Cancer stem cells in gliomas: evolving concepts and therapeutic implications.

Cancer stem cells (CSCs) have been implicated in the hierarchical heterogeneity and treatment resistance of hematologic and solid tumor malignancies, including gliomas, for several decades now but their therapeutic targeting has not been fully realized. Recent studies have uncovered deeper layers of CSC complexity, related to developmental origins, plasticity, cellular states, and interface with the microenvironment.Sequencing and in-vivo lineage-tracing studies in mouse and patient-derived models show evidence of stem and progenitor origin of glioma, at the same time that genomic studies show a relatedness of glioma CSCs with radial glia. The spate of single-cell sequencing analyses demonstrates the diversity of transcriptional cellular states, which are susceptible to transitions, indicating the plasticity of glioma CSCs. The evolution of glioma CSCs and their interactions with niche cells play important roles in CSC treatment resistance and immune evasion, with epigenetic modulation as one of the emerging mechanisms.To harness the potential of CSCs for clinical application, there is urgent need to investigate their complex nature and myriad interactions, to better understand the contribution of these self-renewing, stem-like cancer cells in the pathogenesis and therapy resistance of malignant brain tumors.