Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis
Abstract
Haploinsufficiency of Dll4, a vascular-specific Notch ligand, has shown that it is essential for embryonic vascular development and arteriogenesis. Mechanistically, it is unclear how the Dll4-mediated Notch pathway contributes to complex vascular processes that demand meticulous coordination of multiple signalling pathways. Here we show that Dll4-mediated Notch signalling has a unique role in regulating endothelial cell proliferation and differentiation. Neutralizing Dll4 with a Dll4-selective antibody rendered endothelial cells hyperproliferative, and caused defective cell fate specification or differentiation both in vitro and in vivo. In addition, blocking Dll4 inhibited tumour growth in several tumour models. Remarkably, antibodies against Dll4 and antibodies against vascular endothelial growth factor (VEGF) had paradoxically distinct effects on tumour vasculature. Our data also indicate that Dll4-mediated Notch signalling is crucial during active vascularization, but less important for normal vessel maintenance. Furthermore, unlike blocking Notch signalling globally, neutralizing Dll4 had no discernable impact on intestinal goblet cell differentiation, supporting the idea that Dll4-mediated Notch signalling is largely restricted to the vascular compartment. Therefore, targeting Dll4 might represent a broadly efficacious and well-tolerated approach for the treatment of solid tumours.
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VEGF acting through VEGFR2 induces endothelial proliferation and concurrently upregulates delta-like ligand 4, which signals to microvascular cells in the capillary stalk to downregulate VEGFR2 via Notch 1, preventing uncontrolled capillary sprouting.
“Acting through VEGF receptor 2 (VEGFR2), which is localised at high concentrations at the tip of newly formed capillaries, VEGF induces endothelial proliferation,4,47–49 and concur rently upregulates the transmembrane ligand delta-like ligand 4, which signals to microvascular cells in the capillary stalk, to downregulate VEGFR2 via interaction with its receptor Notch 1, thus pre venting uncontroll”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [51]
Inhibiting Dll4 leads to disruption of tumor vasculature within the TME.
“For example, Notch ligand Dll4 is upregulated in tumor samples from clear cell renal cell carcinoma patients [135], and inhibiting Dll4 leads to the disruption of tumor vasculature within the TME [136, 137].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [137]
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- Authors
- Ridgway, J., Zhang, G., Wu, Y., Stawicki, S., Liang, W.-C., Chanthery, Y., Kowalski, J., Watts, R. J., Callahan, C., Kasman, I., Singh, M., Chien, M., Tan, C., Hongo, J.-A. S., de Sauvage, F., Plowman, G., & Yan, M.
- Affiliations
- Genentech (US)
- Corresponding author
- Yan, Minhong
- Venue
- Nature
- Published
- 2006-12
- Volume
- 444
- Issue
- 7122
- Pages
- 1083-1087
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2040827891
- Cited by
- 986
- References
- 22
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 23 · 2023: 19 · 2022: 22 · 2021: 34 · 2020: 34 · 2019: 29 · 2018: 54 · 2017: 60 · 2016: 55 · 2015: 53 · 2014: 72 · 2013: 83 · 2012: 87
- FWCI
- 22.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Keywords
- DLL4, Notch signaling, tumor angiogenesis, anti-angiogenic therapy, VEGF inhibition, endothelial cell proliferation, endothelial differentiation, tumor vasculature, solid tumors, antibody neutralization, vascular development, Notch ligands
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Endothelium, Vascular, Homeostasis, Humans, Intestine, Small, Membrane Proteins, Neoplasms, Neovascularization, Pathologic, Signal Transduction, Vascular Endothelial Growth Factor A, Intracellular Signaling Peptides and Proteins, Cell Proliferation, Mice, Receptors, Notch
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