Glioma Stem Cells in Pediatric High-Grade Gliomas: From Current Knowledge to Future Perspectives

SIMPLE SUMMARY: Pediatric high-grade glioma (pHGG) has a dismal prognosis in which the younger the patient, the more restricted the treatments are, in regard to the incurred risks. Current therapies destroy many tumor cells but fail to target the highly malignant glioma stem cells (GSCs) that adapt quickly to give rise to recurring, treatment-resistant cancers. Despite a lack of consensus around an efficient detection, GSCs are well described in adult brain tumors but remain poorly investigated in pediatric cases, mostly due to their rarity. An improved knowledge about GSC roles in pediatric tumors would provide a key leverage towards the elimination of this sub-population, based on targeted treatments. The aim of this review is to sum up the state of art about GSCs in pHGG. ABSTRACT: In children, high-grade gliomas (HGG) and diffuse midline gliomas (DMG) account for a high proportion of death due to cancer. Glioma stem cells (GSCs) are tumor cells in a specific state defined by a tumor-initiating capacity following serial transplantation, self-renewal, and an ability to recapitulate tumor heterogeneity. Their presence was demonstrated several decades ago in adult glioblastoma (GBM), and more recently in pediatric HGG and DMG. In adults, we and others have previously suggested that GSCs nest into the subventricular zone (SVZ), a neurogenic niche, where, among others, they find shelter from therapy. Both bench and bedside evidence strongly indicate a role for the GSCs and the SVZ in GBM progression, fostering the development of innovative targeting treatments. Such new therapeutic approaches are of particular interest in infants, in whom standard therapies are often limited due to the risk of late effects. The aim of this review is to describe current knowledge about GSCs in pediatric HGG and DMG, i.e., their characterization, the models that apply to their development and maintenance, the specific signaling pathways that may underlie their activity, and their specific interactions with neurogenic niches. Finally, we will discuss the clinical relevance of these observations and the therapeutic advantages of targeting the SVZ and/or the GSCs in infants.