Departments of1Neurosurgery and.
2Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
J Neurosurg. 2020 Feb 14;134(3):721-732. doi: 10.3171/2019.11.JNS192028. Print 2021 Mar 1.
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. The 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.
尽管采用了积极的多模式治疗方案，胶质母细胞瘤（GBM）仍然预示着预后不良，这在一定程度上是由于分子和细胞水平的肿瘤异质性所致。因此，作者在此试图确定 GBM 肿瘤核心细胞和边缘细胞之间的代谢差异，并以此为中心阐明针对肿瘤代谢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）球体培养模型进行了全面代谢分析。代谢分析的结果与 Ivy GBM 数据集相结合。在对比增强区域（即肿瘤核心）和肿瘤周围脑组织病变（即肿瘤边缘）中，寻找并探讨了 GBM 肿瘤组织代谢之间的差异。最终通过免疫组织化学在蛋白质水平上确认了这些变化。
在 HGG 肿瘤组织和 GBM 球体培养模型中都发现了代谢异质性，分析表明酪氨酸代谢可能是 GBM 的一个潜在治疗靶点，特别是在肿瘤核心中。此外，酪氨酸代谢途径中的酶酪氨酸氨基转移酶（TAT）的激活影响了 GBM 核心的显著治疗抵抗。
选择性抑制酪氨酸代谢途径可能对多模式 GBM 治疗具有重要的辅助作用。
