Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism.
Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism.
复制标题
神经胶质瘤干细胞中线粒体的代谢激活通过活性氧介导的机制促进癌症发展
DOI：
10.1186/s13287-015-0174-2
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发表时间：
2015-10-15
影响因子：
7.5
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Yuan S;Lu Y;Yang J;Chen G;Kim S;Feng L;Ogasawara M;Hammoudi N;Lu W;Zhang H;Liu J;Colman H;Lee JS;Li XN;Xu RH;Huang P;Wang F
肿瘤干细胞（cancer stem cells，CSCs）具有与正常干细胞相关的特征，特别是自我更新和产生所有细胞类型（分化）的能力。假设CSC中分化的诱导将降低其形成肿瘤的能力。是什么触发CSC分化和“分化”在肿瘤发生中的作用仍然难以捉摸.MethodsGlioma stem cell（GSC）lines和皮下以及原位异种移植建立从新鲜手术标本的胶质母细胞瘤multiforme were used. ResultsGSC暴露于血清激活线粒体呼吸，并导致线粒体活性氧（ROS）以及氧化应激反应的增加，导致分化形态学的出现和CSC标志物的表达下降。线粒体电子传递链的化学扰动导致ROS增加并进一步下调干细胞标志物，而抗氧化剂N-乙酰半胱氨酸减少ROS并抑制GSC的分化。令人惊讶的是，血清诱导分化的GSC在原位和皮下异种移植模型中均表现出更大的形成肿瘤的能力，这可以被N-乙酰半胱氨酸抑制。结论血清刺激CSCs后，线粒体活性氧（ROS）激活核因子-κ B（NFκB）通路，是CSCs体内肿瘤发生的重要机制。
IntroductionCancer stem cells (CSCs) possess characteristics associated with normal stem cells, specifically the abilities to renew themselves and to give rise to all cell types (differentiation). It is assumed that induction of differentiation in CSCs would reduce their ability to form tumors. What triggers CSC differentiation and the role of “differentiation” in tumorigenesis remain elusive.MethodsGlioma stem cell (GSC) lines and subcutaneous as well as orthotopic xenografts established from fresh surgical specimens of glioblastoma multiforme were used.ResultsExposure of GSCs to serum activates mitochondrial respiration and causes an increase in mitochondrial reactive oxygen species (ROS) as well as oxidative stress responses, leading to the appearance of differentiation morphology and a deceased expression of CSC markers. Chemical perturbation of the mitochondrial electron transport chain causes ROS increase and further downregulation of stem cell markers, while antioxidant N-acetyl-cysteine reduces ROS and suppresses the differentiation of GSCs. Surprisingly, the serum-induced differentiated GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by N-acetyl-cysteine. Mitochondrial ROS from the serum-stimulated cells triggered the activation of nuclear factor-kappa-B (NFκB) pathway, which is a potential mechanism for the promotion of tumorigenesis.ConclusionThis study suggests that ROS generated from active mitochondrial respiration in the presence of serum is critical in CSCs activation, which promotes tumor developmentin vivo.