Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model
Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model
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DOI：
10.1093/neuonc/nox170
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发表时间：
2018-03-01
期刊：
影响因子：
15.9
通讯作者：
Sampetrean, Oltea
中科院分区：
文献类型：
--
作者：
Shibao, Shunsuke;Minami, Noriaki;Sampetrean, Oltea
背景。胶质母细胞瘤已被证明依赖糖酵解作为能量来源。然而，最近的证据表明，至少有一部分具有干细胞样特性的神经胶质瘤细胞可以在氧化磷酸化下茁壮成长。目前尚不清楚这两种代谢表型是否支持肿瘤增殖、它们是否独立以及它们的稳定性如何。本研究利用同基因小鼠神经胶质瘤干细胞（GSC）研究了这些问题。方法。 GSCs 是由 Ink4a/Arf 缺失、表达 H-Ras(V12) 的神经胶质瘤起始细胞形成的肿瘤建立的，这些细胞的细胞外酸化电位不同。 GSC 的代谢特征通过测量葡萄糖、氧气和谷氨酰胺的摄取、ATP 含量和乳酸产量来确定。还确定了代谢抑制剂以及氧气或营养物质可用性的变化对乳酸产生和肿瘤球生长的影响。结果。研究发现 GSC 要么消耗更多的葡萄糖并产生更多的乳酸，要么消耗更多的氧气并维持更高的 ATP 含量，具体取决于肿瘤细胞来源的代谢特征。后者，线粒体型 GSC 在用氧化磷酸化抑制剂寡霉素或苯乙双胍处理后增加了乳酸的产生。暴露于缺氧还以可逆的方式增加了线粒体型 GSC 中乳酸的产生以及糖酵解相关酶和代谢物的表达。结论。糖酵解和线粒体型能量产生都可以通过同基因 GSC 维持肿瘤增殖。虽然两种表型可以是独立且稳定的，但依赖氧化磷酸化的细胞也可以转变为糖酵解性更强的表型以响应代谢应激，这表明可塑性是 GSC 代谢的另一个特征。
Background. Glioblastomas have been shown to rely on glycolysis as an energy source. However, recent evidence suggests that at least a subset of glioma cells with stem cell-like properties can thrive on oxidative phosphorylation. It remains unclear whether both metabolic phenotypes support tumor propagation, if they are independent, and how stable they are. The present study investigated these questions with the use of isogenic murine glioma stem cells (GSCs).Methods. GSCs were established from tumors formed by Ink4a/Arf-null, H-Ras(V12)-expressing glioma-initiating cells that differed in extracellular acidification potential. Metabolic characteristics of GSCs were determined by measurement of glucose, oxygen, and glutamine uptake, ATP content, and lactate production. Effects of metabolic inhibitors and changes in oxygen or nutrient availability on lactate production and tumorsphere growth were also determined.Results. GSCs were found either to consume more glucose and produce more lactate or to consume more oxygen and maintain a higher ATP content depending on the metabolic characteristics of the tumor cells of origin. The latter, mitochondrial-type GSCs increased lactate production after treatment with the oxidative phosphorylation inhibitor oligomycin or phenformin. Exposure to hypoxia also increased lactate production and expression of glycolysis-related enzymes and metabolites in mitochondrial-type GSCs in a reversible manner.Conclusions. Both glycolytic and mitochondrial-type energy production can sustain tumor propagation by isogenic GSCs. Whereas both phenotypes can be independent and stable, cells that rely on oxidative phosphorylation can also switch to a more glycolytic phenotype in response to metabolic stress, suggesting that plasticity is a further characteristic of GSC metabolism.