{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T17:21:54Z","timestamp":1781716914598,"version":"3.54.5"},"reference-count":78,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T00:00:00Z","timestamp":1599004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the association Fr\u00e9d\u00e9ric Fellay","award":["0111002"],"award-info":[{"award-number":["0111002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, characterized by a high degree of intertumoral heterogeneity. However, a common feature of the GBM microenvironment is hypoxia, which can promote radio- and chemotherapy resistance, immunosuppression, angiogenesis, and stemness. We experimentally defined common GBM adaptations to physiologically relevant oxygen gradients, and we assessed their modulation by the metabolic drug metformin. We directly exposed human GBM cell lines to hypoxia (1% O2) and to physioxia (5% O2). We then performed transcriptional profiling and compared our in vitro findings to predicted hypoxic areas in vivo using in silico analyses. We observed a heterogenous hypoxia response, but also a common gene signature that was induced by a physiologically relevant change in oxygenation from 5% O2 to 1% O2. In silico analyses showed that this hypoxia signature was highly correlated with a perinecrotic localization in GBM tumors, expression of certain glycolytic and immune-related genes, and poor prognosis of GBM patients. Metformin treatment of GBM cell lines under hypoxia and physioxia reduced viable cell number, oxygen consumption rate, and partially reversed the hypoxia gene signature, supporting further exploration of targeting tumor metabolism as a treatment component for hypoxic GBM.<\/jats:p>","DOI":"10.3390\/biology9090264","type":"journal-article","created":{"date-parts":[[2020,9,2]],"date-time":"2020-09-02T09:29:28Z","timestamp":1599038968000},"page":"264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin"],"prefix":"10.3390","volume":"9","author":[{"given":"Marta","family":"Calvo Tard\u00f3n","sequence":"first","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliana","family":"Marinari","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Migliorini","sequence":"additional","affiliation":[{"name":"Department of Oncology, Clinical Research Unit, Dubois Ferri\u00e8re Dinu Lipatti Research Foundation, Geneva University Hospitals, 1205 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviane","family":"Bes","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stoyan","family":"Tankov","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Charrier","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-3136","authenticated-orcid":false,"given":"Thomas A","family":"McKee","sequence":"additional","affiliation":[{"name":"Division of Clinical Pathology, Geneva University Hospitals, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3469-4237","authenticated-orcid":false,"given":"Val\u00e9rie","family":"Dutoit","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Yves","family":"Dietrich","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Cosset","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R","family":"Walker","sequence":"additional","affiliation":[{"name":"Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00401-016-1545-1","article-title":"The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary","volume":"131","author":"Louis","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1056\/NEJMra0708126","article-title":"Malignant gliomas in adults","volume":"359","author":"Wen","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ccr.2009.12.020","article-title":"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_5","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_6","doi-asserted-by":"crossref","first-page":"4009","DOI":"10.1073\/pnas.1219747110","article-title":"Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics","volume":"110","author":"Sottoriva","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1126\/science.1254257","article-title":"Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma","volume":"344","author":"Patel","year":"2014","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/s41588-018-0318-2","article-title":"Molecular landmarks of tumor hypoxia across cancer types","volume":"51","author":"Bhandari","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1093\/jnci\/djm135","article-title":"Drug resistance and the solid tumor microenvironment","volume":"99","author":"Tredan","year":"2007","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1634\/theoncologist.13-S3-21","article-title":"Hypoxia and aggressive tumor phenotype: Implications for therapy and prognosis","volume":"13","author":"Vaupel","year":"2008","journal-title":"Oncologist"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Wei, J., Wu, A., Kong, L.Y., Wang, Y., Fuller, G., Fokt, I., Melillo, G., Priebe, W., and Heimberger, A.B. (2011). Hypoxia potentiates glioma-mediated immunosuppression. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016195"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1152\/physrev.00041.2017","article-title":"Defining physiological normoxia for improved translation of cell physiology to animal models and humans","volume":"99","author":"Keeley","year":"2019","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5716","DOI":"10.1096\/fj.201802279R","article-title":"Physioxic human cell culture improves viability, metabolism, and mitochondrial morphology while reducing DNA damage","volume":"33","author":"Timpano","year":"2019","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0034-5687(01)00306-1","article-title":"Tissue oxygen tension and brain sensitivity to hypoxia","volume":"128","author":"Erecinska","year":"2001","journal-title":"Respir. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1002\/eji.201445284","article-title":"Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells","volume":"45","author":"Ducimetiere","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1089\/ars.2007.1628","article-title":"Detection and characterization of tumor hypoxia using pO2 histography","volume":"9","author":"Vaupel","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1101\/gad.12.2.149","article-title":"Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha","volume":"12","author":"Iyer","year":"1998","journal-title":"Genes Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1038\/emboj.2011.499","article-title":"Hypoxia regulates glutamate receptor trafficking through an HIF-independent mechanism","volume":"31","author":"Park","year":"2012","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29655","DOI":"10.1074\/jbc.M212770200","article-title":"A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets","volume":"278","author":"Arsham","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/neuonc\/noq052","article-title":"mTOR signaling in glioblastoma: Lessons learned from bench to bedside","volume":"12","author":"Akhavan","year":"2010","journal-title":"Neuro Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1954","DOI":"10.1056\/NEJMoa1707358","article-title":"Lomustine and bevacizumab in progressive glioblastoma","volume":"377","author":"Wick","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"254","DOI":"10.2337\/diacare.29.02.06.dc05-1558","article-title":"Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin","volume":"29","author":"Bowker","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"36441","DOI":"10.18632\/oncotarget.5541","article-title":"Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages","volume":"6","author":"Ding","year":"2015","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1073\/pnas.1417636112","article-title":"Immune-mediated antitumor effect by type 2 diabetes drug, metformin","volume":"112","author":"Eikawa","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1158\/2326-6066.CIR-16-0103","article-title":"Efficacy of PD-1 Blockade is potentiated by metformin-induced reduction of tumor hypoxia","volume":"5","author":"Scharping","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sesen, J., Dahan, P., Scotland, S.J., Saland, E., Dang, V.T., Lemarie, A., Tyler, B.M., Brem, H., Toulas, C., and Cohen-Jonathan Moyal, E. (2015). Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123721"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1056\/NEJMoa043331","article-title":"MGMT gene silencing and benefit from temozolomide in glioblastoma","volume":"352","author":"Hegi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.cell.2015.12.028","article-title":"Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma","volume":"164","author":"Ceccarelli","year":"2016","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9065","DOI":"10.1158\/0008-5472.CAN-09-2307","article-title":"Intrinsic gene expression profiles of gliomas are a better predictor of survival than histology","volume":"69","author":"Gravendeel","year":"2009","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s12967-019-1775-9","article-title":"A novel signature derived from immunoregulatory and hypoxia genes predicts prognosis in liver and five other cancers","volume":"17","author":"Chang","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1501137","DOI":"10.1080\/2162402X.2018.1501137","article-title":"Responsiveness to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade in SB28 and GL261 mouse glioma models","volume":"7","author":"Genoud","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6720","DOI":"10.4049\/jimmunol.181.10.6720","article-title":"TLR ligands in the local treatment of established intracerebral murine gliomas","volume":"181","author":"Grauer","year":"2008","journal-title":"J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nbt.2514","article-title":"Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples","volume":"31","author":"Cibulskis","year":"2013","journal-title":"Nat. Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.ccell.2017.10.016","article-title":"Glut3 addiction is a druggable vulnerability for a molecularly defined subpopulation of glioblastoma","volume":"32","author":"Cosset","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s00262-014-1561-8","article-title":"Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells","volume":"63","author":"Kosaka","year":"2014","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1111\/j.1349-7006.2006.00208.x","article-title":"Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy","volume":"97","author":"Szatmari","year":"2006","journal-title":"Cancer Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1002\/humu.23035","article-title":"TP53 Variations in human cancers: New lessons from the IARC TP53 database and genomics data","volume":"37","author":"Bouaoun","year":"2016","journal-title":"Hum Mutat"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1093\/nar\/gng015","article-title":"Summaries of Affymetrix GeneChip probe level data","volume":"31","author":"Irizarry","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_39","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","year":"2008","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1126\/science.aaf2666","article-title":"An anatomic transcriptional atlas of human glioblastoma","volume":"360","author":"Puchalski","year":"2018","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6503","DOI":"10.1158\/0008-5472.CAN-04-0452","article-title":"Gene expression profiling of gliomas strongly predicts survival","volume":"64","author":"Freije","year":"2004","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/neuonc\/now247","article-title":"GlioVis data portal for visualization and analysis of brain tumor expression datasets","volume":"19","author":"Bowman","year":"2017","journal-title":"Neuro Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","unstructured":"R Core Team (2013). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing. Available online: http:\/\/www.R-project.org\/."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1145\/2442116.2442120","article-title":"MORPHEUS: A heterogeneous dynamically reconfigurable platform for designing highly complex embedded systems","volume":"12","author":"Voros","year":"2013","journal-title":"ACM Trans. Embed. Comput. Syst."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1182\/blood-2004-07-2958","article-title":"Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1","volume":"105","author":"Manalo","year":"2005","journal-title":"Blood"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e207","DOI":"10.1182\/blood-2010-10-314427","article-title":"High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq","volume":"117","author":"Schodel","year":"2011","journal-title":"Blood"},{"key":"ref_49","unstructured":"Scarpace, L.F., Flanders, E., Jain, R., Mikkelsen, T., and Andrews, D.W. (2018, November 26). Data From REMBRANDT. The Cancer Imaging Archive. Available online: https:\/\/gdoc.georgetown.edu\/gdoc\/."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of cancer metabolism","volume":"2","author":"DeBerardinis","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.tibs.2012.06.004","article-title":"Passing the baton: The HIF switch","volume":"37","author":"Koh","year":"2012","journal-title":"Trends Biochem. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Murat, A., Migliavacca, E., Hussain, S.F., Heimberger, A.B., Desbaillets, I., Hamou, M.F., Ruegg, C., Stupp, R., Delorenzi, M., and Hegi, M.E. (2009). Modulation of angiogenic and inflammatory response in glioblastoma by hypoxia. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005947"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16238","DOI":"10.1038\/srep16238","article-title":"IDH mutation status is associated with a distinct hypoxia\/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma","volume":"5","author":"Kickingereder","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_54","first-page":"2867","article-title":"Clinical implications of hypoxia-inducible factor-1alpha and caveolin-1 overexpression in isocitrate dehydrogenase-wild type glioblastoma multiforme","volume":"17","author":"Chen","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1007\/s11060-011-0625-2","article-title":"IDH mutation status impact on in vivo hypoxia biomarkers expression: New insights from a clinical, nuclear imaging and immunohistochemical study in 33 glioma patients","volume":"105","author":"Metellus","year":"2011","journal-title":"J. Neurooncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7368","DOI":"10.1158\/0008-5472.CAN-07-0515","article-title":"Dual role of mitochondrial reactive oxygen species in hypoxia signaling: Activation of nuclear factor-{kappa}B via c-SRC and oxidant-dependent cell death","volume":"67","author":"Lluis","year":"2007","journal-title":"Cancer Res."},{"key":"ref_57","first-page":"57","article-title":"Metformin in cancer prevention and therapy","volume":"2","author":"Kasznicki","year":"2014","journal-title":"Ann. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1002\/ijc.31783","article-title":"Use of metformin and survival of patients with high-grade glioma","volume":"144","author":"Seliger","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1002\/ijc.32337","article-title":"Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis","volume":"164","author":"Seliger","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"113090","DOI":"10.18632\/oncotarget.23028","article-title":"Metformin and temozolomide, a synergic option to overcome resistance in glioblastoma multiforme models","volume":"8","author":"Valtorta","year":"2017","journal-title":"Oncotarget"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.4143\/crt.2017.466","article-title":"High-dose metformin plus temozolomide shows increased anti-tumor effects in glioblastoma in vitro and in vivo compared with monotherapy","volume":"50","author":"Lee","year":"2018","journal-title":"Cancer Res. Treat."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1097\/WNR.0b013e32836277fb","article-title":"Metformin inhibits glioma cell U251 invasion by downregulation of fibulin-3","volume":"24","author":"Gao","year":"2013","journal-title":"Neuroreport"},{"key":"ref_63","first-page":"5917470","article-title":"Metformin treatment inhibits motility and invasion of glioblastoma cancer cells","volume":"2018","author":"Fakhoury","year":"2018","journal-title":"Anal. Cell Pathol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1038\/nature11808","article-title":"Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP","volume":"494","author":"Miller","year":"2013","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"372","DOI":"10.3389\/fendo.2018.00372","article-title":"Metabolic profiles associated with metformin efficacy in cancer","volume":"9","author":"Andrzejewski","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"55057","DOI":"10.18632\/oncotarget.10842","article-title":"Metformin increases PDH and suppresses HIF-1alpha under hypoxic conditions and induces cell death in oral squamous cell carcinoma","volume":"7","author":"Guimaraes","year":"2016","journal-title":"Oncotarget"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"873","DOI":"10.18632\/oncotarget.6418","article-title":"Metformin suppresses hypoxia-induced stabilization of HIF-1alpha through reprogramming of oxygen metabolism in hepatocellular carcinoma","volume":"7","author":"Zhou","year":"2016","journal-title":"Oncotarget"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6741","DOI":"10.1158\/1078-0432.CCR-13-1787","article-title":"Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response","volume":"19","author":"Zannella","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1046\/j.1463-1326.2001.00128.x","article-title":"Lactic acidosis in metformin therapy: Searching for a link with metformin in reports of \u2018metformin-associated lactic acidosis\u2019","volume":"3","author":"Lalau","year":"2001","journal-title":"Diabetes Obes. Metab."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Gerthofer, V., Kreutz, M., Renner, K., Jachnik, B., Dettmer, K., Oefner, P., Riemenschneider, M.J., Proescholdt, M., Vollmann-Zwerenz, A., and Hau, P. (2018). Combined modulation of tumor metabolism by metformin and diclofenac in glioma. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092586"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Griss, T., Vincent, E.E., Egnatchik, R., Chen, J., Ma, E.H., Faubert, B., Viollet, B., DeBerardinis, R.J., and Jones, R.G. (2015). Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS Biol., 13.","DOI":"10.1371\/journal.pbio.1002309"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"793","DOI":"10.2174\/1389200219666180416161846","article-title":"Anti-cancer Effects of Metformin: Recent Evidences for its Role in Prevention and Treatment of Cancer","volume":"19","author":"Kheirandish","year":"2018","journal-title":"Curr. Drug Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"400","DOI":"10.3389\/fendo.2018.00400","article-title":"The therapeutic potential of metformin in neurodegenerative diseases","volume":"9","author":"Rotermund","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.canlet.2013.12.025","article-title":"Tumor suppressor p53 and its mutants in cancer metabolism","volume":"356","author":"Liu","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1038\/s41591-018-0052-4","article-title":"An inhibitor of oxidative phosphorylation exploits cancer vulnerability","volume":"24","author":"Molina","year":"2018","journal-title":"Nat. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41586-019-0993-x","article-title":"Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma","volume":"567","author":"Shi","year":"2019","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1158\/0008-5472.CAN-10-1769","article-title":"Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1","volume":"71","author":"Regazzetti","year":"2011","journal-title":"Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1093\/carcin\/bgu001","article-title":"Paradoxic effects of metformin on endothelial cells and angiogenesis","volume":"35","author":"Dallaglio","year":"2014","journal-title":"Carcinogenesis"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/9\/9\/264\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:05:47Z","timestamp":1760177147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/9\/9\/264"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,2]]},"references-count":78,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["biology9090264"],"URL":"https:\/\/doi.org\/10.3390\/biology9090264","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,2]]}}}