Abstract
Glioblastoma (GBM), the most aggressive brain tumor, is associated with a median survival at diagnosis of 16–20 months and limited treatment options. The key hallmark of GBM is altered tumor metabolism and marked increase in the rate of glycolysis. Aerobic glycolysis along with elevated glucose consumption and lactate production supports rapid cell proliferation and GBM growth. In this study, we examined the gene expression profile of metabolic targets in GBM samples from patients with lower grade glioma (LGG) and GBM. We found that gene expression of glycolytic enzymes is up-regulated in GBM samples and significantly associated with an elevated risk for developing GBM. Our findings of clinical outcomes showed that GBM patients with high expression of HK2 and PKM2 in the glycolysis related genes and low expression of genes involved in mitochondrial metabolism-SDHB and COX5A related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS), respectively, was associated with poor patient overall survival. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in GBM compared to LGG but was lower compared to normal brain. The fact that in GBM the expression levels of TCA cycle and OXPHOS-related genes are higher than those in LGG patients suggests the metabolic shift in GBM cells when progressing from LGG to GBM. These results are an important step forward in our understanding of the role of metabolic reprogramming in glioma as drivers of the tumor and could be potential prognostic targets in GBM therapies.
Highlights
Glioblastoma Multiforme (GBM) is the most prolific and deadly malignant brain tumor in the United States with an age-adjusted incidence rate of 3.2 cases per 100,000 population and more than 13,000 cases projected in 2020 (Louis et al, 2016; Ostrom et al, 2017; Ostrom et al, 2019)
To have a complete overview of the metabolic genes expressed in lower grade glioma (LGG) and GBM stages of disease, we analyzed the transcription profiling of enzymes involved in glycolysis, PPP, tricarboxylic acid (TCA), and oxidative phosphorylation (OXPHOS) in brain samples from patients with LGG and GBM
We report that the changes in transcript expression of glycolysis and PPP genes in GBM is consistent with a Warburg-type metabolism and show a positive correlation between glycolytic gene expression and the risk of developing GBM and poor patient survival (Figure 6)
Summary
Glioblastoma Multiforme (GBM) is the most prolific and deadly malignant brain tumor in the United States with an age-adjusted incidence rate of 3.2 cases per 100,000 population and more than 13,000 cases projected in 2020 (Louis et al, 2016; Ostrom et al, 2017; Ostrom et al, 2019). Glioblastoma, Glycolysis and Survival availability, the median survival has only been improved from less than 10 months in the late 1970s (Salcman, 1980; Prados et al, 1998) to approximately 15 months (Stupp et al, 2005; Koshy et al, 2012; Ostrom et al, 2017; Ostrom et al, 2019) It remains that a more thorough understanding of GBM-centric biology is crucial in the improving clinical outcomes for GBM patients. A better understanding of the molecular basis of GBM formation and the identification of markers are essential for the development of preventive therapies targeting the specific GBM-promoting factors and thereby improve prognosis
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