Tumor Cell Infiltration into the Brain in Glioblastoma: From Mechanisms to Clinical Perspectives

Abstract

Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.

Keywords: dispersal; glioblastoma; high-throughput screening; invasion; therapeutics.

Figure 1

Post gadolinium contrast administration, T1-weighted axial images. (A) Preoperative, heterogeneous irregular enhancement, associated with the left frontal-lobe glioblastoma (arrow). (B) Postoperative (at 1 month) axial weighted image. On postoperative image, there is no residual enhancement. Arrow shows operation cavity. (C) Postoperative (at 18 months) axial weighted image shows recurrence of the tumor (white arrow) on contralateral hemisphere, associated with peripheral edema.

Figure 2

Routes of glioblastoma cell invasion. Glioblastoma cells generally invade using tracts in parenchyma, white-matter tracts, and leptomeningeal and perivascular spaces. Among these, perivascular space and white-matter tracts are the most preferred routes for glioblastoma invasion. Perivascular space attracts the tumor cells with the presence of blood vessels, which provide oxygen and nutrients. White-matter tracts are composed of myelinated axons, and tumor cells exploit these structures to reach distant locations in the brain. Parenchymal cells facilitate glioblastoma invasion by secreting several factors. Figure generated at Biorender.com, combined with representative MRI images from our clinic.

Figure 3

Steps of tumor cell invasion. Dynamic regulation of attachment–detachment cycles to break and generate contacts with ECM, and readjustment of cytoskeleton to generate protrusions are crucial for cell invasion. Figure generated at Biorender.com.

Figure 4

Effect of SERPINE1 on glioblastoma cell invasion. Transcriptome profiling of motile and nonmotile glioblastoma cells identified SERPINE1 as a regulator of glioblastoma cell motility. Inhibition or knock-down of SERPINE1 reduces glioblastoma cell invasion by regulating cell adhesion and directional persistence of the cells. As a result, SERPINE1 inhibition has the potential to reduce tumor progression in vivo. Figure generated at Biorender.com (adapted from Seker, F., et al. [149]).