Neural Stem Cells of the Subventricular Zone as the Origin of Human Glioblastoma Stem Cells. Therapeutic Implications

Abstract

Human glioblastoma is the most aggressive type of primary malignant brain tumors. Standard treatment includes surgical resection followed by radiation and chemotherapy but it only provides short-term benefits and the prognosis of these brain tumors is still very poor. Glioblastomas contain a population of glioma stem cells (GSCs), with self-renewal ability, which are partly responsible for the tumor resistance to therapy and for the tumor recurrence after treatment. The human adult subventricular zone contains astrocyte-like neural stem cells (NSCs) that are probably reminiscent of the radial glia present in embryonic brain development. There are numerous molecules involved in the biology of subventricular zone NSCs that are also instrumental in glioblastoma development. These include cytoskeletal proteins, telomerase, tumor suppressor proteins, transcription factors, and growth factors. Interestingly, genes encoding these molecules are frequently mutated in glioblastoma cells. Indeed, it has been recently shown that NSCs in the subventricular zone are a potential cell of origin that contains the driver mutations of human glioblastoma. In this review we will describe common features between GSCs and subventricular zone NSCs, and we will discuss the relevance of this important finding in terms of possible future therapeutic strategies.

Keywords: adult neurogenesis; driver mutations; glioblastoma stem cells; neural stem cells; subventricular zone; tumor microenvironment.

Figure 1

Cell types in the neuroepithelium and in the subventricular zone. (A) Schematic representation of the ventricular zone (neuroepithelium) during development of the vertebrate central nervous system. Radial glia are represented in blue, neural progenitor cells in green, neuroblasts in red, and microglia in gray. A blood vessel is illustrated bordering the pial surface in dark red. (B) Schematic representation of the adult rodent subventricular zone (SVZ). Ependymal cells are represented in yellow, type B1 astrocytes in blue, type B2 astrocytes in pale blue, type C cells (transit-amplifying neural progenitor cells) in green, type A cell (neuroblasts) in red, and microglia in gray. (C) Schematic representation of the human adult SVZ. Ependymal cells are represented in yellow, astrocyte-like neural stem cells in blue, astrocytes in pale blue and microglia in gray. Layer I is constituted by the ependymal cells. Layers II and III are indicated in in the illustration. Layer IV is not shown. (D) Schematic representation of the human adult SVZ and an adjacent glioblastoma. Ependymal cells are represented in yellow, astrocyte-like neural stem cells in blue, astrocytes in pale blue, microglia in gray, glioma stem cells in purple, other type of glioma cells in pale purple. Astrocyte-like neural stem cells acquire driver mutations that generate glioma stem cells which divide to form the tumor mass.