Old Stars and New Players in the Brain Tumor Microenvironment

Abstract

In recent years, the direct interaction between cancer cells and tumor microenvironment (TME) has emerged as a crucial regulator of tumor growth and a promising therapeutic target. The TME, including the surrounding peritumoral regions, is dynamically modified during tumor progression and in response to therapies. However, the mechanisms regulating the crosstalk between malignant and non-malignant cells are still poorly understood, especially in the case of glioma, an aggressive form of brain tumor. The presence of unique brain-resident cell types, namely neurons and glial cells, and an exceptionally immunosuppressive microenvironment pose additional important challenges to the development of effective treatments targeting the TME. In this review, we provide an overview on the direct and indirect interplay between glioma and neuronal and glial cells, introducing new players and mechanisms that still deserve further investigation. We will focus on the effects of neural activity and glial response in controlling glioma cell behavior and discuss the potential of exploiting these cellular interactions to develop new therapeutic approaches with the aim to preserve proper brain functionality.

Keywords: OPCs; glial cells; glioblastoma; glioma; neural activity; peritumoral tissue; reactive astrocyte; tumor-associated microglia/macrophages (TAM).

FIGURE 1

Neurons and glial cells in the glioma microenvironment. Tumor-associated microglia and macrophages (TAMs) are reprogrammed by tumor cells through the release of cytokines, chemokines, metabolites or through cell-cell contacts. Activated TAM produce factors that stimulate glioma proliferation, invasion, angiogenesis, and therapy resistance. Metalloproteinases (MMPs) are released by both tumor cells and TAMs to facilitate glioma cells migration. TME-associated astrocytes are efficiently coopted by tumor cells. They promote tumor migration by expressing chemoattractant factors like GDNF and support stemness via SPP1-CD44 axis. Both TAMs and astrocytes also play a role in immunomodulation, expressing high levels of immunosuppressive cytokines, such as TGFβ and IL-10. Oligodendrocytes and oligodendrocyte progenitor cells (OPCs) release factors like EGF, FGF1 and PDGFA that favor proliferation, stemness and chemotherapy resistance of glioma cells. But, at the same time, OPCs can also impair tumor growth through Wnt inhibition. Neural progenitor cells delay tumor growth and induce tumor cell death via endovanilloids stimulation of TRPV1. Neurons have a multifaceted role in glioma. Peritumoral neurons were found to counteract glioma progression through programmed death-ligand 1 (PD-L1) protein, but recent evidence has shown that the activation of peritumoral excitatory neurons was able to increase glioma proliferation. Selective activation of peritumoral parvalbumin interneurons elicited, instead, the opposite effect. In addition, tumor cells extrude glutamate outside predominantly through the overexpression of the cystine-glutamate antiporter (system xc-, SXC); this event is not harmonized by peritumoral astrocytes, which show a compromised glutamate uptake via the Na⁺-dependent glutamate transporters (i.e., EAAT1 or EAAT2). High amount of glutamate provokes an over-activation of both NMDA and AMPA receptors on neuronal cells, resulting in excitotoxicity and hyperexcitability of neural tissues and eventually promotes survival, growth and migration of glioma cells. Glutamatergic neurons can enhance glioma progression also by releasing NLGN3 and neurotrophins and by establishing functional bona fide AMPA-mediated synapses with tumor cells. Invading glioma cells, together with activated glial cells in the tumor microenvironment, cause also secondary alterations like perineural nets (PNNs) remodeling, partial demyelination and blood-brain-barrier (BBB) leakage. Image created with BioRender.com.