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

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.

Retinal astrocyte morphology predicts integration of vascular and neuronal architecture

“…Single-cell RNA sequencing currently drives our understanding of astrocytes in both naïve and disease contexts. It has revealed a heterogeneous response to injury and disease, suggesting cells exist on a reactivity spectrum between neurotoxic (A1) and neuroprotective (A2) phenotypes ( Escartin et al, 2021 ; Hasel et al, 2021 ; Debom et al, 2022 ). Due to the diversity in molecular states identified, it has been proposed that classification of reactivity should include not only transcriptomic, proteomic, and functional criteria, but also morphology ( Escartin et al, 2021 ).…”

Neurotransmitters: Potential Targets in Glioblastoma

“…Commonly, the expression of adenosine (P1) and nucleotide (P2) receptors is found not only on neurons, but also on glial cells. As a major regulator in presynaptic activities, P1 receptors serve as critical elements in the crosstalk among tumor cells, astrocytes and microglia, influencing tumor-related astrocyte phenotypic differentiation [ 66 ]. On the one hand, P2X ionotropic receptors participate in synaptic remodeling and rapid synaptic transmission.…”

Adenylate kinase immobilized on graphene oxide impairs progression of human lung carcinoma epithelial cells through adenosinergic pathway

“…CD73 has been reported to be highly expressed in many solid tumors, and adenosine has been considered as a critical factor enhancing the cancer progression 14–17 . Thus, adenosinergic pathway has recently gained the growing research attention, and CD73 emerges as a pivotal target for novel anti‐cancer therapies based on its small molecule inhibitors, CD73‐targeted antibodies or siRNA 13,18–21 . Importantly, the presence of many pathways coordinately regulating ATP and adenosine levels implies the necessity of understanding the role of a particular molecule or an ecto‐enzyme within the larger framework, where any deregulation contributes to various disorders 16 …”

“…[14][15][16][17] Thus, adenosinergic pathway has recently gained the growing research attention, and CD73 emerges as a pivotal target for novel anti-cancer therapies based on its small molecule inhibitors, CD73-targeted antibodies or siRNA. 13,[18][19][20][21] Importantly, the presence of many pathways coordinately regulating ATP and adenosine levels implies the necessity of understanding the role of a particular molecule or an ecto-enzyme within the larger framework, where any deregulation contributes to various disorders. 16 Bearing in mind that AK can be potentially used in biological systems to control and maintain adenine nucleotides/nucleosides balance, we aimed at the detailed study on physicochemical and biochemical properties of the developed AK-GO nanobiocatalytic system.…”