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dc.contributor.authorLi, J-Len
dc.contributor.authorSainson, RCAen
dc.contributor.authorOon, CEen
dc.contributor.authorTurley, Hen
dc.contributor.authorLeek, Ren
dc.contributor.authorSheldon, Hen
dc.contributor.authorBridges, Een
dc.contributor.authorShi, Wen
dc.contributor.authorSnell, Cen
dc.contributor.authorBowden, ETen
dc.contributor.authorWu, Hen
dc.contributor.authorChowdhury, PSen
dc.contributor.authorRussell, AJen
dc.contributor.authorMontgomery, CPen
dc.contributor.authorPoulsom, Ren
dc.contributor.authorHarris, ALen
dc.date.accessioned2017-11-27T15:29:42Z
dc.date.available2017-11-27T15:29:42Z
dc.date.issued2011-09-15en
dc.identifier.urihttp://hdl.handle.net/10026.1/10291
dc.description.abstract

Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a γ-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxia-induced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic.

en
dc.format.extent6073 - 6083en
dc.languageengen
dc.language.isoengen
dc.subjectAngiogenesis Inhibitorsen
dc.subjectAnimalsen
dc.subjectAntibodies, Monoclonal, Humanizeden
dc.subjectBevacizumaben
dc.subjectCell Hypoxiaen
dc.subjectCell Line, Tumoren
dc.subjectDibenzazepinesen
dc.subjectDrug Resistance, Neoplasmen
dc.subjectFemaleen
dc.subjectFibrosarcomaen
dc.subjectGlioblastomaen
dc.subjectHumansen
dc.subjectIntracellular Signaling Peptides and Proteinsen
dc.subjectMembrane Proteinsen
dc.subjectMiceen
dc.subjectMice, Inbred BALB Cen
dc.subjectMice, SCIDen
dc.subjectNeovascularization, Pathologicen
dc.subjectReceptors, Notchen
dc.subjectSignal Transductionen
dc.subjectTransplantation, Heterologousen
dc.subjectVascular Endothelial Growth Factor Aen
dc.titleDLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/21803743en
plymouth.issue18en
plymouth.volume71en
plymouth.publication-statusPublisheden
plymouth.journalCancer Resen
dc.identifier.doi10.1158/0008-5472.CAN-11-1704en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine/UoA01 Clinical Medicine
dc.publisher.placeUnited Statesen
dc.identifier.eissn1538-7445en
dc.rights.embargoperiodNot knownen
rioxxterms.versionofrecord10.1158/0008-5472.CAN-11-1704en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.typeJournal Article/Reviewen


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