The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

Abstract

Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.

A Composite Bioinformatic Analysis to Explore Endoplasmic Reticulum Stress-Related Prognostic Marker and Potential Pathogenic Mechanisms in Glioma by Integrating Multiomics Data

“…Recently, accumulating studies have illustrated that activated aerobic glycolysis participated in various cellular and clinical activities of glioma, thus influencing the efficacy of radiotherapy and chemotherapy [ 80 ]. Taken together, miRNA dysregulation in glioma disables proper tumor suppression, increases glycolytic metabolism, and augments tumor malignancy through multiple effectors and signaling pathways [ 81 ].…”

Brain‐targeting drug delivery systems

“…However, due to the invasive nature of gliomas and the structural similarity between malignant and normal brain tissue, intraoperative delineation of the infiltrating area of gliomas is important. Metabolic reprogramming in gliomas manifests as a shift in tumor cell glucose metabolism from OXPHOS to aerobic glycolysis, resulting in acidification of the extracellular fluid (pH 6.2-6.9), which is a clear hallmark of solid tumors (Reuss et al, 2021). The researchers developed a surface-enhanced Raman scattering (SERS) chip that sensed the acidity of a sample by designing a pH-responsive Raman signal, a hand-held Raman scanner that collected the Raman signal of the sample placed on the SERS chip, and an automated process to determine the sample pH (Figure 5f).…”

Application of 7T MRS to High-Grade Gliomas

“…Although its significance in HGGs and other brain tumors is still not entirely clear, Lac reflects anaerobic glycolysis, which may be a sign of neoplastic growth. 176,177 Increased glycolysis and perfusion in tumor tissue lead to elevated Lac, with higher levels corresponding with increased aggressiveness. 178,179 Imaging Lac in HGGs via techniques such as MRS is crucial because this metabolite may be a biomarker of more aggressive tumors, with increased Lac correlating particularly strongly with grade IV gliomas.…”