The dual action of glioma-derived exosomes on neuronal activity: synchronization and disruption of synchrony

Abstract

Seizures represent a frequent symptom in gliomas and significantly impact patient morbidity and quality of life. Although the pathogenesis of tumor-related seizures is not fully understood, accumulating evidence indicates a key role of the peritumoral microenvironment. Brain cancer cells interact with neurons by forming synapses with them and by releasing exosomes, cytokines, and other small molecules. Strong interactions among neurons often lead to the synchronization of their activity. In this paper, we used an in vitro model to investigate the role of exosomes released by glioma cell lines and by patient-derived glioma stem cells (GSCs). The addition of exosomes released by U87 glioma cells to neuronal cultures at day in vitro (DIV) 4, when neurons are not yet synchronous, induces synchronization. At DIV 7–12 neurons become highly synchronous, and the addition of the same exosomes disrupts synchrony. By combining Ca2+ imaging, electrical recordings from single neurons with patch-clamp electrodes, substrate-integrated microelectrode arrays, and immunohistochemistry, we show that synchronization and de-synchronization are caused by the combined effect of (i) the formation of new neuronal branches, associated with a higher expression of Arp3, (ii) the modification of synaptic efficiency, and (iii) a direct action of exosomes on the electrical properties of neurons, more evident at DIV 7–12 when the threshold for spike initiation is significantly reduced. At DIV 7–12 exosomes also selectively boost glutamatergic signaling by increasing the number of excitatory synapses. Remarkably, de-synchronization was also observed with exosomes released by glioma-associated stem cells (GASCs) from patients with low-grade glioma but not from patients with high-grade glioma, where a more variable outcome was observed. These results show that exosomes released from glioma modify the electrical properties of neuronal networks and that de-synchronization caused by exosomes from low-grade glioma can contribute to the neurological pathologies of patients with brain cancers.

The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy

“…Exosomes released by glioma selectively enhance glutamatergic signal transduction by increasing the number of excitatory synapses in patients with brain cancer. 182 Due to the lack of research on tumor nerves, there is insufficient evidence to elucidate the communication effect of exosomes between tumors and neurons. It is important to explore this direction in the future.…”

“…Recent studies have preliminarily confirmed this conjecture. Exosomes released by glioma selectively enhance glutamatergic signal transduction by increasing the number of excitatory synapses in patients with brain cancer 182 …”

Altered Extracellular Matrix as an Alternative Risk Factor for Epileptogenicity in Brain Tumors

“…Furthermore, glioma cells are known to secrete exosomes that interact with the peritumoral environment, promoting proliferation, angiogenesis and immunosuppression [ 81 ]. Recently, it was found that these glioma-secreted exosomes also modify the electrical properties and cause de-synchronization of surrounding neurons [ 82 ]. Considering the massive cellular alterations found in cerebral tumors including LEATs, it is not strange to imagine profound changes in extracellular proteins that accompany the pathological intracellular protein synthesis.…”

Microglial Extracellular Vesicles as Modulators of Brain Microenvironment in Glioma

“…GBM-derived EVs can regulate neuronal excitability [ 69 ] and miRs transfer (miR-148a and miR-9-5p) promotes angiogenesis in endothelial cells [ 70 , 71 , 72 , 73 ]. In bidirectional communication, brain endothelial cells release EVs containing tetraspanin CD9 to GBM [ 74 ], enhancing tumor progression through the inhibition of ubiquitination of IL6 receptor gp30 and promoting the activation of the signal transducer and activator of transcription 3 (STAT3) [ 75 , 76 , 77 , 78 ].…”