{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T01:38:00Z","timestamp":1777081080613,"version":"3.51.4"},"reference-count":102,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T00:00:00Z","timestamp":1612137600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7ao para a Ciencia e a Tecnologia, Portugal","award":["IF\/00614\/2014"],"award-info":[{"award-number":["IF\/00614\/2014"]}]},{"name":"Funda\u00e7ao para a Ciencia e a Tecnologia, Portugal","award":["IF\/00614\/2014\/CP12340006"],"award-info":[{"award-number":["IF\/00614\/2014\/CP12340006"]}]},{"name":"Funda\u00e7ao para a Ciencia e a Tecnologia, Portugal","award":["UID\/BIM\/04773\/2013CBMR1334"],"award-info":[{"award-number":["UID\/BIM\/04773\/2013CBMR1334"]}]},{"DOI":"10.13039\/501100005736","name":"Universit\u00e9 Paris Diderot","doi-asserted-by":"publisher","award":["PhD fellowship"],"award-info":[{"award-number":["PhD fellowship"]}],"id":[{"id":"10.13039\/501100005736","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding the development of targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains the most clinically effective treatment for these patients. Nevertheless, radiotherapy resistance (radioresistance) is commonly observed in GB patients leading to tumor recurrence and eventually patient death. It is therefore essential to unravel the molecular mechanisms underpinning GB cell radioresistance in order to develop novel strategies and combinational therapies focused on enhancing tumor cell sensitivity to radiotherapy. In this review, we present a comprehensive examination of the current literature regarding the role of hypoxia (O2 partial pressure less than 10 mmHg), a main GB microenvironmental factor, in radioresistance with the ultimate goal of identifying potential molecular markers and therapeutic targets to overcome this issue in the future.<\/jats:p>","DOI":"10.3390\/cancers13030542","type":"journal-article","created":{"date-parts":[[2021,2,1]],"date-time":"2021-02-01T05:16:28Z","timestamp":1612156588000},"page":"542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":88,"title":["The Role of Hypoxia in Glioblastoma Radiotherapy Resistance"],"prefix":"10.3390","volume":"13","author":[{"given":"Agathe L.","family":"Ch\u00e9deville","sequence":"first","affiliation":[{"name":"INSERM, UMR 1287, Gustave Roussy, CEDEX 94805 Villejuif, France"},{"name":"Universit\u00e9 Paris-Saclay, UMR 1287, Gustave Roussy, CEDEX 94805 Villejuif, France"},{"name":"Gustave Roussy, UMR 1287, 114, Rue Edouard-Vaillant, CEDEX 94805 Villejuif, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4856-3908","authenticated-orcid":false,"given":"Patricia A.","family":"Madureira","sequence":"additional","affiliation":[{"name":"Centre for Biomedical Research (CBMR), University of Algarve, Gambelas Campus, Building 8, Room 2.22, 9005-139 Faro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1200\/JCO.2013.49.6968","article-title":"Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial","volume":"31","author":"Gilbert","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S1470-2045(09)70025-7","article-title":"European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial","volume":"10","author":"Stupp","year":"2009","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1093\/neuonc\/nov009","article-title":"Variation over time and interdependence between disease progression and death among patients with glioblastoma on RTOG 0525","volume":"17","author":"Wang","year":"2015","journal-title":"Neuro-Oncology"},{"key":"ref_4","unstructured":"Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., and Ellison, D.W. (2016). WHO Classification of Tumours of the Central Nervous System WHO Classification of Tumours, IARC Publications. [4th ed.]. Available online: https:\/\/www.iarc.who.int\/news-events\/iarc-publications-who-classification-of-tumours-of-the-central-nervous-system\/."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e000144","DOI":"10.1136\/esmoopen-2016-000144","article-title":"Hallmarks of glioblastoma: A systematic review","volume":"1","author":"Poulsen","year":"2016","journal-title":"ESMO Open"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nature07385","article-title":"Comprehensive genomic characterization defines human glioblastoma genes and core pathways","volume":"455","author":"McLendon","year":"2008","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"Cancer Genome Atlas Research Network Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1","volume":"17","author":"Verhaak","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.ccr.2006.02.019","article-title":"Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis","volume":"9","author":"Phillips","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Monteiro, A.R., Hill, R., Pilkington, G.J., and Madureira, P.A. (2017). The Role of Hypoxia in Glioblastoma Invasion. Cells, 6.","DOI":"10.3390\/cells6040045"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.cell.2013.09.034","article-title":"The somatic genomic landscape of glioblastoma","volume":"155","author":"Brennan","year":"2013","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1016\/j.ccr.2010.03.017","article-title":"Cancer Genome Atlas Research Network Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma","volume":"17","author":"Noushmehr","year":"2010","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Birzu, C., French, P., Caccese, M., Cerretti, G., Idbaih, A., Zagonel, V., and Lombardi, G. (2020). Recurrent Glioblastoma: From Molecular Landscape to New Treatment Perspectives. Cancers, 13.","DOI":"10.3390\/cancers13010047"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.3389\/fonc.2019.01547","article-title":"O6-Methylguanine-DNA Methyltransferase (MGMT): Challenges and New Opportunities in Glioma Chemotherapy","volume":"9","author":"Yu","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rajaratnam, V., Islam, M.M., Yang, M., Slaby, R., Ramirez, H.M., and Mirza, S.P. (2020). Glioblastoma: Pathogenesis and current status of chemotherapy and other novel treatments. Cancers, 12.","DOI":"10.3390\/cancers12040937"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1016\/j.yexcr.2012.07.017","article-title":"Hypoxia and hypoxia-inducible factors in glioblastoma multiforme progression and therapeutic implications","volume":"318","author":"Yang","year":"2012","journal-title":"Exp. Cell Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1215\/S1152851704001115","article-title":"Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis","volume":"7","author":"Kaur","year":"2005","journal-title":"Neuro-Oncology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/neup.12111","article-title":"Angiogenesis and expression of PDGF-C, VEGF, CD105 and HIF-1\u03b1 in human glioblastoma","volume":"34","author":"Clara","year":"2014","journal-title":"Neuropathology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1093\/neuonc\/not148","article-title":"Preoperative dynamic contrast-enhanced MRI correlates with molecular markers of hypoxia and vascularity in specific areas of intratumoral microenvironment and is predictive of patient outcome","volume":"16","author":"Jensen","year":"2014","journal-title":"Neuro-Oncology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1002\/1097-0142(197702)39:2+<689::AID-CNCR2820390702>3.0.CO;2-W","article-title":"Basic principles in radiation oncology","volume":"39","author":"Kaplan","year":"1977","journal-title":"Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1089\/ars.2013.5668","article-title":"Ionizing Radiation-Induced DNA Damage, Response, and Repair","volume":"21","author":"Santivasi","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nickoloff, J.A., Sharma, N., and Taylor, L. (2020). Clustered DNA Double-Strand Breaks: Biological Effects and Relevance to Cancer Radiotherapy. Genes, 15.","DOI":"10.3390\/genes11010099"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"235","DOI":"10.3390\/w3010235","article-title":"Water Radiolysis: Influence of Oxide Surfaces on H 2 Production under Ionizing Radiation","volume":"3","year":"2011","journal-title":"Water"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/em.22087","article-title":"Mechanisms of DNA damage, repair and mutagenesis","volume":"58","author":"Chatterjee","year":"2017","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1016\/j.dnarep.2008.05.007","article-title":"Chromium-mediated apoptosis: Involvement of DNA-dependent protein kinase (DNA-PK) and differential induction of p53 target genes","volume":"7","author":"Hill","year":"2008","journal-title":"DNA Repair"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3109\/09553002.2014.892227","article-title":"Cancer stem cells and radioresistance","volume":"90","author":"Rycaj","year":"2014","journal-title":"Int. J. Radiat. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"94","DOI":"10.3389\/fphar.2012.00094","article-title":"Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy","volume":"3","author":"Jordan","year":"2012","journal-title":"Front. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.ijrobp.2004.03.005","article-title":"Role of cell cycle in mediating sensitivity to radiotherapy","volume":"59","author":"Pawlik","year":"2004","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.2353\/ajpath.2010.091021","article-title":"Hypoxia increases the expression of stem-cell markers and promotes clonogenicity in glioblastoma neurospheres","volume":"177","author":"Bar","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_30","first-page":"553","article-title":"Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases","volume":"6","author":"Winkler","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_31","first-page":"4564","article-title":"Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows","volume":"54","author":"Yuan","year":"1994","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0940-2993(11)80292-7","article-title":"Vascular morphology and angiogenesis in glial tumors","volume":"47","author":"Plate","year":"1995","journal-title":"Exp. Toxicol. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1016\/j.acra.2005.05.027","article-title":"Vessel tortuosity and brain tumor malignancy: A blinded study","volume":"12","author":"Bullitt","year":"2005","journal-title":"Acad. Radiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1097\/00005072-200606000-00001","article-title":"\u201cPseudopalisading\u201d necrosis in glioblastoma: A familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis","volume":"65","author":"Rong","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/nrn2175","article-title":"Angiogenesis in brain tumours","volume":"8","author":"Jain","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Saxena, K., and Jolly, M.K. (2019). Acute vs. Chronic vs. cyclic hypoxia: Their differential dynamics, molecular mechanisms, and effects on tumor progression. Biomolecules, 9.","DOI":"10.3390\/biom9080339"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.molcel.2010.09.022","article-title":"Hypoxia-Inducible Factors and the Response to Hypoxic Stress","volume":"40","author":"Majmundar","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrc3183","article-title":"HIF1\u03b1 and HIF2\u03b1: Sibling rivalry in hypoxic tumour growth and progression","volume":"12","author":"Keith","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19575","DOI":"10.1074\/jbc.R200030200","article-title":"Hypoxia-inducible factor and its biomedical relevance","volume":"278","author":"Huang","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/nrm1366","article-title":"Oxygen sensing by HIF hydroxylases","volume":"5","author":"Schofield","year":"2004","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1146\/annurev.cellbio.15.1.551","article-title":"Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1","volume":"15","author":"Semenza","year":"1999","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"C260","DOI":"10.1152\/ajpcell.00315.2015","article-title":"Hypoxia-inducible factor 3 biology: Complexities and emerging themes","volume":"310","author":"Duan","year":"2016","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"25733","DOI":"10.1074\/jbc.M002740200","article-title":"Hypoxia Inducible Factor-\u03b1 Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein","volume":"275","author":"Cockman","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/20459","article-title":"The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1006\/bbrc.1999.0878","article-title":"Characterization of an oxygen\/redox-dependent degradation domain of hypoxia-inducible factor alpha (HIF-alpha) proteins","volume":"260","author":"Srinivas","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.1128\/MCB.18.7.4089","article-title":"Regulation of transcription by hypoxia requires a multiprotein complex that includes hypoxia-inducible factor 1, an adjacent transcription factor, and p300\/CREB binding protein","volume":"18","author":"Ebert","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"32253","DOI":"10.1074\/jbc.271.50.32253","article-title":"Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit","volume":"271","author":"Huang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5667","DOI":"10.1073\/pnas.94.11.5667","article-title":"Activation of hypoxia-inducible factor 1alpha: Posttranscriptional regulation and conformational change by recruitment of the Arnt transcription factor","volume":"94","author":"Kallio","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1101\/gad.924501","article-title":"FIH-1: A novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity","volume":"15","author":"Mahon","year":"2001","journal-title":"Genes Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1101\/gad.991402","article-title":"FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor","volume":"16","author":"Lando","year":"2002","journal-title":"Genes Dev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1016\/j.celrep.2014.02.011","article-title":"Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia","volume":"6","author":"Zhang","year":"2014","journal-title":"Cell Rep."},{"key":"ref_52","first-page":"1383","article-title":"Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas","volume":"60","author":"Frederick","year":"2000","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1200\/JCO.2004.02.141","article-title":"The biology and clinical relevance of the PTEN tumor suppressor pathway","volume":"22","author":"Sansal","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1101\/gad.14.1.34","article-title":"Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha","volume":"14","author":"Ravi","year":"2000","journal-title":"Genes Dev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1101\/gad.12.23.3675","article-title":"A constitutively active epidermal growth factor receptor cooperates with disruption of G1 cell-cycle arrest pathways to induce glioma-like lesions in mice","volume":"12","author":"Holland","year":"1998","journal-title":"Genes Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1054\/bjoc.2001.1805","article-title":"Mutant epidermal growth factor receptor enhances induction of vascular endothelial growth factor by hypoxia and insulin-like growth factor-1 via a PI3 kinase dependent pathway","volume":"84","author":"Clarke","year":"2001","journal-title":"Br. J. Cancer"},{"key":"ref_57","first-page":"1541","article-title":"Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor\/phosphatidylinositol 3-kinase\/PTEN\/AKT\/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics","volume":"60","author":"Zhong","year":"2000","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"8413032","DOI":"10.1155\/2016\/8413032","article-title":"The Tumorigenic Roles of the Cellular REDOX Regulatory Systems","volume":"2016","author":"Castaldo","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ch\u00e9deville, A.L., Lourdusamy, A., Monteiro, A.R., Hill, R., and Madureira, P.A. (2020). Investigating glioblastoma response to hypoxia. Biomedicines, 8.","DOI":"10.3390\/biomedicines8090310"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Sanzey, M., Abdul Rahim, S.A., Oudin, A., Dirkse, A., Kaoma, T., Vallar, L., Herold-Mende, C., Bjerkvig, R., Golebiewska, A., and Niclou, S.P. (2015). Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123544"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/359845a0","article-title":"Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo","volume":"359","author":"Plate","year":"1992","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/359843a0","article-title":"Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis","volume":"359","author":"Shweiki","year":"1992","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s007010050112","article-title":"Production of urokinase-type plasminogen activator (u-PA) and plasminogen activator inhibitor-1 (PAI-1) in human brain tumours","volume":"140","author":"Arai","year":"1998","journal-title":"Acta Neurochir."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s10555-019-09806-4","article-title":"The plasminogen activator inhibitor-1 paradox in cancer: A mechanistic understanding","volume":"38","author":"Kubala","year":"2019","journal-title":"Cancer Metastasis Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.1182\/blood-2011-06-334672","article-title":"The role of the annexin A2 heterotetramer in vascular fibrinolysis","volume":"118","author":"Madureira","year":"2011","journal-title":"Blood"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"353687","DOI":"10.1155\/2012\/353687","article-title":"The biochemistry and regulation of S100A10: A multifunctional plasminogen receptor involved in oncogenesis","volume":"2012","author":"Madureira","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"33257","DOI":"10.18632\/oncotarget.8921","article-title":"c-MYC inhibition impairs hypoxia response in glioblastoma multiforme","volume":"7","author":"Mongiardi","year":"2016","journal-title":"Oncotarget"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1158\/0008-5472.CAN-11-3831","article-title":"Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma","volume":"72","author":"Hu","year":"2012","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Tsai, Y.-T., Wu, A.-C., Yang, W.-B., Kao, T.-J., Chuang, J.-Y., Chang, W.-C., and Hsu, T.-I. (2019). ANGPTL4 Induces TMZ Resistance of Glioblastoma by Promoting Cancer Stemness Enrichment via the EGFR\/AKT\/4E-BP1 Cascade. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225625"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41416-018-0368-3","article-title":"The physiological mTOR complex 1 inhibitor DDIT4 mediates therapy resistance in glioblastoma","volume":"120","author":"Foltyn","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_71","first-page":"237","article-title":"Oxygen-dependent regulation of NDRG1 in human glioblastoma cells in vitro and in vivo","volume":"21","author":"Said","year":"2009","journal-title":"Oncol. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3625","DOI":"10.3892\/or.2017.5620","article-title":"Time- and oxygen-dependent expression and regulation of NDRG1 in human brain cancer cells","volume":"37","author":"Said","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1073\/pnas.1314469111","article-title":"mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy","volume":"111","author":"Weiler","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-12734-3_1","article-title":"Hypoxia mediates tumor malignancy and therapy resistance","volume":"Volume 1136","author":"Luo","year":"2019","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.3892\/ijo.2014.2358","article-title":"Hypoxia sustains glioblastoma radioresistance through ERKs\/DNA-PKcs\/HIF- 1\u03b1 functional interplay","volume":"45","author":"Marampon","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1158\/0008-5472.CAN-15-2058","article-title":"Therapeutics, Targets, and Chemical Biology FGFR1 Induces Glioblastoma Radioresistance through the PLCg\/Hif1a Pathway","volume":"76","author":"Delmas","year":"2016","journal-title":"Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1101\/gad.1617608","article-title":"Hypoxia regulates TSC1\/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling","volume":"22","author":"Horak","year":"2008","journal-title":"Genes Dev."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1038\/s41598-017-01207-3","article-title":"In silico evaluation of DNA Damage Inducible Transcript 4 gene (DDIT4) as prognostic biomarker in several malignancies","volume":"7","author":"Pinto","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature03205","article-title":"Regulation of cap-dependent translation by eIF4E inhibitory proteins","volume":"433","author":"Richter","year":"2005","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.ijrobp.2008.12.003","article-title":"Inhibition of 4E-BP1 Sensitizes U87 Glioblastoma Xenograft Tumors to Irradiation by Decreasing Hypoxia Tolerance","volume":"73","author":"Dubois","year":"2009","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1016\/j.ymthe.2019.07.011","article-title":"Hypoxic Glioma Cell-Secreted Exosomal miR-301a Activates Wnt\/\u03b2-catenin Signaling and Promotes Radiation Resistance by Targeting TCEAL7","volume":"27","author":"Yue","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1158\/1535-7163.MCT-15-0247","article-title":"Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism","volume":"14","author":"Shen","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Castaldo, S.A., Ajime, T., Serr\u00e3o, G., Anast\u00e1cio, F., Rosa, J.T., Giacomantonio, C.A., Howarth, A., Hill, R., and Madureira, P.A. (2019). Annexin A2 regulates akt upon h2o2-dependent signaling activation in cancer cells. Cancers, 11.","DOI":"10.3390\/cancers11040492"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1089\/ars.2015.6589","article-title":"Targeted Inhibition of Glutamine-Dependent Glutathione Metabolism Overcomes Death Resistance Induced by Chronic Cycling Hypoxia","volume":"25","author":"Matschke","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3389\/fonc.2018.00170","article-title":"The mitochondrial citrate carrier (SLC25A1) sustains redox homeostasis and mitochondrial metabolism supporting radioresistance of cancer cells with tolerance to cycling severe hypoxia","volume":"8","author":"Hlouschek","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"105132","DOI":"10.1016\/j.phrs.2020.105132","article-title":"Advances into Understanding the Vital Role of the Mitochondrial Citrate Carrier (CIC) in Metabolic Diseases","volume":"161","author":"Peng","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.18632\/oncotarget.714","article-title":"The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis","volume":"3","author":"Kolukula","year":"2012","journal-title":"Oncotarget"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.freeradbiomed.2012.06.009","article-title":"NADPH oxidase subunit 4 mediates cycling hypoxia-promoted radiation resistance in glioblastoma multiforme","volume":"53","author":"Hsieh","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.3892\/or_00001027","article-title":"Cycling hypoxia increases U87 glioma cell radioresistance via ROS induced higher and long-term HIF-1 signal transduction activity","volume":"24","author":"Hsieh","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/nm0797-730","article-title":"Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell","volume":"3","author":"Bonnet","year":"1997","journal-title":"Nat. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s40139-013-0035-6","article-title":"Cancer Stem Cells Under Hypoxia as a Chemoresistance Factor in the Breast and Brain","volume":"2","author":"Crowder","year":"2014","journal-title":"Curr. Pathobiol. Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1056\/NEJMra061808","article-title":"Cancer Stem Cells","volume":"355","author":"Jordan","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2016\/6809105","article-title":"Glioblastoma Stem Cells Microenvironment: The Paracrine Roles of the Niche in Drug and Radioresistance","volume":"2016","author":"Fidoamore","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11060-010-0357-8","article-title":"Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids","volume":"103","author":"Kolenda","year":"2011","journal-title":"J. Neurooncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.1158\/0008-5472.CAN-10-3320","article-title":"HIF induces human embryonic stem cell markers in cancer cells","volume":"71","author":"Mathieu","year":"2011","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/brain\/awq042","article-title":"A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2\u03b1","volume":"133","author":"Seidel","year":"2010","journal-title":"Brain"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/1476-4598-9-133","article-title":"Knock down of HIF-1\u03b1 in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres","volume":"9","author":"Zavadil","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/cdd.2011.109","article-title":"Hypoxia-induced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential","volume":"19","author":"Heddleston","year":"2012","journal-title":"Cell Death Differ."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/nature05236","article-title":"Glioma stem cells promote radioresistance by preferential activation of the DNA damage response","volume":"444","author":"Bao","year":"2006","journal-title":"Nature"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/cdd.2008.21","article-title":"The role of hypoxia-inducible factors in tumorigenesis","volume":"15","author":"Rankin","year":"2008","journal-title":"Cell Death Differ."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e1543","DOI":"10.1038\/cddis.2014.509","article-title":"Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: Possible involvement in radioresistance","volume":"5","author":"Dahan","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s11060-017-2427-7","article-title":"GBM radiosensitizers: Dead in the water \u2026 or just the beginning?","volume":"134","author":"Bindra","year":"2017","journal-title":"J. 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