Metabolic reprogramming in the pathogenesis of glioma: Update

Abstract

Cancer is a genetic disease that is currently classified not only by its tissue and cell type of origin but increasingly by its molecular composition. Increasingly, tumor classification and subtyping is being performed based upon the oncogene gains, tumor suppressor losses, and associated epigenetic and transcriptional features. However, cancers, including brain tumors, are also characterized by profound alterations in cellular metabolism. At present, even though signature mutations in known metabolic enzymes are recognized as being important, the metabolic landscape of tumors is not currently incorporated into tumor diagnostic categories. Here we describe a set of recent discoveries on metabolic reprogramming driven by mutations in the genes for the isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways, which are the most commonly observed aberrations in diffuse gliomas. We highlight the importance of oncometabolites to dynamically shift the epigenetic landscape in IDH‐mutant gliomas, and c‐Myc and mechanistic target of rapamycin (mTOR) complexes in RTK‐mutated gliomas to adapt to the microenvironment through metabolic reprogramming. These signify the integration of the genetic mutations with metabolic reprogramming and epigenetic shifts in diffuse gliomas, shedding new light onto potential patient subsets, coupled with information to guide the development of new therapeutic opportunities against the deadly types of brain tumors.

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

“…The standard treatments surgery, radio-and chemotherapydominantlyhave many limitations in GBM patients [29], the most important ones are the following: a. the special site of the The detected proliferation rates were given relative to controls (%). The additive (A) or the synergistic (S) effects of different drug combinations (RAPArapamycin 50 ng/ml; TMZ -temozolomide 100 μM; DOXYdoxycycline 10 μM; ETOetomoxir 50 μM; CHLchloroquine 50 μM; BPTESbis-2-(5-phenylacetoamido-1,3,4-thiadiazol-2-yl)-ethyl sulfide 10 μM) were calculated using the data sets of parallel monotherapies Table 1 bodythe blood-brain barrier filters many drugs; b. the tissue and genetic heterogeneity of the tumours; c. high resistance rate; and d. toxic side-effects (main targeted processes are also active in normal/non-malignant proliferating cells, as well).…”

Codependency of Metabolism and Epigenetics Drives Cancer Progression: A Review

“…epidermal growth factor receptor (EGFR), RAS, MYC] and dysregulated tumor suppressor genes (e.g. TP53, RB1), which are also hallmark genetic aberrations for GBM [51,55]. Additionally, isocitrate dehydrogenase (IDH) gene mutations (IDH1 and IDH2) were detected in more than 70% of grade II/III diffuse gliomas as well as in a small fraction of GBMs that progress from lower grade gliomas (LGGs).…”

Extracellular Vesicles in Glioblastoma Tumor Microenvironment

“…Tricarboxylic acid (TCA) pathway enzyme, isocitrate dehydrogenase (IDH) mutations are implicated in 5% of primary GBMs and 80% of secondary GBMs, and are also associated with the production of an oncogenic metabolite alpha-ketoglutarate (58,59,63). Khurshed et al showed that IDH1 wildtype glioma cells depend on glycolysis and lactate metabolism while IDH1 mutant glioma cells use oxidative TCA pathway (64).…”