The Quiescent Metabolic Phenotype of Glioma Stem Cells

Abstract

Introduction: Glioblastoma (GBM) is the most common primary malignant brain tumor in humans and, even with aggressive treatment that includes surgical resection, radiation (IR), and chemotherapy administration, prognosis is poor due to tumor recurrence. There is evidence that within GBMs a small number of glioma stem-like cells (GSLCs) exist, which are thought to be therapy resistant and are thus capable of repopulating a tumor after treatment. Like most cancers, GBMs largely employ aerobic glycolysis to create ATP, a phenomenon known as the Warburg Effect. There is no consensus on the metabolic characteristics of cancer stem cells. GSLCs have been shown to rely more heavily on oxidative phosphorylation, but there is also evidence that cancer stem cells can adapt their metabolism by fluctuating between energy pathways or acquiring intermediate metabolic phenotypes. We hypothesized that the metabolism of GSLCs differs from that of differentiated GBM tumor cell lines, and that the steady state metabolism would be differentially altered following radiation treatment. Materials and Methods: We evaluated the oxygen consumption rate, extracellular acidification rate, and metabolic enzyme levels of GBM cell lines and GSLCs before and after irradiation using extracellular flux assays. We also measured absolute metabolite levels in these cells via mass spectroscopy with and without radiation treatment. Results: GSLCs were found to be significantly more quiescent in comparison to adherent GBM cell lines, highlighted by lower glycolytic and maximal respiratory capacities as well as lower oxygen consumption and extracellular acidification rates. Analysis of individual metabolite concentrations revealed lower total metabolite concentrations overall but also elevated levels of metabolites in different energy pathways for GSLCs compared to GBM cell lines. Additionally, the metabolism of both GSLCs and GBM cell lines were found to be altered by IR. Conclusion: While there is not one metabolic alteration that distinguishes irradiated GSLC metabolism from that of GBM cell lines, therapies targeting more metabolically quiescent tumor cells and thus the resistant GSLC population may increase a cancer's sensitivity to radiotherapy.

Beyond the Warburg Effect: Oxidative and Glycolytic Phenotypes Coexist within the Metabolic Heterogeneity of Glioblastoma

“…Consistent with our results, GSCs have been characterized by ample metabolic heterogeneity, exhibiting both glycolytic/oxidative characteristics [ 29 , 65 , 66 ]. Surprisingly, GBM27 exhibited a highly oxidative phenotype, at odds with Warburg’s central hypothesis of dysfunctional mitochondria; the presence of such metabolic subpopulations will need to be addressed to prevent tumor recurrence after antiglycolytic therapy.…”

The adaptive transition of glioblastoma stem cells and its implications on treatments

“…Tumor cells metabolic reprogramming, also known as the Warburg effect, refers to tumor cells preferring glycolysis rather than the tricarboxylic acid cycle even with adequate oxygen. 86 In contrast to GBM cells, the metabolic profile of GSCs, including lower glycolytic, lower extracellular acidification rate, less oxygen consumption and maximal respiratory capacities, 87 is more quiescent. It should be noted that recent studies reported different metabolic phenotypes of GSCs.…”

The “Superoncogene” Myc at the Crossroad between Metabolism and Gene Expression in Glioblastoma Multiforme

“…Moreover, GSCs present globally lower levels of metabolites (such as GTP and ATP), nonessential amino acids, fructose 6-phosphate, and fructose 1,6-bisphosphate. However, metabolites belonging to the pentose phosphate and galactose metabolism, glutaminolysis, and the citric acid cycle are present at high levels in GSCs [ 114 ]. Notably, the metabolic profile reflects GSC subtype identity.…”