Molecular Pathways and Genomic Landscape of Glioblastoma Stem Cells: Opportunities for Targeted Therapy

Abstract

Glioblastoma (GBM) is an aggressive tumor of the central nervous system categorized by the World Health Organization as a Grade 4 astrocytoma. Despite treatment with surgical resection, adjuvant chemotherapy, and radiation therapy, outcomes remain poor, with a median survival of only 14-16 months. Although tumor regression is often observed initially after treatment, long-term recurrence or progression invariably occurs. Tumor growth, invasion, and recurrence is mediated by a unique population of glioblastoma stem cells (GSCs). Their high mutation rate and dysregulated transcriptional landscape augment their resistance to conventional chemotherapy and radiation therapy, explaining the poor outcomes observed in patients. Consequently, GSCs have emerged as targets of interest in new treatment paradigms. Here, we review the unique properties of GSCs, including their interactions with the hypoxic microenvironment that drives their proliferation. We discuss vital signaling pathways in GSCs that mediate stemness, self-renewal, proliferation, and invasion, including the Notch, epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt, sonic hedgehog, transforming growth factor beta, Wnt, signal transducer and activator of transcription 3, and inhibitors of differentiation pathways. We also review epigenomic changes in GSCs that influence their transcriptional state, including DNA methylation, histone methylation and acetylation, and miRNA expression. The constituent molecular components of the signaling pathways and epigenomic regulators represent potential sites for targeted therapy, and representative examples of inhibitory molecules and pharmaceuticals are discussed. Continued investigation into the molecular pathways of GSCs and candidate therapeutics is needed to discover new effective treatments for GBM and improve survival.

TRPML2 Mucolipin Channels Drive the Response of Glioma Stem Cells to Temozolomide and Affect the Overall Survival in Glioblastoma Patients

“…The glioblastoma cell population is heterogeneous, with tumor-differentiated cells coexisting with subpopulations displaying stem cell characteristics. It is thought that GSCs derived from the normal NS/PC compartment [ 27 ] are responsible for recurrence and clinical relapse of glioblastoma [ 28 , 29 , 30 ]. Given that pharmacological modulation of the TRP ion channel activity in cancer cells is linked to their sensitivity to chemotherapeutic drugs [ 31 ], our goal was to examine the TRPML2 expression in GSCs and its relationship to resistance to TMZ, the standard chemotherapy for newly diagnosed GBM since 2005 and the subsequent use of the Stupp regimen [ 32 ].…”

Approaches to Incidental Intradural Tumors of the Spine in the Pediatric Population

“…Liquid biopsies could be used for more frequent follow-up compared to MRI scans. Additionally, the molecular profile of tumor cells and tumor stem-like cells driving proliferative activity can be analyzed to generate personalized therapies [80]. Several clinical trials are underway examining use of liquid biopsies in intracranial tumors [81].…”