Guo Xiaoran, Wang Tao, Huang Guohao, Li Ruohan, Da Costa Clive, Li Huafu, Lv Shengqing, Li Ningning
Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-Sen University (SYSU), No.628, Zhenyuan Rd, Guangming Dist., Shenzhen 518107, China.
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, No. 183 Xinqiao Street, Shapingba District, Chongqing City 400037, China.
Curr Cancer Drug Targets. 2021;21(7):558-574. doi: 10.2174/1568009621666210504091722.
Gliomas are the most common type of malignant brain tumors. Despite significant medical advances, gliomas remain incurable and are associated with high mortality. Although numerous biomarkers of diagnostic value have been identified and significant progress in the prognosis of the outcome has been made, the treatment has not been parallelly improved during the last three decades. This review summarizes and discusses three aspects of recent discoveries related to glioma, with the objective to highlight the advantages of glioma-specific drugs targeting the cell of origin, microenvironment, and metabolism. Given the heterogeneous nature of gliomas, various cell populations have been implicated as likely sources of the tumor. Depending on the mutation(s) acquired by the cells, it is believed that neural stem/progenitor cells, oligodendrocyte progenitor cells, mature neurons, and glial cells can initiate cell transformation into a malignant phenotype. The level of tumorigenicity appears to be inversely correlated with the maturation of a given cell population. The microenvironment of gliomas includes non-cancer cells such as immune cells, fibroblasts, and cells of blood vessels, as well as secreted molecules and the extracellular matrix, and all these components play a vital role during tumor initiation and progression. We will discuss in detail how the tumor microenvironment can stimulate and drive the transformation of non-tumor cell populations into tumor-supporting cells or glioma cells. Metabolic reprogramming is a key feature of gliomas and is thought to reflect the adaptation to the increased nutritional requirements of tumor cell proliferation, growth, and survival. Mutations in the IDH gene can shape metabolic reprogramming and may generate some vulnerabilities in glioma cells, such as abnormal lipid metabolism and sensitivity to endoplasmic reticulum stress (ERS). We will analyze the prominent metabolic features of malignant gliomas and the key pathways regulating glioma metabolism. This review is intended to provide a conceptual background for the development of glioma therapies based on the properties of tumor cell populations, microenvironment, and metabolism.
神经胶质瘤是最常见的恶性脑肿瘤类型。尽管医学取得了重大进展，但神经胶质瘤仍然无法治愈，且死亡率很高。虽然已经鉴定出许多具有诊断价值的生物标志物，并且在预后方面取得了显著进展，但在过去三十年中治疗并未同步改善。本综述总结并讨论了与神经胶质瘤相关的近期发现的三个方面，目的是突出针对肿瘤起源细胞、微环境和代谢的神经胶质瘤特异性药物的优势。鉴于神经胶质瘤的异质性，各种细胞群体被认为可能是肿瘤的来源。根据细胞获得的突变，人们认为神经干/祖细胞、少突胶质细胞祖细胞、成熟神经元和神经胶质细胞可以引发细胞转化为恶性表型。致瘤性水平似乎与给定细胞群体的成熟程度呈负相关。神经胶质瘤的微环境包括免疫细胞、成纤维细胞和血管细胞等非癌细胞，以及分泌分子和细胞外基质，所有这些成分在肿瘤发生和进展过程中都起着至关重要的作用。我们将详细讨论肿瘤微环境如何刺激并驱动非肿瘤细胞群体转化为肿瘤支持细胞或神经胶质瘤细胞。代谢重编程是神经胶质瘤的一个关键特征，被认为反映了对肿瘤细胞增殖、生长和存活增加的营养需求的适应。异柠檬酸脱氢酶（IDH）基因的突变可以塑造代谢重编程，并可能在神经胶质瘤细胞中产生一些脆弱性，如异常脂质代谢和对内质网应激（ERS）的敏感性。我们将分析恶性神经胶质瘤的突出代谢特征以及调节神经胶质瘤代谢的关键途径。本综述旨在为基于肿瘤细胞群体、微环境和代谢特性的神经胶质瘤治疗发展提供概念背景。
