Incomplete Dll4/Notch signaling inhibition promotes functional angiogenesis supporting the growth of skin papillomas.
BMC Cancer
; 15: 608, 2015 Aug 28.
Article
em En
| MEDLINE
| ID: mdl-26314892
ABSTRACT
BACKGROUND:
In invasive malignancies, Dll4/Notch signaling inhibition enhances non-functional vessel proliferation and limits tumor growth by reducing its blood perfusion.METHODS:
To 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.RESULTS:
We 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.CONCLUSION:
Tumor promoting effect of low-dosage inhibition needs to be considered when implementing Dll4 targeting therapies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Papiloma
/
Neoplasias Cutâneas
/
Peptídeos e Proteínas de Sinalização Intracelular
/
Proteínas de Membrana
/
Neovascularização Patológica
Limite:
Animals
Idioma:
En
Revista:
BMC Cancer
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Portugal