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

BMC Cancer

Research Article

Adrian L. Harris¹  Dusan Djokovic²  Mario Pinho²  Alexandre Trindade²  Antonio Duarte²  Joana Gigante² 

[1]Cancer Research UK Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

[2]Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Universidade de Lisboa (ULisboa), Lisbon, Portugal

关键词: Sorafenib;    Papilloma;    DMBA;    Skin Tumor;    Platelet Endothelial Cell Adhesion Molecule;   

DOI  :  10.1186/s12885-015-1605-2

 received in 2014-11-11, accepted in 2015-08-17,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Djokovic et al. 2015