Abstract
Arising from: J. Ridgway et al. Nature 444, 1083–1087 (2006)10.1038/nature05313
Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy1,2. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising important safety concerns.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006)
Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006)
Li, J. L. & Harris, A. L. Crosstalk of VEGF and Notch pathways in tumour angiogenesis: therapeutic implications. Front. Biosci. 14, 3094–3110 (2009)
Hicklin, D. J. Promoting angiogenesis to a fault. Nature Biotechnol. 25, 300–302 (2007)
Seton-Rogers, S. Tumour suppressors: Different roads to inactivation. Nature Rev. Cancer 7, 72 (2007)
ClinicalTrials.gov. A multiple-ascending-dose study of the safety and tolerability of REGN421 in patients with advanced solid malignancies 〈http://clinicaltrials.gov/ct2/show/NCT00871559〉 (Accessed, 7 January 2010)
ClinicalTrials.gov. A phase 1 dose escalation study of OMP-21M18 in subjects with solid tumors 〈http://clinicaltrials.gov/ct2/show/NCT00744562〉 (Accessed, 7 January 2010)
Schmidt, M. et al. EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution. Development 134, 2913–2923 (2007)
Hsieh, S. H. et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27, 3746–3753 (2008)
Author information
Authors and Affiliations
Ethics declarations
Competing interests
All authors are employees of Genentech, Inc.
PowerPoint slides
Rights and permissions
About this article
Cite this article
Yan, M., Callahan, C., Beyer, J. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010). https://doi.org/10.1038/nature08751
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature08751
- Springer Nature Limited
This article is cited by
-
BICC1 drives pancreatic cancer progression by inducing VEGF-independent angiogenesis
Signal Transduction and Targeted Therapy (2023)
-
Targeting angiogenesis in oncology, ophthalmology and beyond
Nature Reviews Drug Discovery (2023)
-
A Notch between vascular morphogenesis and transcriptional identity
Nature Cardiovascular Research (2023)
-
Transcriptional states do not always predict vascular function and pathology
Nature Cardiovascular Research (2023)
-
Notch1 and Notch4 core binding domain peptibodies exhibit distinct ligand-binding and anti-angiogenic properties
Angiogenesis (2023)