The Role of SVZ Stem Cells in Glioblastoma

Abstract

As most common primary brain cancer, glioblastoma is also the most aggressive and malignant form of cancer in the adult central nervous system. Glioblastomas are genetic and transcriptional heterogeneous tumors, which in spite of intensive research are poorly understood. Over the years conventional therapies failed to affect a cure, resulting in low survival rates of affected patients. To improve the clinical outcome, an important approach is to identify the cells of origin. One potential source for these are neural stem cells (NSCs) located in the subventricular zone, which is one of two niches in the adult nervous system where NSCs with the capacity of self-renewal and proliferation reside. These cells normally give rise to neuronal as well as glial progenitor cells. This review summarizes current findings about links between NSCs and cancer stem cells in glioblastoma and discusses current therapeutic approaches, which arise as a result of identifying the cell of origin in glioblastoma.

Keywords: brain tumor stem cells; glioblastoma; neural stem cells; neurogenesis; subventricular zone; therapy.

Figure 1

Schematic representation of the subventricular zone (SVZ) in a coronal view of the human brain and the adult human neurogenic niche in the sub-ependymal zone showing the cellular composition. The neurogenic niche in the SVZ can be divided into four layers (layer I–IV). The ependymal layer (layer I) separates the SVZ form the lumen of the ventricle by a thin single layer (monolayer) of ependymal cells (grey), which feature several apical microvilli and basal expansions. The ependyma is followed by the hypocellular layer (layer II), mainly containing astrocytic and ependymal processes. The astrocytic ribbon (layer III) primary contains astrocyte-like neural stem cells (NSCs) (red) and neuroblasts (orange), closely followed by the transitional zone (layer IV) which contains myelinated axons (black) and oligodendrocytes (violet). Thereafter the parenchyma begins, which mostly consists of neurons (green) and glia.

Figure 2

Schematic representation of the origin of brain tumor propagating cells (BTPCs) based on the cancer stem cell theory. In the SVZ of the adult brain, NSCs can be found in the sub-ependymal zone. There are two properties that NSCs need to achieve to become BTPCs. First, the cells need to become tumorigenic, including several mutations, resulting in mutated NSCs. Second these mutated NSCs have to be able to migrate over a long distance into other brain regions, where they form a tumor, which consists of BTPCs and more differentiated cancer cells which originate from the BTPCs themselves.

Figure 3

There are three therapeutic strategies to target brain tumor propagating cells (BTPCs). (I) Most common approaches include targeting specific cell surface markers, aberrantly up- or down-regulated signaling pathways or the BTPCs’ microenvironment. (II) The induction of apoptosis or stem cell differentiation as well as the inhibition of autophagy, which aims to reduce the number of BTPCs. (III) Application of vaccines or epigenetic drugs, which are still in development.