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

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.

Keywords: Ca2+; extracellular matrix; glioblastoma; glutamate; invasion; ion channels.

FIGURE 1

ECM, Ca²⁺ signaling, and glutamate mediates invasion and migration in glioma cells. (A) Extracellular matrix and their binding partners regulate invasion and motility in GBM cells. (B) Intracellular Ca²⁺ elevation from ER and extracellular region affects glioma cell migration and invasion. Ca²⁺ influx through TRP channels, P2 × 7Rs, and t-type Ca²⁺ channels are critically involved in glioma cell infiltration. (C) Glioma cells release glutamate through a cysteine-glutamate exchanger (system x_C^–). Released glutamate from glioma cells activates Ca²⁺-permeable AMPARs and NMDARs and affects migration and invasion. Sustained Ca²⁺ influx causes excitotoxic death of surrounding cells to make microenvironment for invasion.

FIGURE 2

Schematic linking mechanisms of ECM, Ca²⁺ signaling, and glutamate in GBM invasion. Summary of mechanisms of glioma invasion related to ECM, Ca²⁺ signaling, and glutamate. Glutamate release from GBM cells activates Ca²⁺ permeable AMPARs and NMDARs in an autocrine manner, thereby cause an intracellular Ca²⁺ increase in GBM cells. ECM and their binding partners affect GBM invasion by regulating Ca²⁺ signaling.