Show simple item record

dc.contributor.authorLi, J-Len
dc.contributor.authorSainson, RCAen
dc.contributor.authorShi, Wen
dc.contributor.authorLeek, Ren
dc.contributor.authorHarrington, LSen
dc.contributor.authorPreusser, Men
dc.contributor.authorBiswas, Sen
dc.contributor.authorTurley, Hen
dc.contributor.authorHeikamp, Een
dc.contributor.authorHainfellner, JAen
dc.contributor.authorHarris, ALen

The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy.

dc.format.extent11244 - 11253en
dc.subjectAntibodies, Monoclonalen
dc.subjectAntibodies, Monoclonal, Humanizeden
dc.subjectCHO Cellsen
dc.subjectCell Proliferationen
dc.subjectCells, Cultureden
dc.subjectEndothelium, Vascularen
dc.subjectIntercellular Signaling Peptides and Proteinsen
dc.subjectMice, Inbred BALB Cen
dc.subjectMice, SCIDen
dc.subjectNeoplasms, Experimentalen
dc.subjectNeovascularization, Pathologicen
dc.subjectReceptors, Notchen
dc.subjectSignal Transductionen
dc.subjectStromal Cellsen
dc.subjectTransplantation, Heterologousen
dc.subjectUmbilical Veinsen
dc.subjectVascular Endothelial Growth Factor Aen
dc.titleDelta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo.en
dc.typeJournal Article
plymouth.journalCancer Resen
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
dc.rights.embargoperiodNot knownen
rioxxterms.typeJournal Article/Reviewen

Files in this item


This item appears in the following Collection(s)

Show simple item record

All items in PEARL are protected by copyright law.
Author manuscripts deposited to comply with open access mandates are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author.
Theme by 
@mire NV