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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.

Original publication




Journal article


BMC Cancer

Publication Date





Animals, Antineoplastic Agents, Disease Progression, Down-Regulation, Gene Deletion, Intracellular Signaling Peptides and Proteins, Male, Membrane Proteins, Mice, Neovascularization, Pathologic, Niacinamide, Papilloma, Phenylurea Compounds, Real-Time Polymerase Chain Reaction, Signal Transduction, Skin Neoplasms, Sorafenib, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2