Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model
Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model
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DOI：
10.1093/neuonc/nou096
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发表时间：
2014-08-01
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：
Saga, Isako;Shibao, Shunsuke;Sampetrean, Oltea
恶性胶质瘤对糖酵解作为能量来源的代谢偏好是一个潜在的治疗靶点。然而，由于这些肿瘤的细胞异质性，糖酵解偏好、肿瘤形成和肿瘤细胞克隆形成之间的关系仍然未知。为了解决这个问题，我们分析了小鼠模型中等基因胶质瘤起始细胞（GIC）的代谢谱，GIC是通过在Ink 4a/Arf-null神经干细胞中过表达H-Ras（V12）建立的。通过单细胞克隆获得这些细胞的亚群，并评估细胞外酸化潜力不同的克隆的代谢特征。将这些克隆植入小鼠颅内后形成的肿瘤检查了神经胶质瘤的病理特征和糖酵解酶的表达。神经干细胞的恶性转化导致以乳酸产生增加为特征的代谢转变。然而，GIC的同基因克隆群体在葡萄糖和氧消耗、乳酸产生和核苷水平方面表现出明显的差异。这些差异被糖酵解酶如己糖激酶2和丙酮酸激酶M2的差异表达所掩盖，这种差异表达在这些克隆体内形成的肿瘤中也是明显的。胶质瘤细胞的代谢特征在恶性转化的早期出现，并持续到肿瘤形成的晚期。然而，即使是同基因克隆在代谢特征方面也可能是异质的，这表明更详细地了解胶质瘤的代谢特征对于有效的治疗靶向是必要的。
The metabolic preference of malignant glioma for glycolysis as an energy source is a potential therapeutic target. As a result of the cellular heterogeneity of these tumors, however, the relation between glycolytic preference, tumor formation, and tumor cell clonogenicity has remained unknown. To address this issue, we analyzed the metabolic profiles of isogenic glioma-initiating cells (GICs) in a mouse model.GICs were established by overexpression of H-Ras(V12) in Ink4a/Arf-null neural stem cells. Subpopulations of these cells were obtained by single-cell cloning, and clones differing in extracellular acidification potential were assessed for metabolic characteristics. Tumors formed after intracranial implantation of these clones in mice were examined for pathological features of glioma and expression of glycolytic enzymes.Malignant transformation of neural stem cells resulted in a shift in metabolism characterized by an increase in lactic acid production. However, isogenic clonal populations of GICs manifested pronounced differences in glucose and oxygen consumption, lactate production, and nucleoside levels. These differences were paralleled by differential expression of glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2, with this differential expression also being evident in tumors formed by these clones in vivo.The metabolic characteristics of glioma cells appear early during malignant transformation and persist until the late stages of tumor formation. Even isogenic clones may be heterogeneous in terms of metabolic features, however, suggesting that a more detailed understanding of the metabolic profile of glioma is imperative for effective therapeutic targeting.