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.
Highlights
Glioblastoma (GB), classified by the World Health Organization (WHO) as a grade IV astrocytoma is the most common and deadly type of primary malignant brain tumor, with a patient median survival of only 15–17 months following diagnosis [1,2,3].The standard of treatment for GB patients is the “Stupp protocol” which comprises tumor resection surgery, followed by concomitant radiotherapy and chemotherapy with temozolomide [4]
Gene expression analysis in SEBTA-023 cells revealed the differential expression of 20 genes at 6 h, and 24 genes at 48 h post-hypoxia incubation compared to normoxic control cells; 16 genes were conserved in both hypoxia time-points (Figure 1C,E and Table S4)
Our results showed either a decrease or no significant change in urokinase Plasminogen Activator (uPA) levels in hypoxic GB cells compared to their normoxic controls, suggesting that uPA produced by cells within the tumor microenvironment might play a critical role in uPA/plasmin dependent extra-cellular matrix (ECM) degradation in GB during hypoxia
Summary
The standard of treatment for GB patients is the “Stupp protocol” which comprises tumor resection surgery (if possible based on MRI imaging), followed by concomitant radiotherapy and chemotherapy with temozolomide [4]. While radiotherapy alone has been shown to significantly increase overall survival, subgroup analysis determined that clinical response to temozolomide was limited to those tumors containing O6-methylguanine DNA methyltransferase (MGMT) promoter methylation [1,5]. Irrespective of MGMT methylation, almost all GB patients develop resistance to therapy and succumb to the disease [6]. New targets and treatments against this devastating disease are urgently required. To this end it is essential to better understand the complex biology of GBs and their response(s) to the tumor microenvironment
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