Cancer stem cells in glioblastoma

Abstract

Tissues with defined cellular hierarchies in development and homeostasis give rise to tumors with cellular hierarchies, suggesting that tumors recapitulate specific tissues and mimic their origins. Glioblastoma (GBM) is the most prevalent and malignant primary brain tumor and contains self-renewing, tumorigenic cancer stem cells (CSCs) that contribute to tumor initiation and therapeutic resistance. As normal stem and progenitor cells participate in tissue development and repair, these developmental programs re-emerge in CSCs to support the development and progressive growth of tumors. Elucidation of the molecular mechanisms that govern CSCs has informed the development of novel targeted therapeutics for GBM and other brain cancers. CSCs are not self-autonomous units; rather, they function within an ecological system, both actively remodeling the microenvironment and receiving critical maintenance cues from their niches. To fulfill the future goal of developing novel therapies to collapse CSC dynamics, drawing parallels to other normal and pathological states that are highly interactive with their microenvironments and that use developmental signaling pathways will be beneficial.

Keywords: brain tumor; cancer stem cell; glioblastoma; glioma; stem cell; tumor-initiating cell.

Figure 1.

Functional criteria of CSCs. CSCs are defined by functional characteristics that include sustained self-renewal, persistent proliferation, and tumor initiation upon secondary transplantation, which is the definitive functional CSC assay. CSCs also share features with somatic stem cells, including frequency within a tissue (or tumor), stem cell marker expression (examples relevant to GBM and the brain are provided), and the ability to generate progeny of multiple lineages.

Figure 2.

Regulation of CSCs. Cell-autonomous (intrinsic) and external (extrinsic) forces regulate the CSC state. Key intrinsic regulators include genetic, epigenetic, and metabolic regulation, while extrinsic regulators include interaction with the microenvironment, including niche factors and the immune system.

Figure 3.

Proposed features of CSCs. Non-cell-autonomous aspects of CSCs may drive tumor growth but also serve as points of fragility. These include the increased ability to invade through the brain parenchyma, immune evasion, relationship with a niche, and promotion of angiogenesis.