A map of the altered glioma metabolism

The neomorphic IDH1/2 mutations broadly perturb the metabolism of glioma cells, including their redox balance, but the oncogenic drive of the mutation seems to reside with the epigenetic effect of 2-HG. The avid uptake of glucose is a metabolic hallmark of the central nervous system that is maintained in glioma, impairing the detection of these tumors by 18F-FDG PET. Naïve glioblastoma cells cultured in serum-free conditions express neural stem cell markers, but display metabolic features typical of differentiated astrocytes, such as glutamine synthesis. Glutamate metabolism is at the crossroad of glioma biology and neurotransmission. The frequent occurrence of neomorphic isocitrate dehydrogenase 1 (IDH1) mutations in low-grade glioma led to an IDH-centric classification of these tumors. However, exploiting metabolic alterations of glioma for diagnostic imaging and treatment has marginally improved patients’ prognosis. Here we discuss the nutritional microenvironment of glioma, shaped by the distinctive dependence of the brain on glucose and ketone bodies for energy, and on amino acids for neurotransmission. We highlight the progress in metabolic applications for glioma diagnosis and therapy, and present a map that streamlines the rewired glioma metabolism. The map illustrates the altered reactions in central carbon and nitrogen metabolism that drive glioma biology, and represent metabolic vulnerabilities with translational potential. The frequent occurrence of neomorphic isocitrate dehydrogenase 1 (IDH1) mutations in low-grade glioma led to an IDH-centric classification of these tumors. However, exploiting metabolic alterations of glioma for diagnostic imaging and treatment has marginally improved patients’ prognosis. Here we discuss the nutritional microenvironment of glioma, shaped by the distinctive dependence of the brain on glucose and ketone bodies for energy, and on amino acids for neurotransmission. We highlight the progress in metabolic applications for glioma diagnosis and therapy, and present a map that streamlines the rewired glioma metabolism. The map illustrates the altered reactions in central carbon and nitrogen metabolism that drive glioma biology, and represent metabolic vulnerabilities with translational potential. PET using 18F-FDG as tracer is a noninvasive imaging technique employed for cancer visualization and diagnosis. 18F-FDG PET is usually coupled with CT (18F-FDG PET-CT). 18F-FDG is a positron-emitting glucose analog and is generally taken up and phosphorylated more efficiently by cancer cells than normal ones. This allows the acquisition of radiographic images where the tumor is distinguishable from the surrounding normal tissues. However, 18F-FDG PET is not employed to visualize gliomas because the uptake rate of glucose is comparable between these tumors and normal brain. reactions replenishing the TCA cycle intermediates (from the Greek ana: up, and plerotikos: to fill). reactions that utilize TCA cycle intermediates for biosynthesis (from the Greek cata: down, and plerotikos: to fill). nutritional regimen characterized by high-fat and low-carbohydrate content with a ratio (fat to combined carbohydrate and proteins) of about 4:1. This type of diet leads to a physiological state of ketosis, with increased blood concentrations of acetoacetate, beta-hydroxybutyrate, and acetone (ketone bodies). a genetic mutation that confers a new function to the gene product not pertinent to the wild-type gene. This type of mutation is not frequent in cancer. The point mutations occurring in the IDH1/2 genes are examples of oncogenic neomorphic mutations. a histologic feature characterized by a necrotic area surrounded by cancer cells whose orientation point away from irregular foci of tumor necrosis. This histologic architecture is frequently found in glioblastoma and takes its name from the Greek words pseudo, meaning false, and palisade, meaning a strong fence or protective perimeter made of wooden poles. a mass spectrometry-based analytical method used to trace the metabolic fate of a specific nutrient or metabolite (i.e., tracer). This technique involves the administration to cells or organisms of compounds in which one or more atoms are substituted by their stable, non-radioactive, heavy isotope(s). The biological activities of labeled compounds and downstream metabolites remain unaltered. Therefore, the mass shifts associated with the incorporated stable isotopes can be detected by mass spectrometry, and used to infer about the flux in the metabolic pathways downstream of the tracer.