線粒體自噬，從而清除受損的線粒體並限制ROS。然而，缺氧和線粒體功能的降低促進了對產生ATP的糖酵解的依賴，這由胞漿的氧化還原平衡所產生。阻止這種代謝適應或破壞細胞聚集會導致ROS積累、細胞死亡和體內轉移能力的降低。這些結果為細胞聚集在促進細胞外基質分離和轉移擴散期間存活中的作用提供了機制解釋，並且找到一個可供靶向的弱點。
附：英文原文
Title: Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization
Author: Christiaan F. Labuschagne, Eric C. Cheung, Julianna Blagih, Marie-Charlotte Domart, Karen H. Vousden
Issue&Volume: 22 August 2019
Abstract: Cancer metastasis depends on cell survival following loss of extracellular matrix attachment and dissemination through the circulation. The metastatic spread can be enhanced by the clustering of detached cancer cells and increased antioxidant defense. Here, we link these responses by describing how cell clustering limits reactive oxygen species (ROS). Loss of attachment causes mitochondrial perturbations and increased ROS production. The formation of cell clusters induces a hypoxic environment that drives hypoxia-inducible factor 1-alpha (Hif1α)-mediated mitophagy, clearing damaged mitochondria and limiting ROS. However, hypoxia and reduced mitochondrial capacity promote dependence on glycolysis for ATP production that is supported by cytosolic reductive metabolism. Preventing this metabolic adaptation or disruption of cell clusters results in ROS accumulation, cell death, and a reduction of metastatic capacity in vivo. Our results provide a mechanistic explanation for the role of cell clustering in supporting survival during extracellular matrix detachment and metastatic spread and may point to targetable vulnerabilities.
DOI: https://doi.org/10.1016/j.cmet.2019.07.014
Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30387-0#