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dc.contributor.authorOon, CEen
dc.contributor.authorBridges, Een
dc.contributor.authorSheldon, Hen
dc.contributor.authorSainson, RCAen
dc.contributor.authorJubb, Aen
dc.contributor.authorTurley, Hen
dc.contributor.authorLeek, Ren
dc.contributor.authorBuffa, Fen
dc.contributor.authorHarris, ALen
dc.contributor.authorLi, J-Len
dc.date.accessioned2017-11-27T15:04:35Z
dc.date.available2017-11-27T15:04:35Z
dc.date.issued2017-06-20en
dc.identifier.urihttp://hdl.handle.net/10026.1/10283
dc.description.abstract

Delta-like 4 (DLL4) and Jagged1 (JAG1) are two key Notch ligands implicated in tumour angiogenesis. They were shown to have opposite effects on mouse retinal and adult regenerative angiogenesis. In tumours, both ligands are upregulated but their relative effects and interactions in tumour biology, particularly in tumour response to therapeutic intervention are unclear. Here we demonstrate that DLL4 and JAG1 displayed equal potency in stimulating Notch target genes in HMEC-1 endothelial cells but had opposing effects on sprouting angiogenesis in vitro. Mouse DLL4 or JAG1 expressed in glioblastoma cells decreased tumour cell proliferation in vitro but promoted tumour growth in vivo. mDLL4-expressing tumours showed fewer but larger vessels whereas mJAG1-tumours produced more vessels. In both tumour types pericyte coverage was decreased but the vessels were more perfused. Both ligands increased tumour resistance towards anti-VEGF therapy but the resistance was higher in mDLL4-tumours versus mJAG1-tumours. However, their sensitivity to the therapy was restored by blocking Notch signalling with dibenzazepine. Importantly, anti-DLL4 antibody blocked the effect of JAG1 on tumour growth and increased vessel branching in vivo. The mechanism behind the differential responsiveness was due to a positive feedback loop for DLL4-Notch signalling, rendering DLL4 more dominant in activating Notch signalling in the tumour microenvironment. We concluded that DLL4 and JAG1 promote tumour growth by modulating tumour angiogenesis via different mechanisms. JAG1 is not antagonistic but utilises DLL4 in tumour angiogenesis. The results suggest that anti-JAG1 therapy should be explored in conjunction with anti-DLL4 treatment in developing anti-Notch therapies in clinics.

en
dc.format.extent40115 - 40131en
dc.languageengen
dc.language.isoengen
dc.subjectDLL4en
dc.subjectJAG1en
dc.subjectNotch signallingen
dc.subjectangiogenesisen
dc.subjectbevacizumaben
dc.subjectAnimalsen
dc.subjectBevacizumaben
dc.subjectCell Lineen
dc.subjectCell Line, Tumoren
dc.subjectCell Proliferationen
dc.subjectCells, Cultureden
dc.subjectDibenzazepinesen
dc.subjectHumansen
dc.subjectIntracellular Signaling Peptides and Proteinsen
dc.subjectJagged-1 Proteinen
dc.subjectKaplan-Meier Estimateen
dc.subjectMembrane Proteinsen
dc.subjectMiceen
dc.subjectNeoplasmsen
dc.subjectNeovascularization, Pathologicen
dc.subjectRNA Interferenceen
dc.subjectTumor Burdenen
dc.subjectXenograft Model Antitumor Assaysen
dc.titleRole of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/28445154en
plymouth.issue25en
plymouth.volume8en
plymouth.publication-statusPublisheden
plymouth.journalOncotargeten
dc.identifier.doi10.18632/oncotarget.16969en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/00 Groups by role
plymouth.organisational-group/Plymouth/00 Groups by role/Academics
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Biomedical Research Group
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Biomedical Research Group/RC Reporting Group BRG
plymouth.organisational-group/Plymouth/Faculty of Medicine and Dentistry/Collaboration for the Advancement of Medical Education Research Assessment
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
dc.publisher.placeUnited Statesen
dcterms.dateAccepted2017-03-11en
dc.identifier.eissn1949-2553en
dc.rights.embargoperiodNot knownen
rioxxterms.versionofrecord10.18632/oncotarget.16969en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-06-20en
rioxxterms.typeJournal Article/Reviewen


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