Investigating Glioblastoma Response to Hypoxia

Abstract

Glioblastoma (GB) is the most common and deadly type of primary malignant brain tumor with an average patient survival of only 15–17 months. GBs typically have hypoxic regions associated with aggressiveness and chemoresistance. Using patient derived GB cells, we characterized how GB responds to hypoxia. We noted a hypoxia-dependent glycolytic switch characterized by the up-regulation of HK2, PFKFB3, PFKFB4, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CAIX, and SLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM, ANGPTL4, and SERPINE1/PAI-1 were up-regulated during hypoxia. We detected the hypoxic induction of invasion proteins, including the plasminogen receptor, S100A10, and the urokinase plasminogen activator receptor, uPAR. Furthermore, we observed a hypoxia-dependent up-regulation of the autophagy genes, BNIP-3 and DDIT4 and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of EGR1 and TFRC (Graphical abstract). Analysis of GB patient cohorts’ revealed differential expression of these genes in patient samples (except SLC16A3) compared to non-neoplastic brain tissue. High expression of SLC2A1, LDHA, PDK1, PFKFB4, HK2, VEGFA, SERPINE1, TFRC, and ADM was associated with significantly lower overall survival. Together these data provide important information regarding GB response to hypoxia which could support the development of more effective treatments for GB patients.

The Role of Hypoxia in Glioblastoma Radiotherapy Resistance

“…HIFs induce the transcription of hundreds of genes involved in the regulation of main cellular processes including angiogenesis, glycolysis, autophagy, motility and invasion, chemo- and radioresistance [ 58 , 59 ].…”

“…Several studies using GB cell lines and/or clinical samples support a hypoxia triggered metabolic switch towards glycolysis including the up-regulation of HK2, PFKFB3, PFKFB4, PFKFP, LDHA, PDK1, SLC2A1/GLUT-1, CA9/CA IX, PGAM1, ENO1, ENO2, ALDOA and SLC16A3/ MCT-4 genes and proteins ( Figure 4 ) [ 9 , 59 , 60 ]. Hypoxic up-regulation of many pro-angiogenic genes and proteins is also commonly observed in GB.…”

“…Hypoxic up-regulation of many pro-angiogenic genes and proteins is also commonly observed in GB. These include VEGFA, VEGFC, VEGFD, PGF/PlGF, ADM and ANGPTL4 ( Figure 4 ) [ 32 , 59 , 61 , 62 ]. GB is a highly invasive tumor and hypoxia has been shown to induce proteins of the plasminogen system.…”

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

“…A very recent study explained the role of the hypoxic state in patient-derived glioma cells to escalate the antigenic and invasive potential. The aggressive nature was accompanied by upregulated autophagy-related genes, including BCL-2 interacting protein 3 (BNIP-3) and DNA damage inducible transcript 4 (DDIT4), which are associated with chemoresistance [ 133 ]. EGFR, VEGF and RET tyrosine kinase are shown to be a contributing factor in the underlying drug-resistance mechanisms in glioblastoma patients.…”

Understanding the glioblastoma tumor biology to optimize photodynamic therapy: From molecular to cellular events

“…It has also been observed that these necrotic foci have surrounding cells arranged in a pseudopalised structure and microvascular hyperplasia (capillaries) associated with rapid tumor progression and invasion, further deteriorating the prognosis of patients (Monteiro et al, 2017). One of the main characteristics observed in GBM is the presence of hypoxic nuclei regions with partial pressures of oxygen (O 2 ) below 10 mmHg, a fact that is associated with both tumor aggressiveness and resistance to chemotherapy drugs (Chédeville et al, 2020). These hypoxic areas are associated with the layer of cancer cell spreading (invasion) into the healthy brain tissue in order to evade this adverse microenvironment.…”