Glioma Stem-Like Cells and Metabolism: Potential for Novel Therapeutic Strategies

Abstract

Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance.

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

“…Nonetheless, GSCs are not exclusively reliant on glycolysis, and can indeed generate energy using the citric acid cycle. Indeed, some GSCs contain higher levels of ATP than differentiated GBM cells, complicating the overall picture of metabolic reprogramming and illustrating intratumoral heterogeneity at the metabolic level, while suggesting that purely targeting the glycolytic pathway may not be effective against all GSCs [ 66 , 67 ]. In fact, mutations are found throughout the mitochondrial DNA genome in GBM cells, altering metabolic pathways and energy generation and contributing to therapeutic resistance [ 68 ].…”

“…In fact, mutations are found throughout the mitochondrial DNA genome in GBM cells, altering metabolic pathways and energy generation and contributing to therapeutic resistance [ 68 ]. Certain GSC subtypes rely on the glycolytic pathway to greater extents than other subtypes, which also utilize the mitochondrial pathways, illustrating the need for multiple therapeutic targets [ 63 , 67 ].…”

“…The pathway is initially suppressed under hypoxic conditions, resulting in a metabolic switch between glycolysis during periods of hypoxia and the pentose phosphate pathway during periods of oxygenation [ 69 ]. Long-term exposure to hypoxia may upregulate pentose phosphate pathway enzymes critical for GSC proliferation [ 67 ]. Oxidation of fatty acids can also promote GSC self-renewal and progression [ 63 ].…”

“…Conversely, blockade of the glycolytic pathway can be particularly effective against GSCs and differentiated tumor cells reliant on the Warburg effect. Indinavir and ritonavir are antagonists of the GLUT1 transporter that can reduce GSC proliferation in vitro, although strategies are needed to overcome the blood–brain barrier and localize therapy [ 67 ]. Pelaz et al designed a peptide that targets c-Src, an oncoprotein that interacts with gap junction proteins to regulate gluocse metabolism and promote GSC survival and invasion.…”

Carbon dot-based fluorescent antibody nanoprobes as brain tumour glioblastoma diagnostics

“…2 The most common malignant primary brain tumour called glioblastoma is characterised by abnormal blood vessels resulting in a leaky Blood–Brain Barrier (BBB). 3 Glial Fibrillary Acid Protein (GFAP) is unique to the brain and not present in normal peripheral blood. Antibodies targeting GFAP are used to diagnose gliomas in tissue samples.…”