{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:55:29Z","timestamp":1791262529702,"version":"4.1.0"},"reference-count":69,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T00:00:00Z","timestamp":1591833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Berliner Krebsgesellschaft","award":["xxx"],"award-info":[{"award-number":["xxx"]}]},{"DOI":"10.13039\/100008672","name":"Wilhelm Sander-Stiftung","doi-asserted-by":"publisher","award":["2013.111.1"],"award-info":[{"award-number":["2013.111.1"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Anni-Hofmann Stiftung","award":["xy"],"award-info":[{"award-number":["xy"]}]},{"name":"Familie Mehdorn Stiftung","award":["yy"],"award-info":[{"award-number":["yy"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma (GBM) present with an abundant and aberrant tumor neo-vasculature. While rapid growth of solid tumors depends on the initiation of tumor angiogenesis, GBM also progress by infiltrative growth and vascular co-option. The angiogenic factor apelin (APLN) and its receptor (APLNR) are upregulated in GBM patient samples as compared to normal brain tissue. Here, we studied the role of apelin\/APLNR signaling in GBM angiogenesis and growth. By functional analysis of apelin in orthotopic GBM mouse models, we found that apelin\/APLNR signaling is required for in vivo tumor angiogenesis. Knockdown of tumor cell-derived APLN massively reduced the tumor vasculature. Additional loss of the apelin signal in endothelial tip cells using the APLN-knockout (KO) mouse led to a further reduction of GBM angiogenesis. Direct infusion of the bioactive peptide apelin-13 rescued the vascular loss-of-function phenotype specifically. In addition, APLN depletion massively reduced angiogenesis-dependent tumor growth. Consequently, survival of GBM-bearing mice was significantly increased when APLN expression was missing in the brain tumor microenvironment. Thus, we suggest that targeting vascular apelin may serve as an alternative strategy for anti-angiogenesis in GBM.<\/jats:p>","DOI":"10.3390\/ijms21114179","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T03:17:32Z","timestamp":1592191052000},"page":"4179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Apelin Controls Angiogenesis-Dependent Glioblastoma Growth"],"prefix":"10.3390","volume":"21","author":[{"given":"Anne","family":"Frisch","sequence":"first","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9\u2013Universit\u00e4tsmedizin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"K\u00e4lin","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9\u2013Universit\u00e4tsmedizin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Monk","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9\u2013Universit\u00e4tsmedizin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9860-2007","authenticated-orcid":false,"given":"Josefine","family":"Radke","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9\u2013Universit\u00e4tsmedizin, 10117 Berlin, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Charit\u00e9 Berlin AND Berlin Institute of Health (BIH), 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank L.","family":"Heppner","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9\u2013Universit\u00e4tsmedizin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland E.","family":"K\u00e4lin","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9\u2013Universit\u00e4tsmedizin, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,11]]},"reference":[{"key":"ref_1","unstructured":"Kleihues, P., and Cavenee, W.K. (2000). Pathology and Genetics of Tumours of the Nervous System, IARC Press."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"e315","DOI":"10.1016\/S1470-2045(17)30194-8","article-title":"European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas","volume":"18","author":"Weller","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_4","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_5","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_6","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1007\/s11910-005-0047-7","article-title":"Optimal role of temozolomide in the treatment of malignant gliomas","volume":"5","author":"Stupp","year":"2005","journal-title":"Curr. Neurol. Neurosci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1056\/NEJM197111182852108","article-title":"Tumor angiogenesis: Therapeutic implications","volume":"285","author":"Folkman","year":"1971","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/0006-291X(89)92678-8","article-title":"Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells","volume":"161","author":"Ferrara","year":"1989","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/362841a0","article-title":"Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo","volume":"362","author":"Kim","year":"1993","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1056\/NEJMoa032691","article-title":"Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer","volume":"350","author":"Hurwitz","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJMoa1308345","article-title":"Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma","volume":"370","author":"Chinot","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1056\/NEJMoa1308573","article-title":"A randomized trial of bevacizumab for newly diagnosed glioblastoma","volume":"370","author":"Gilbert","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1126\/science.284.5422.1994","article-title":"Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF","volume":"284","author":"Holash","year":"1999","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2217\/cns.12.36","article-title":"Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma","volume":"2","author":"Lu","year":"2013","journal-title":"CNS Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ccr.2013.06.004","article-title":"A core human primary tumor angiogenesis signature identifies the endothelial orphan receptor ELTD1 as a key regulator of angiogenesis","volume":"24","author":"Masiero","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/0378-1119(93)90495-O","article-title":"A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11","volume":"136","author":"Heiber","year":"1993","journal-title":"Gene"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/bbrc.1998.9489","article-title":"Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor","volume":"251","author":"Tatemoto","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S0167-4889(00)00143-9","article-title":"Molecular properties of apelin: Tissue distribution and receptor binding","volume":"1538","author":"Kawamata","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.ydbio.2007.03.004","article-title":"Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis","volume":"305","author":"Kretz","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_20","first-page":"787","article-title":"G protein-coupled APJ receptor signaling induces focal adhesion formation and cell motility","volume":"16","author":"Hashimoto","year":"2005","journal-title":"Int. J. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"21061","DOI":"10.1074\/jbc.M908417199","article-title":"Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin","volume":"275","author":"Hosoya","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.ydbio.2006.04.452","article-title":"Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo","volume":"296","author":"Cox","year":"2006","journal-title":"Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.bbrc.2004.10.042","article-title":"Apelin is a novel angiogenic factor in retinal endothelial cells","volume":"325","author":"Kasai","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19379","DOI":"10.1038\/srep19379","article-title":"Combinatorial Treatment with Apelin-13 Enhances the Therapeutic Efficacy of a Preconditioned Cell-Based Therapy for Peripheral Ischemia","volume":"6","author":"Samura","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8170","DOI":"10.1038\/srep08170","article-title":"Elabela-apelin receptor signaling pathway is functional in mammalian systems","volume":"5","author":"Wang","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4426","DOI":"10.18632\/oncotarget.2032","article-title":"Apelin promotes lymphangiogenesis and lymph node metastasis","volume":"5","author":"Berta","year":"2014","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1111\/1440-1681.12563","article-title":"PAK1-cofilin phosphorylation mediates human lung adenocarcinoma cells migration induced by apelin-13","volume":"43","author":"Lv","year":"2016","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1182\/blood-2010-02-270819","article-title":"Identification and functional analysis of endothelial tip cell-enriched genes","volume":"116","author":"Prahst","year":"2010","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1161\/ATVBAHA.108.163402","article-title":"Retardation of retinal vascular development in apelin-deficient mice","volume":"28","author":"Kasai","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/sj.emboj.7601982","article-title":"Spatial and temporal role of the apelin\/APJ system in the caliber size regulation of blood vessels during angiogenesis","volume":"27","author":"Kidoya","year":"2008","journal-title":"EMBO J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5102","DOI":"10.1182\/blood-2009-07-230284","article-title":"Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching","volume":"115","author":"Strasser","year":"2010","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6020","DOI":"10.1038\/ncomms7020","article-title":"Genetic targeting of sprouting angiogenesis using Apln-CreER","volume":"6","author":"Liu","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"H88","DOI":"10.1152\/ajpheart.00935.2007","article-title":"F genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure","volume":"294","author":"Sheikh","year":"2008","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1161\/CIRCRESAHA.107.158659","article-title":"Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload","volume":"101","author":"Kuba","year":"2007","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3166","DOI":"10.1182\/blood-2009-07-232306","article-title":"Apelin induces enlarged and nonleaky blood vessels for functional recovery from ischemia","volume":"115","author":"Kidoya","year":"2010","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"H1904","DOI":"10.1152\/ajpheart.00686.2009","article-title":"Endogenous regulation of cardiovascular function by apelin-APJ","volume":"297","author":"Charo","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.2144\/02336st01","article-title":"Targeting the kinesin Eg5 to monitor siRNA transfection in mammalian cells","volume":"33","author":"Weil","year":"2002","journal-title":"Biotechniques"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1111\/j.1750-3639.2003.tb00487.x","article-title":"Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas","volume":"13","author":"Machein","year":"2003","journal-title":"Brain Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12530","DOI":"10.1073\/pnas.0804273106","article-title":"Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion","volume":"106","author":"Markovic","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.yexmp.2006.12.011","article-title":"The quantification of vascular beds: A stereological approach","volume":"82","author":"Dockery","year":"2007","journal-title":"Exp. Mol. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/hipo.1088","article-title":"Stereological estimates of number and length of capillaries in subdivisions of the human hippocampal region","volume":"11","author":"Lokkegaard","year":"2001","journal-title":"Hippocampus"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1046\/j.1365-2818.2002.01006.x","article-title":"Stereological length estimation using spherical probes","volume":"206","author":"Mouton","year":"2002","journal-title":"J. Microsc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1750-1326-4-42","article-title":"Novel cerebrovascular pathology in mice fed a high cholesterol diet","volume":"4","author":"Franciosi","year":"2009","journal-title":"Mol. Neurodegener."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1038\/nprot.2015.002","article-title":"Quantitative assessment of angiogenesis, perfused blood vessels and endothelial tip cells in the postnatal mouse brain","volume":"10","author":"Walchli","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1210\/en.2004-0359","article-title":"Modification of the terminal residue of apelin-13 antagonizes its hypotensive action","volume":"146","author":"Lee","year":"2005","journal-title":"Endocrinology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nrd1381","article-title":"Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer","volume":"3","author":"Ferrara","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_48","first-page":"1120","article-title":"Apelin expression in human non-small cell lung cancer: Role in angiogenesis and prognosis","volume":"5","author":"Berta","year":"2010","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7692","DOI":"10.1038\/sj.onc.1210573","article-title":"Apelin is a potent activator of tumour neoangiogenesis","volume":"26","author":"Sorli","year":"2007","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e10892","DOI":"10.15252\/emmm.201910892","article-title":"What is normal? Apelin and VEGFA, drivers of tumor vessel abnormality","volume":"11","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e9266","DOI":"10.15252\/emmm.201809266","article-title":"Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy","volume":"11","author":"Uribesalgo","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Reizes, O., and Berger, N.A. (2017). Adipocitokines, Energy Balance and Cancer\u2014Energy Balance and Cancer, Springer International Publishing Switzerland.","DOI":"10.1007\/978-3-319-41677-9"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Ganguly, D., Cai, C., Sims, M.M., He Yang, C., Thomas, M., Cheng, J., Saad, A.G., and Pfeffer, L.M. (2019). APELA Expression in Glioma, and Its Association with Patient Survival and Tumor Grade. Pharmaceuticals, 12.","DOI":"10.3390\/ph12010045"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.devcel.2013.11.002","article-title":"Elabela: A hormone essential for heart development signals via the apelin receptor","volume":"27","author":"Chng","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1248636","DOI":"10.1126\/science.1248636","article-title":"Toddler: An embryonic signal that promotes cell movement via apelin receptors","volume":"343","author":"Pauli","year":"2014","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3254","DOI":"10.1038\/onc.2011.489","article-title":"The apelin\/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy","volume":"31","author":"Kidoya","year":"2011","journal-title":"Oncogene"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1158\/0008-5472.CAN-18-0881","article-title":"Targeting APLN\/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA\/VEGFR2 Blockade in Glioblastoma","volume":"79","author":"Mastrella","year":"2019","journal-title":"Cancer Res."},{"key":"ref_58","first-page":"6624","article-title":"Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a monoclonal antibody against vascular endothelial growth factor receptor-2","volume":"61","author":"Kunkel","year":"2001","journal-title":"Cancer Res."},{"key":"ref_59","first-page":"169","article-title":"Invasion as limitation to anti-angiogenic glioma therapy","volume":"88","author":"Lamszus","year":"2003","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.1073\/pnas.1014480108","article-title":"Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma","volume":"108","author":"Keunen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1093\/brain\/awx253","article-title":"Pharmacological targeting of apelin impairs glioblastoma growth","volume":"140","author":"Jacobs","year":"2017","journal-title":"Brain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3389\/fonc.2014.00047","article-title":"Prognostic and predictive biomarkers in adult and pediatric gliomas: Toward personalized treatment","volume":"4","author":"Haynes","year":"2014","journal-title":"Front. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.oraloncology.2011.12.015","article-title":"Hypoxia-induced up-regulation of apelin is associated with a poor prognosis in oral squamous cell carcinoma patients","volume":"48","author":"Heo","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"42949","DOI":"10.18632\/oncotarget.17306","article-title":"Apelin: A putative novel predictive biomarker for bevacizumab response in colorectal cancer","volume":"8","author":"Zuurbier","year":"2017","journal-title":"Oncotarget"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/j.celrep.2018.10.015","article-title":"Apj (+) Vessels Drive Tumor Growth and Represent a Tractable Therapeutic Target","volume":"25","author":"Zhao","year":"2018","journal-title":"Cell Rep."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1158\/0008-5472.CAN-19-0749","article-title":"Role of Apelin in Glioblastoma Vascularization and Invasion after Anti-VEGF Therapy: What Is the Impact on the Immune System?","volume":"79","author":"Amoozgar","year":"2019","journal-title":"Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"United Kingdom Co-Ordinating Committee on Cancer (1989). Guidelines for the welfare of animals in experimental neoplasia. Cancer Metastasis Rev., 8, 82\u201388.","DOI":"10.1007\/BF00047058"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","article-title":"RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement","volume":"68","author":"Shinkai","year":"1992","journal-title":"Cell"},{"key":"ref_69","first-page":"177","article-title":"Stereological and allometric studies on mammalian cerebral cortex with implications for medical brain imaging","volume":"189","author":"Mayhew","year":"1996","journal-title":"J. Anat."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4179\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:38:02Z","timestamp":1760175482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/11\/4179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,11]]},"references-count":69,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21114179"],"URL":"https:\/\/doi.org\/10.3390\/ijms21114179","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,11]]}}}