Targeting Glioblastoma Stem Cells: A Review on Biomarkers, Signal Pathways and Targeted Therapy

Abstract

Glioblastoma (GBM) remains the most lethal and common primary brain tumor, even after treatment with multiple therapies, such as surgical resection, chemotherapy, and radiation. Although great advances in medical development and improvements in therapeutic methods of GBM have led to a certain extension of the median survival time of patients, prognosis remains poor. The primary cause of its dismal outcomes is the high rate of tumor recurrence, which is closely related to its resistance to standard therapies. During the last decade, glioblastoma stem cells (GSCs) have been successfully isolated from GBM, and it has been demonstrated that these cells are likely to play an indispensable role in the formation, maintenance, and recurrence of GBM tumors, indicating that GSCs are a crucial target for treatment. Herein, we summarize the current knowledge regarding GSCs, their related signaling pathways, resistance mechanisms, crosstalk linking mechanisms, and microenvironment or niche. Subsequently, we present a framework of targeted therapy for GSCs based on direct strategies, including blockade of the pathways necessary to overcome resistance or prevent their function, promotion of GSC differentiation, virotherapy, and indirect strategies, including targeting the perivascular, hypoxic, and immune niches of the GSCs. In summary, targeting GSCs provides a tremendous opportunity for revolutionary approaches to improve the prognosis and therapy of GBM, despite a variety of challenges.

Nanobody-based retargeting of an oncolytic herpesvirus for eliminating CXCR4+ GBM cells: A proof of principle

“…A wide variety of therapeutic strategies aiming to target GSCs have been evaluated in preclinical models and are being clinically translated. 26 However, considering the biological complexity and phenotypic plasticity of those cells, the main hurdle is to target GSCs without impairing normal tissue. In the perspective of eradicating peculiar GBM cell entities, such as GSCs, highly specific and targeted strategies should be considered.…”

“… 3 , 5 Targeting GSCs and particularly CXCR4 + cells therefore provides an opportunity to reach tumor cells that escape current treatments. 26 …”

Glioblastoma Microenvironment and Cellular Interactions

“…There is no consensus for the surface markers used for identifying the GSCs, which are constantly updated [ 181 ]. The usual markers used for identification of GSCs tumoral subpopulations, are: CD133 (prominin-1), L1 cell adhesion molecule (L1CAM), CD44, CD90, A2B5, GPD1, CD49f, EGFR, CD184 [ 169 , 179 , 182 , 183 , 184 ]. Nuclear protein Ki-67, associated Nestin or HOX genes, MUSASHI-1 protein (translation regulator), KLF4, SALL4, OCT-4, GFAP [ 184 ] were also used for the GSCs characterization.…”

Immunotherapeutic Approaches for Glioblastoma Treatment

“…The GSC niche is a highly heterogeneous and complex environment, with contributions from macrophages, pericytes, astrocytes, endothelial cells, and fibroblasts. In this context, studies suggest that there are three major GSC niches, namely the perivascular niche, perinecrotic/hypoxic niche, and immune niche [ 53 ]. The perivascular niche is characterized by poor and irregularly formed leaky and friable blood vessels, and GSCs act to regulate this vasculature and promote tumor angiogenesis [ 54 , 55 ].…”