Deadly teamwork: neural cancer stem cells and the tumor microenvironment

Abstract

Neural cancers display cellular hierarchies with self-renewing tumorigenic cancer stem cells (CSCs) at the apex. Instructive cues to maintain CSCs are generated by both intrinsic networks and the niche microenvironment. The CSC-microenvironment relationship is complex, as CSCs can modify their environment and extrinsic forces induce plasticity in the cellular hierarchy.

Figure 1. Microenvironmental factors modulate intrinsic cancer stem cell pathways

Cancer stem cells (CSC) in neural tumors (A) are enriched in niches including the perivascular compartment (C), hypoxic regions (B) and possibly the invasive edge (D). (B) Regions of hypoxia in neural tumors have been well-characterized near areas of necrosis. Recent studies have suggested that low oxygen helps to maintain the CSC population, therefore supporting hypoxic regions as a niche for CSCs. Hypoxia modulates cell phenotypes via HIF signaling, which drives expression of stem cell related genes. (C) The perivascular niche is the most well-defined CSC niche in neural tumors. Experimental evidence has demonstrated that cells expressing integrin alpha 6 are localized in the perivascular region denoted by CD31-positive endothelial cells of the blood vessel. Interaction of the integrin cell surface proteins with the extracellular matrix (ECM) within the perivascular space supports CSC maintenance in gliomas. Notch-ligand interaction between endothelial cells of the blood vessels and the cancer cell is also crucial for CSC maintenance but the cross-talk between key signaling receptors such as integrins and Notch are yet to be fully elucidated. Inhibition of the Notch pathway has been shown to have detrimental effects on the CSC phenotype as well as survival following irradiation in gliomas. (D) The invasive front of neural tumors is thought to contain CSCs and provide an interface of interactions with immune cells and normal brain stroma. It is hypothesized that the microenvironment of these invasive regions supports CSC maintenance. However, the invasive niche has not been well characterized.