Adenosinergic Signaling as a Key Modulator of the Glioma Microenvironment and Reactive Astrocytes.

Gabriela N Debom,Elizandra Braganhol,Dominique S Rubenich

doi:10.3389/fnins.2021.648476

Abstract

Astrocytes are numerous glial cells of the central nervous system (CNS) and play important roles in brain homeostasis. These cells can directly communicate with neurons by releasing gliotransmitters, such as adenosine triphosphate (ATP) and glutamate, into the multipartite synapse. Moreover, astrocytes respond to tissue injury in the CNS environment. Recently, astrocytic heterogeneity and plasticity have been discussed by several authors, with studies proposing a spectrum of astrocytic activation characterized by A1/neurotoxic and A2/neuroprotective polarization extremes. The fundamental roles of astrocytes in communicating with other cells and sustaining homeostasis are regulated by purinergic signaling. In the CNS environment, the gliotransmitter ATP acts cooperatively with other glial signaling molecules, such as cytokines, which may impact CNS functions by facilitating/inhibiting neurotransmitter release. Adenosine (ADO), the main product of extracellular ATP metabolism, is an important homeostatic modulator and acts as a neuromodulator in synaptic transmission via P1 receptor sensitization. Furthermore, purinergic signaling is a key factor in the tumor microenvironment (TME), as damaged cells release ATP, leading to ADO accumulation in the TME through the ectonucleotidase cascade. Indeed, the enzyme CD73, which converts AMP to ADO, is overexpressed in glioblastoma cells; this upregulation is associated with tumor aggressiveness. Because of the crucial activity of CD73 in these cells, extracellular ADO accumulation in the TME contributes to sustaining glioblastoma immune escape while promoting A2-like activation. The present review describes the importance of ADO in modulating astrocyte polarization and simultaneously promoting tumor growth. We also discuss whether targeting of CD73 to block ADO production can be used as an alternative cancer therapy.

Highlights

In the last few years, astrocytes have received increased attention, with many studies aimed at in-depth understanding of their functions in the healthy brain and in central nervous system (CNS) pathologies (Khakh and Sofroniew, 2015; Escartin et al, 2019)
The present review raises the hypothesis that reactive astrocytes are involved in the progression of brain tumors, such as GB
As astrocytes are instrumental to the microenvironment of the CNS, they can be corrupted by tumor cells and directly and indirectly participate in the tumor microenvironment (TME), regulating crosstalk among tumor, glial, and endothelial cells

Summary

INTRODUCTION

In the last few years, astrocytes have received increased attention, with many studies aimed at in-depth understanding of their functions in the healthy brain and in central nervous system (CNS) pathologies (Khakh and Sofroniew, 2015; Escartin et al, 2019). Tumor cells can effectively alter the immune system from a protective to a detrimental state and favor tumor progression (Chen and Hambardzumyan, 2018) In accordance with these observations, increasing evidence has revealed that astrocytes contribute to the immunosuppressive characteristics of the TME, and that microglia-astrocyte crosstalk is an important subject that requires further study (Placone et al, 2016).

A R A2 A R A2 A R A2 A R A2 A R A2 A R A2AR – A2BR A2 B R ADA

Findings

CONCLUDING REMARKS