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.

Keywords: cancer stem cell; diffuse intrinsic pontine glioma; diffuse midline glioma; glioblastoma; glioma stem cell; high grade glioma; recurrence; subventricular zone.

Figure 1

Illustration and schematic representation of a mouse and a human subventricular zone. (A) Coronal sections of a mouse (left) and a human (right) brain at the level of the lateral ventricles (LV). (B) Zoomed images of a mouse and a human brain subventricular zone stained with haematoxylin and eosin. The four human layers are indicated as layers I to IV from the lumen of the LV toward the parenchyma. (C) Schematic representation of the cellular composition of the mouse and the human subventricular zone (SVZ). In adult rodents, neural stem cells (NSCs), also called type B cells, are separated from the LV lumen by ependymal cells. Type B cells undergo asymmetrical cell divisions to give rise to a new type of B cell population with self-renewal properties (one of the hallmarks of a stem cell), as well as transit amplifying progenitor cells, also known as type C cells. Type C cells then migrate to become neural precursor cells including migrating neuroblasts (type A cells) or oligodendrocytes precursor cells. In the SVZ, type B cells display a double contact, one with the ventricle and one with the basal lamina of blood vessels, where the blood-brain barrier (BBB) is not complete. The human SVZ is composed of four distinct layers going from I to IV from the innermost toward the outermost layer. Layer I runs alongside the ventricular cavity and is a monolayer of ependymal cells responsible for the production and secretion of cerebrospinal fluid. Layer II is known as the hypocellular space as it contains cellular processes with only very few cell bodies. Layer III is a cellular ribbon mainly comprising cells expressing glial fibrillary acidic protein (GFAP) and neuroblasts. Finally, layer IV, the outermost layer adjacent to the parenchyma, is a transition zone mainly composed of myelinated axons and oligodendrocytes.

Figure 2

Mouse model of glioblastoma cell invasion into the subventricular zone. (A) Schematic representation of adult glioblastoma (GBM) cells grafted into the right striatum of a mouse brain (schematically drawn as a coronal section ahead of the hippocampus) and generating a tumor mass. Some GBM cells expressing CXCR4 (light brown cells) migrated through the corpus callosum to reach the subventricular zone (SVZ) of the lateral ventricles (LV), following a CXCL12 gradient (45, 46). (B) Schematic representation of pediatric diffuse midline glioma (DMG) cells grafted into the pons of a mouse brain (schematically drawn as a sagittal section) and generating a tumor mass. Some DMG cells (light brown cells) have migrated out of the tumor mass and reached the SVZ, following a gradient of proteins including pleiotrophin (47).