Glioblastoma stem cells: Molecular characteristics and therapeutic implications

Abstract

Glioblastoma Multiforme (GBM) is a grade IV astrocytoma, with a median survival of 14.6 mo. Within GBM, stem-like cells, namely glioblastoma stem cells (GSCs), have the ability to self-renew, differentiate into distinct lineages within the tumor and initiate tumor xenografts in immunocompromised animal models. More importantly, GSCs utilize cell-autonomous and tumor microenvironment-mediated mechanisms to overcome current therapeutic approaches. They are, therefore, very important therapeutic targets. Although the functional criteria defining GSCs are well defined, their molecular characteristics, the mechanisms whereby they establish the cellular hierarchy within tumors, and their contribution to tumor heterogeneity are not well understood. This review is aimed at summarizing current findings about GSCs and their therapeutic importance from a molecular and cellular point of view. A better characterization of GSCs is crucial for designing effective GSC-targeted therapies.

Keywords: Differentiation; Glioblastoma; Glioblastoma stem cells; Molecular markers; Self-renewal; Therapy resistance.

Figure 1

Biological significance of glioblastoma stem cells. A: Glioblastoma stem cells (GSCs) have the ability to self-renew and differentiate into distinct lineages through different intermediate progenitors, a property termed multipotency. Co-existence of cells with different differentiation capacities defines the cellular hierarchy within the tumor; B: GSCs have the ability to initiate tumors more efficiently than differentiated cells. Tumor initation ability can be tested via intracranial xenograft models in immunodeficient animals. (1) These tumors can be imaged with Magnetic Resonance Imaging (MRI); (2) Microscopic analysis shows that xenografts maintain the histologic heterogeneity of the patient tumor, including the invasion of normal surrounding brain (arrowheads) (hNuc: human nuclear antigen marking human tumor cells in mouse brain, GFAP: Glial Fibrilary Acidic Protein, DAPI: nuclear counterstain); and (3) GSCs promote tumor heterogeneity by giving rise to distinct tumor lineages including tumor endothelium and pericytes, and maintain the phenotype of the parent tumor; C: GSCs are resistant to current therapeutic approaches causing relapse of the tumor.