Association for NeuroOncology (EANO) (2017). European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncology, 18(6):e315-e329. DOI: https://doi.org/10.1016/ S1470-2045(17) Implementing this guideline requires multidisciplinary and multiprofessional structures of care and defined processes of diagnosis and treatment.
There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme (GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A (LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non-neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic. LACTATE DEHYDROGENASELactate dehydrogenase (LDH) is a tetrameric enzyme, belonging to the 2-hydroxy acid oxidoreductase family, which increases the rate of the simultaneous inter-conversion of pyruvate to lactate and nicotinamide adenine dinucleotide (NAD)H to NAD + by 14 orders of magnitude (10) (Figure 1). The reaction involves the transfer of a hydride ion from NADH to the C2 carbon of pyruvate (99) and is commonly used by cells for anaerobic respiration. There are four LDH genes: LDHA, LDHB, LDHC and LDHD (Figure 2). LDHA, LDHB and LDHC are L isomers, whereas LDHD is a D isomer. The L isomers use or produce L-lactate, which is the major enantiomer found in vertebrates.The human LDHA gene is located on chromosome 11p15.4, the transcribed protein has 332 amino acids, a predicted molecular weight of 37 kDa and 24 splice variants; the human genome also contains several non-transcribed LDHA pseudogenes (32, 126). Evolutionarily, LDHA and LDHB are thought to have arisen from the duplication of a single LDHA-like LDH gene (82). LDHC, a testes-specific gene, is also thought to have evolved in mammals from the duplication of the LDHA gene after the A-B duplication (82).LDHA is also known as the M subunit as it is predominantly found in skeletal muscle, and LDHB is also known as the H subunit as it is predominantly found in the heart. Unlike the other LDH genes, which can form only homotetramers, LDHA and LDHB can form homo-or heterotetramers. There are five isoenzymes of LDH that can be made from the M and H subunits: LDH-1 (4H), LDH-2 (3H, 1M), LDH-3 (2H, 2M), LDH-4 (1H, 3M), and LDH-5 (5M) (Figure 2). LDH-1 and LDH-5 have identical active site regions and only differ in 81 out of 332 amino acid positions, mo...
Glioblastoma multiforme (GBM), a grade IV astrocytoma, is the most common and deadly type of primary malignant brain tumor, with a patient’s median survival rate ranging from 15 to 17 months. The current treatment for GBM involves tumor resection surgery based on MRI image analysis, followed by radiotherapy and treatment with temozolomide. However, the gradual development of tumor resistance to temozolomide is frequent in GBM patients leading to subsequent tumor regrowth/relapse. For this reason, the development of more effective therapeutic approaches for GBM is of critical importance. Low tumor oxygenation, also known as hypoxia, constitutes a major concern for GBM patients, since it promotes cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment. Tumor invasion not only constitutes a major obstacle to surgery, radiotherapy, and chemotherapy, but it is also the main cause of death in GBM patients. Understanding how hypoxia triggers the GBM cells to become invasive is paramount to developing novel and more effective therapies against this devastating disease. In this review, we will present a comprehensive examination of the available literature focused on investigating how GBM hypoxia triggers an invasive cancer cell phenotype and the role of these invasive proteins in GBM progression.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.