Mechanisms of Invasion in Glioblastoma: Extracellular Matrix, Ca2+ Signaling, and Glutamate.

Jae-Seon So,Hyeono Kim,Kyung-Seok Han

doi:10.3389/fncel.2021.663092

Abstract

Glioblastoma (GBM) is the most common and malignant form of primary brain tumor with a median survival time of 14–16 months in GBM patients. Surgical treatment with chemotherapy and radiotherapy may help increase survival by removing GBM from the brain. However, complete surgical resection to eliminate GBM is almost impossible due to its high invasiveness. When GBM cells migrate to the brain, they interact with various cells, including astrocytes, neurons, endothelial cells, and the extracellular matrix (ECM). They can also make their cell body shrink to infiltrate into narrow spaces in the brain; thereby, they can invade regions of the brain and escape from surgery. Brain tumor cells create an appropriate microenvironment for migration and invasion by modifying and degrading the ECM. During those processes, the Ca2+ signaling pathway and other signaling cascades mediated by various ion channels contribute mainly to gene expression, motility, and invasion of GBM cells. Furthermore, GBM cells release glutamate, affecting migration via activation of ionotropic glutamate receptors in an autocrine manner. This review focuses on the cellular mechanisms of glioblastoma invasion and motility related to ECM, Ca2+ signaling, and glutamate. Finally, we discuss possible therapeutic interventions to inhibit invasion by GBM cells.

Highlights

Gliomas are a common type of primary central nervous system tumors derived from non-neuronal glial cells and include astrocytomas, oligodendrogliomas, and ependymomas
Invasion is the main characteristic of malignant glioma and one of the obstacles to radiotherapeutic, chemotherapeutic, and surgical treatments
This review provides an overview of extracellular matrix (ECM), Ca2+ signaling, and glutamate release and their associations with glioma cell invasion and migration

Summary

INTRODUCTION

Gliomas are a common type of primary central nervous system tumors derived from non-neuronal glial cells and include astrocytomas, oligodendrogliomas, and ependymomas. Glioblastoma invasiveness is directly affected by HA polymer molecular weight within a methacrylamide-functionalized gelatin (GelMA) hydrogel (Chen et al, 2018) Consistent with these results, the CD44 expression level is higher in severe grade glioma cells, and the anti-CD44 antibody effectively reduces the migration of GBM (Yoshida et al, 2012). Signaling mediated by integrins can modulate the activities of MMP and PA to degrade the ECM and allow glioma to invade Taken together, through their interactions with the ECM, integrins are critically involved in glioma pathogenesis, migration, and infiltration (Figure 1A). Proteoglycans, hyaluronan, and tenascins have major roles in the brain ECM during invasion, and the associated binding partners, including CD44, RHAMM, and integrins, have critical roles. Abnormal interaction between ECM and its binding partners could cause long-term memory deficit, one of the symptoms in GBM patients, which could be further tested

CALCIUM SIGNALING IN GLIOBLASTOMA IS RELATED TO MIGRATION AND INVASION

GLUTAMATE SIGNALING FOR INVASION IN GLIOMA CELLS

Findings

CONCLUSION