The Subventricular Zone, a Hideout for Adult and Pediatric High-Grade Glioma Stem Cells

Abstract

Both in adult and children, high-grade gliomas (WHO grades III and IV) account for a high proportion of death due to cancer. This poor prognosis is a direct consequence of tumor recurrences occurring within few months despite a multimodal therapy consisting of a surgical resection followed by chemotherapy and radiotherapy. There is increasing evidence that glioma stem cells (GSCs) contribute to tumor recurrences. In fact, GSCs can migrate out of the tumor mass and reach the subventricular zone (SVZ), a neurogenic niche persisting after birth. Once nested in the SVZ, GSCs can escape a surgical intervention and resist to treatments. The present review will define GSCs and describe their similarities with neural stem cells, residents of the SVZ. The architectural organization of the SVZ will be described both for humans and rodents. The migratory routes taken by GSCs to reach the SVZ and the signaling pathways involved in their migration will also be described hereafter. In addition, we will debate the advantages of the microenvironment provided by the SVZ for GSCs and how this could contribute to tumor recurrences. Finally, we will discuss the clinical relevance of the SVZ in adult GBM and pediatric HGG and the therapeutic advantages of targeting that neurogenic region in both clinical situations.

Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle

“…GSCs hosted in the SVZ display an improved DNA double-strand break repair, and hence are resistant to radiotherapy 22,23 . These observations have been confirmed in GBM patients, in which GSCs can be found both in the tumor core where the hypoxic environment constitutes an appropriate niche and in the SVZ, reinforcing the role of these CXCR4 + cells in GBM recurrence 24,25 . Importantly, a high expression of CXCR4 positively correlates with tumor size, tumor progression, recurrence and ultimately with patient survival 3,5 .…”

“… 22 , 23 These observations have been confirmed in GBM patients, in which GSCs can be found both in the tumor core, where the hypoxic environment constitutes an appropriate niche, and in the SVZ, reinforcing the role of these CXCR4 + cells in GBM recurrence. 24 , 25 Importantly, a high expression of CXCR4 positively correlates with tumor size, tumor progression, recurrence, and ultimately with patient survival. 3 , 5 Targeting GSCs and particularly CXCR4 + cells therefore provides an opportunity to reach tumor cells that escape current treatments.…”

Glioblastoma Microenvironment and Cellular Interactions

“…The surface markers CD133, L1CAM, CD44, and the intracellular proteins and transcriptional factors, such as NANOG, NESTIN-neuroepithelial stem cell protein, Bmi1, SOX2, OLIG2, and MYC, overrun with those determined for recognition of NCS, thus challenging the recognition of GSCs in a mingled tumor [ 169 , 179 , 185 ]. Surface proteins (such as CD9, CD15, integrin-α6, enzymatic activity of aldehyde dehydrogenase 1 (ALDH1)) and signaling pathways (such as NOTCH, SHH, WNT/β-catenin, EGFR) are also overexpressed and overlap with those in NCS in terms of maintaining an undifferentiated character, a perpetual self-renewal state and a strong potency in initiating tumor development and proliferation [ 182 , 186 , 187 ]. All these markers reflect the GSCs’ high heterogeneity and try to define the GSCs’ multiple cellular subclones or multipotent microstates, which are inducing strong adaptability and high invasiveness in GBM [ 188 ].…”

CAR-T Therapy for Pediatric High-Grade Gliomas: Peculiarities, Current Investigations and Future Strategies

“…GSCs are characterized by their self-renewal properties and play a key role in drug escape mechanisms, for example driving radiation-induced DNA methylation changes after radiotherapy ( 48 ) GSCs can promote a microinvasion of healthy tissues in areas that support their proliferation – such as subventricular, perinecrotic and perivascular areas ( 49 ) - evading therapeutic agents and contributing to recurrence of disease. Recently, a mouse model of disease derived by orthotopic transplantation of GSCs of pHGGs samples was developed ( 50 ).…”