Neurotransmitter-Mediated Signaling in Glioblastoma and Glial Tumors: Biology and Therapeutic Opportunities

Glioblastoma (GB) is the most common primary malignant brain tumor of adulthood, and despite optimal safe resection and chemoradiation, it is still lethal. Neuroscience of cancer has shown that neuronal activities, as well as neurotransmitters, play an active role in the glioma microenvironment. This article aims to integrate the existing literature on the role of neurotransmitters and their receptors in glioblastoma, as well as other gliomas, highlighting areas of therapeutic intervention in the neuron-tumor interface. We will describe the neuro–glioma interface, including functional neuron–glioma synapses and activity-dependent tumor growth. We will also discuss major neurotransmitter systems involved in glioma pathobiology: glutamate, gamma aminobutyric acid, acetylcholine, dopamine, serotonin, norepinephrine, and other neurotransmitters. We will highlight that these neurotransmitter systems activate common intracellular signaling pathways that control tumor proliferation, invasion, metabolic reprogramming, immune suppression, therapy resistance, etc. In addition, some reports have found tumor-suppressing effects depending on the context. The involvement of neurotransmitter-driven signaling pathways represents a promising area of clinical potential in glioma pathobiology. In particular, focusing on key neurotransmitter systems with blood–brain barrier-permeable agents like alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA/Xc−) system, Muscarinic acetylcholine receptor M3 (CHRM3), dopamine receptor D2, monoamine oxidase A, etc., may enhance drug-repurposing research as well as development of novel anti–neuron–glioma agents.