Targeting Glioma Stem Cells: Therapeutic Opportunities and Challenges

Abstract

Glioblastoma (GBM), or grade 4 glioma, is the most common and aggressive primary brain tumor in adults with a median survival of 15 months. Increasing evidence suggests that GBM's aggressiveness, invasiveness, and therapy resistance are driven by glioma stem cells (GSCs), a subpopulation of tumor cells that share molecular and functional characteristics with neural stem cells (NSCs). GSCs are heterogeneous and highly plastic. They evade conventional treatments by shifting their state and entering in quiescence, where they become metabolically inactive and resistant to radiotherapy and chemotherapy. GSCs can exit quiescence and be reactivated to divide into highly proliferative tumor cells which contributes to recurrence. Understanding the molecular mechanisms regulating the biology of GSCs, their plasticity, and the switch between quiescence and mitotic activity is essential to shape new therapeutic strategies. This review examines the latest evidence on GSC biology, their role in glioblastoma progression and recurrence, emerging therapeutic approaches aimed at disrupting their proliferation and survival, and the mechanisms underlying their resistance to therapy.

Keywords: glioma stem cells; plasticity; quiescence; therapeutic targets; therapy resistance.

Figure 1

Similarities between neurogenesis and glioma genesis: implications for GBM cell states and cells of origin. During neurogenesis, neural stem cells (NSCs) differentiate into radical glia cells (RGCs), which give rise to two types of committed progenitor cells, namely the neural progenitor cells (NPCs) and glial progenitor cells (GPCs). Subsequently, NPCs produce neurons, whereas GPCs diversify into oligodendrocytes progenitor cells (OPCs) that generate oligodendrocytes and astrocyte progenitor cells (APC) that generate astrocytes [40]. Single-cell RNA analysis of GBM revealed the presence of NPC-like, OPC-like, and APC-like cell states, which have similar transcriptional features as NPCs, OPCs, and APCs, respectively. The mesenchymal-like (MES-like) cell state has relatively more distant similarities with RGCs [24].