Interactions between Tumor Cells, Neurons, and Microglia in the Glioma Microenvironment

Abstract

Despite significant strides made in understanding the pathophysiology of high-grade gliomas over the past two decades, most patients succumb to these neoplasias within two years of diagnosis. Furthermore, there are various co-morbidities associated with glioma and standard of care treatments. Emerging evidence suggests that aberrant glutamate secretion in the glioma microenvironment promotes tumor progression and contributes to the development of co-morbidities, such as cognitive defects, epilepsy, and widespread neurodegeneration. Recent data clearly illustrate that neurons directly synapse onto glioma cells and drive their proliferation and spread via glutamatergic action. Microglia are central nervous system-resident myeloid cells, modulate glioma growth, and possess the capacity to prune synapses and encourage synapse formation. However, current literature has yet to investigate the potential role of microglia in shaping synapse formation between neurons and glioma cells. Herein, we present the literature concerning glutamate’s role in glioma progression, involving hyperexcitability and excitotoxic cell death of peritumoral neurons and stimulation of glioma proliferation and invasion. Furthermore, we discuss instances in which microglia are more likely to sculpt or encourage synapse formation during glioma treatment and propose studies to delineate the role of microglia in synapse formation between neurons and glioma cells. The sex-dependent oncogenic or oncolytic actions of microglia and myeloid cells, in general, are considered in addition to the functional differences between microglia and macrophages in tumor progression. We also put forth tractable methods to safely perturb aberrant glutamatergic action in the tumor microenvironment without significantly increasing the toxicities of the standard of care therapies for glioma therapy.

Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas

“… 42–44 Therefore, when studying the potential acquisition of anti-tumoral properties by microglia, their crosstalk with other cell types, for example macrophages, astrocytes, and neurons, will have to be taken into account. 45 , 46 Hence, these investigations should grant interest for further investigation of the contribution of microglia to the initiation, progression, and response of DIPG tumors to treatments.…”

Meningioma–Brain Crosstalk: A Scoping Review

“…This study provides an overview of the existing evidence of reciprocal crosstalk between tumour cells and the brain parenchyma in meningiomas. Meningiomas express several factors, which are known to have chemotactic properties on microglia in glioblastoma multiforme (e.g., CCL2, CX3CL1, SDF-1, G-CSF and GM-CSF) [ 18 , 26 , 56 , 69 ]. We inferred that brain invasion in meningioma is mandatory to elicit an immune response in the brain parenchyma; however, direct invasion is only seen in a minor subset of cases.…”

Research Progress About Glioma Stem Cells in the Immune Microenvironment of Glioma

“…Macrophages and microglias showed mutual activation and counterbalance in glioma immune microenvironment and tumor progression. The specific and unique roles of microglia and macrophages depend on their localization in and around the tumor ( Radin and Tsirka, 2020 ). Studies on IDH mutated gliomas have found that macrophage transcription programs on microglias increase with tumor grade ( Venteicher et al, 2017 ).…”