Epilepsy in Patients with Gliomas

Abstract

Brain tumor-related epilepsy (BTRE) is a complication that significantly impairs the quality of life and course of treatment of patients with brain tumors. Several recent studies have shed further light on the mechanisms and pathways by which genes and biological molecules in the tumor microenvironment can cause epilepsy. Moreover, epileptic seizures have been found to promote the growth of brain tumors, making the control of epilepsy a critical factor in treating brain tumors. In this study, we summarize the previous research and recent findings concerning BTRE. Expectedly, a deeper understanding of the underlying genetic and molecular mechanisms leads to safer and more effective treatments for suppressing epileptic symptoms and tumor growth.

Keywords: brain tumor; epilepsy; glioma; glutamate.

Fig. 1

Relationships between epilepsy and tumor growth in the tumor microenvironment. Glutamate binding to AMPA and NMDA receptors increases Ca levels in tumor cells, activating the PI3K-Akt and MAPK pathways, leading to tumor growth. Overexpression of xCT on the tumor cell membrane increases the glutamate concentration in the surroundings, leading to epileptogenicity. Conversely, EAAT1 and EAAT2 are expressed at lower levels on tumor cell membranes, and the intracellular uptake of glutamate is suppressed. xCT increases the concentration of glutathione, an antioxidant, in tumor cells, promoting tumor growth. BCAT1, which produces glutamate from branched-chain amino acids, is also expressed at high levels, especially in glioblastomas. The high expression of BCAT1 in glioblastomas can result in increased glutamate levels within tumor cells, ultimately causing an increase in extracellular glutamate levels. In glioma cells with IDH mutations, D2HG, structurally similar to glutamate, is produced and excites neurons extracellularly, rendering them epileptogenic. In gliomas, GABAergic synaptic density on nearby pyramidal cells is reduced, and GABA-mediated inhibition is impaired. Meanwhile, in gliomas, mTOR overactivity can result from changes in upstream regulation, such as upregulation of PI3K–Akt signaling, and mutations in PTEN. Hyperactivation of the mTOR pathway affects neuronal excitability, causing excessive neuronal firing. Tumor cells stimulate astrocytes and microglia via gap junctions and activate surrounding neurons. The activated neurons, in turn, activate the PI3K–mTOR pathway in the surrounding tumor cells via NGSs, thereby promoting tumor growth. Tumor cells communicate with each other through TMs, which are structures mediated by gap junctions. Glu: glutamate, D2HG: D-2-hydroxyglutarate, xCT: cystine–glutamate transporter, NMDA-R: N-methyl-D-aspartate receptor, AMPA: α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, EAAT: excitatory amino acid transporter, BCAT1: branched-chain amino acid transaminase 1, PI3K: phosphatidylinositol-3 kinase, Akt: protein kinase B, MAPK: mitogen-activated protein kinase, GABA: γ-aminobutyric acid, mTOR: mammalian target of rapamycin, GapJ: gap junction, TMs: tumor microtubes, NGS: neurogliomal synapse