Role of Notch Signaling Pathway in Glioblastoma Multiforme Pathogenesis

Notch signaling is an evolutionarily conserved pathway that regulates important biological processes, such as cell proliferation, apoptosis, migration, self-renewal, and differentiation. In mammals, Notch signaling is composed of four receptors (Notch1⁻4) and five ligands (Dll1-3⁻4, Jagged1⁻2) that mainly contribute to the development and maintenance of the central nervous system (CNS). Neural stem cells (NSCs) are the starting point for neurogenesis and other neurological functions, representing an essential aspect for the homeostasis of the CNS. Therefore, genetic and functional alterations to NSCs can lead to the development of brain tumors, including glioblastoma multiforme (GBM). GBM remains an incurable disease, and the reason for the failure of current therapies and tumor relapse is the presence of a small subpopulation of tumor cells known as glioma stem cells (GSCs), characterized by their stem cell-like properties and aggressive phenotype. Growing evidence reveals that Notch signaling is highly active in GSCs, where it suppresses differentiation and maintains stem-like properties, contributing to GBM tumorigenesis and conventional-treatment resistance. In this review, we try to give a comprehensive view of the contribution of Notch signaling to GBM and its possible implication as a target for new therapeutic approaches.