Abstract
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. Glioblastoma 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 Glioblastoma tumorigenesis and conventional-treatment resistance. In this review, we try to give a comprehensive view of the contribution of Notch signaling to Glioblastoma and its possible implication as a target for new therapeutic approaches.
Highlights
Glioblastoma is the most common and fatal type of primary brain tumor [1]
Conventional therapies have failed to improve patient survival due to a small subpopulation of cancer cells known as glioma stem cells (GSCs) that exhibit an enhanced self-renewal capacity, compromised differentiation, in vivo tumorigenicity, and resistance to radio- and chemotherapy
The Notch pathway could represent an attractive target for treatment in order to induce cell differentiation and kill both undifferentiated and differentiated tumor cells
Summary
Glioblastoma is the most common and fatal type of primary brain tumor [1]. It comprises 70% of all gliomas and is classified as a Grade IV astrocytoma (World Health Organization classification) [2]. The failure of current therapies is due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation [6,7] and the presence of a small subset of tumor cells that display stem cell-like properties, which are responsible for tumor relapse after conventional treatments [8,9]. This population, known as glioma stem cells (GSCs), exhibits an enhanced self-renewal capacity, compromised differentiation, and in vivo tumorigenicity, besides being radio- and chemoresistant [10,11].
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