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.

Keywords: biomarkers; glioblastoma; glioblastoma stem cells; signal pathways; targeted therapy.

Figure 1

Glioblastoma stem cells (GSCs) are likely to be one of the potential causes of tumor proliferation, maintenance, malignant recurrence and metastasis in GBM, which aid in the self-renew, multilineage differentiation and proliferation of GSCs. Therefore, standard therapies alongside targeting GSCs or targeting GSCs niche might be the optimal therapy strategy for GBM.

Figure 2

The perivascular niche The self-renewal and maintenance of neighboring GSCs within the perivascular maintenance niche could been promoted via secretion of endothelial-derived diffusible signals including nitric oxide (NO), SHH, angiopoietin-1 (Ang-1), IL-8 and other soluble factors. GSCs are capable of stimulating the proliferation of endothelial cells and the sprouting of new vessels via secretion of VEGF and SDF-1 in the local tumor environment for sustainability and expansion of the vascular maintenance niche. The hypoxic niche With the constant invasion of GSCs, activation of hypoxia-related factors might take an active role in stemcell maintenance and one of the main factors is the hypoxia response Hypoxia Inducible Factor 1α (HIF-1α). The immune niche On the one hand, for TAMs, GSCs could chemo-attract and recruit TAMs to the tumor site, prompt the growth of macrophages and induce the polarization of TAMs into the immunosuppressive M2 phenotype through secreting chemokines and growth factors like VEGF, transforming growth factor-β (TGF-β), SDF1 and soluble colony-stimulating factor 1 (sCSF-1). On the other hand, the accumulation of these pro-tumorigenic TAMs in tumor could secrete cytokines and signaling molecules such as basic fibroblast growth factor (bFGF), TGFβ, SDF1, VEGF, and nitric oxide (NO), contributing to tumor progression and GSCs maintenance in turn.