Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-08-28

AUTHORS

Dusan Djokovic, Alexandre Trindade, Joana Gigante, Mario Pinho, Adrian L. Harris, Antonio Duarte

ABSTRACT

BackgroundIn invasive malignancies, Dll4/Notch signaling inhibition enhances non-functional vessel proliferation and limits tumor growth by reducing its blood perfusion.MethodsTo assess the effects of targeted Dll4 allelic deletion in the incipient stages of tumor pathogenesis, we chemically induced skin papillomas in wild-type and Dll4+/− littermates, and compared tumor growth, their histological features, vascularization and the expression of angiogenesis-related molecules.ResultsWe observed that Dll4 down-regulation promotes productive angiogenesis, although with less mature vessels, in chemically-induced pre-cancerous skin papillomas stimulating their growth. The increase in endothelial activation was associated with an increase in the VEGFR2 to VEGFR1 ratio, which neutralized the tumor-suppressive effect of VEGFR-targeting sorafenib. Thus, in early papillomas, lower levels of Dll4 increase vascularization through raised VEGFR2 levels, enhancing sensitivity to endogenous levels of VEGF, promoting functional angiogenesis and tumor growth.ConclusionTumor promoting effect of low-dosage inhibition needs to be considered when implementing Dll4 targeting therapies. More... »

PAGES

608

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12885-015-1605-2

DOI

http://dx.doi.org/10.1186/s12885-015-1605-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1033560587

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26314892


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