Related Experiment Video
Updated: Mar 6, 2026
Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo
Alexandre Trindade1, Dusan Djokovic1,2,3, Joana Gigante1
1Centro Interdisciplinar de Investigação em Sanidade Animal (CIISA), Faculdade de Medicina Veterinária, University of Lisbon, Lisbon, Portugal.
Background:
The inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models.
Methods:
We used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas.
Results:
We found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy.
Conclusions:
By reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control.
Insights
Overexpressing Delta-like 4 (Dll4) in tumor blood vessels normalizes them, reducing tumor growth and metastasis. This endothelial Dll4 overexpression strategy improves chemotherapy delivery and efficacy in preclinical cancer models.
Area of Science:
- Oncology
- Vascular Biology
- Cancer Therapeutics
Background:
- Inhibiting Delta-like 4 (Dll4)/Notch signaling causes nonfunctional vessel growth and tumor suppression, but chronic blockade has safety concerns.
- Exploring endothelial Dll4 overexpression offers an alternative strategy to Dll4/Notch blockade for cancer treatment.
Purpose of the Study:
- To investigate the effects of endothelial-specific Dll4 overexpression on tumor growth, vascularization, and metastasis in various mouse models.
- To evaluate Dll4 overexpression as a potential anti-angiogenic therapy for solid cancers.
Main Methods:
- Utilized a previously developed transgenic mouse model with endothelial-specific Dll4 overexpression.
- Assessed tumor growth kinetics and vascular histopathology in Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas, and RIP1-Tag2 insulinomas.
Main Results:
- Increased Dll4/Notch signaling reduced tumor growth by decreasing VEGF-induced endothelial proliferation, tumor vessel density, and blood supply.
- Dll4 overexpression improved tumor vascular maturation and functionality, evidenced by larger vessel calibers, enhanced mural cell recruitment, and increased perfusion.
- Tumor vessel normalization prevented metastasis and improved chemotherapy delivery and efficacy.
Conclusions:
- Endothelial Dll4/Notch stimulation in the tumor microenvironment can reduce primary tumor size, enhance drug delivery, and decrease metastasis.
- Endothelial-specific Dll4 overexpression represents a promising anti-angiogenic approach for improved cancer control.
