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, <i>SLC2A1</i>/GLUT-1, <i>CA9</i>/CAIX, and <i>SLC16A3</i>/MCT-4. Moreover, many proangiogenic genes and proteins, including VEGFA, VEGFC, VEGFD, <i>PGF</i>/PlGF, ADM, ANGPTL4, and <i>SERPINE1/</i>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, <i>BNIP-3</i> and <i>DDIT4</i> and of the multi-functional protein, NDRG1 associated with GB chemoresistance; and down-regulation of <i>EGR1</i> and <i>TFRC</i> (Graphical abstract). Analysis of GB patient cohorts' revealed differential expression of these genes in patient samples (except <i>SLC16A3</i>) compared to non-neoplastic brain tissue. High expression of <i>SLC2A1</i>, <i>LDHA</i>, <i>PDK1</i>, <i>PFKFB4</i>, <i>HK2</i>, <i>VEGFA</i>, <i>SERPINE1</i>, <i>TFRC</i>, and <i>ADM</i> 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.