Targeting glioma-initiating cells via the tyrosine metabolic pathway.
Targeting glioma-initiating cells via the tyrosine metabolic pathway.
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DOI：
10.3171/2019.11.jns192028
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发表时间：
2021-03-01
影响因子：
4.1
通讯作者：
Nakano I
中科院分区：
文献类型：
--
作者：
Yamashita D;Bernstock JD;Elsayed G;Sadahiro H;Mohyeldin A;Chagoya G;Ilyas A;Mooney J;Estevez-Ordonez D;Yamaguchi S;Flanary VL;Hackney JR;Bhat KP;Kornblum HI;Zamboni N;Kim SH;Chiocca EA;Nakano I
尽管有积极的多模式治疗方案，胶质母细胞瘤（GBM）继续预示着严重的预后，这部分是由肿瘤异质性在分子和细胞水平。因此，在本文中，作者试图鉴定GBM肿瘤核心细胞和边缘细胞之间的代谢差异，并且在这样做的过程中，阐明以肿瘤代谢为中心的新的可行治疗靶点。对20例高级别胶质瘤（HGG）组织和30例胶质瘤起始细胞（GIC）球培养模型进行了全面的代谢分析。将代谢分析结果与Ivy GBM数据集合并。来自对比度增强区域内的GBM肿瘤组织之间的肿瘤代谢差异（即，肿瘤核心）和来自肿瘤周围脑病变的（即，肿瘤边缘）进行寻找和探索。这些变化最终通过免疫组织化学在蛋白质水平上得到证实。HGG肿瘤组织和GBM球培养模型中的代谢异质性被鉴定，并且分析表明酪氨酸代谢可以作为GBM中的可能的治疗靶点，特别是在肿瘤核心中。此外，酪氨酸代谢途径中酪氨酸氨基转移酶（达特）的激活影响了GBM核心的显著治疗抗性。酪氨酸代谢途径的选择性抑制可以证明作为多模式GBM疗法的佐剂是非常有益的。
Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. Results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.