Mondal Jayanta, Huse Jason T
Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
Acta Neuropathol Commun. 2025 Apr 30;13(1):85. doi: 10.1186/s40478-025-02009-9.
Gliomas and brain metastases are notorious for their dismal prognosis and low survival rates, a challenge exacerbated by our incomplete grasp of the complex dynamics that govern brain cancers. Recently, a groundbreaking paradigm shift has emerged, highlighting the crucial role of synaptic communication between neurons and brain tumor cells in reshaping neuronal signaling to favor tumor growth. This review delves into the pivotal interplay of synaptic mechanisms, focusing on excitatory glutamatergic and inhibitory GABAergic pathways. Glutamatergic synapses utilize glutamate to propagate excitatory signals, while GABAergic synapses employ gamma-aminobutyric acid (GABA) to inhibit neuronal firing. Glutamatergic signaling can be broadly classified into ionotropic (NMDAR, AMPAR and kainite receptors) and metabotropic subtypes. The harmonious orchestration of these synaptic types is essential for normal brain function, and their dysregulation is implicated in neurodegenerative disorders such as Alzheimer's disease and epilepsy. Emerging evidence reveals that glioma and brain metastatic cells exploit these synaptic pathways and neurotransmitters to enhance their proliferation and survival. In this review, we will first explore the intricate mechanisms underlying glutamatergic and GABAergic signaling. Next, we will summarize recent advancements in understanding how brain cancer cells hijack these pathways to their advantage. Finally, we will propose novel therapeutic strategies aimed at disrupting the aberrant neuron-tumor synaptic communication, offering potential treatment strategies for combating these otherwise incurable brain cancers.
神经胶质瘤和脑转移瘤因其预后不佳和生存率低而声名狼藉，而我们对控制脑癌的复杂动态过程的不完全理解又加剧了这一挑战。最近，出现了一个具有开创性的范式转变，突出了神经元与脑肿瘤细胞之间的突触通讯在重塑神经元信号以促进肿瘤生长方面的关键作用。这篇综述深入探讨了突触机制的关键相互作用，重点关注兴奋性谷氨酸能和抑制性γ-氨基丁酸能（GABA能）途径。谷氨酸能突触利用谷氨酸来传递兴奋性信号，而GABA能突触则利用γ-氨基丁酸（GABA）来抑制神经元放电。谷氨酸能信号传导可大致分为离子型（NMDAR、AMPAR和红藻氨酸受体）和代谢型亚型。这些突触类型的协调对于正常脑功能至关重要，它们的失调与诸如阿尔茨海默病和癫痫等神经退行性疾病有关。新出现的证据表明，神经胶质瘤和脑转移瘤细胞利用这些突触途径和神经递质来增强它们的增殖和存活能力。在这篇综述中，我们将首先探讨谷氨酸能和GABA能信号传导的复杂机制。接下来，我们将总结在理解脑癌细胞如何利用这些途径为自身谋利方面的最新进展。最后，我们将提出旨在破坏异常的神经元-肿瘤突触通讯的新治疗策略，为对抗这些原本无法治愈的脑癌提供潜在的治疗策略。
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