Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania ''Luigi Vanvitelli", 80138 Naples, Italy.
School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy.
Int J Mol Sci. 2021 Mar 24;22(7):3301. doi: 10.3390/ijms22073301.
Different functional states determine glioblastoma (GBM) heterogeneity. Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.
不同的功能状态决定了胶质母细胞瘤（GBM）的异质性。脑癌细胞与神经胶质细胞在功能上共存于一个合胞体中，基于连续的代谢重编程。然而，标准的胶质瘤疗法并没有考虑到肿瘤微环境中神经胶质细胞的影响。这可能是高级别胶质瘤患者治疗效果缺乏改善的一个原因。细胞代谢和生物能量适应性取决于微环境中营养物质的可用性和相互作用。它与肿瘤内细胞的位置严格相关，与血管的接近程度、生化梯度和肿瘤的演变有关，这说明了上下文和时间线在抗肿瘤治疗方法中的影响。除了癌症代谢策略外，我们在这里还回顾了与 GBM 相关的神经胶质细胞中发现的修饰，重点关注形态、分子和代谢特征。我们建议从系统生物学的角度来分析 GBM 的代谢重编程过程。我们的目的是将 GBM 与神经胶质细胞之间的相互作用定义为模块。复杂的网络可能通过与 GBM 生长和扩散阶段相对应的代谢模块来表达。氧化磷酸化（OXPHOS）速率和调节的变化似乎是代谢和功能异质性的最重要部分，与糖酵解和对缺氧的反应有关。整合的代谢模块以及分子和形态特征，可以识别出控制 GBM-基质代谢的关键因素，从而实现多靶点、时变的治疗。
