Investigating Glioblastoma Response to Hypoxia

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, andSLC16A3/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD,PGF/PlGF, ADM, ANGPTL4, andSERPINE1/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-3andDDIT4and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation ofEGR1andTFRC(Graphical abstract). Analysis of GB patient cohorts' revealed differential expression of these genes in patient samples (exceptSLC16A3) compared to non-neoplastic brain tissue. High expression ofSLC2A1,LDHA,PDK1,PFKFB4,HK2,VEGFA,SERPINE1,TFRC, andADMwas 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.