Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues
Article first published online: 8 APR 2009
© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Limited
Volume 54, Issue 5, pages 598–606, April 2009
How to Cite
Martinez, J. C., Müller, M. M., Turley, H., Steers, G., Choteau, L., Li, J.-L., Sainson, R., Harris, A. L., Pezzella, F. and Gatter, K. C. (2009), Nuclear and membrane expression of the angiogenesis regulator delta-like ligand 4 (DLL4) in normal and malignant human tissues. Histopathology, 54: 598–606. doi: 10.1111/j.1365-2559.2009.03279.x
- Issue published online: 8 APR 2009
- Article first published online: 8 APR 2009
- Date of submission 9 May 2008 Accepted for publication 26 October 2008
Vol. 55, Issue 4, 463–464, Article first published online: 7 OCT 2009
- delta-like ligand 4;
- human tissues;
- nuclear relocation
Aims: Delta-like ligand 4 (DLL4) is one of five known Notch ligands in mammals and interacts predominantly with Notch 1. DLL4 is induced by vascular endothelial growth factor (VEGF) and acts downstream of VEGF as a ‘brake’ on VEGF-induced vessel growth, forming an autoregulatory negative feedback loop inactivating VEGF. This action was believed to occur only in vascular development, raising hopes that DLL4 could be a specific drug target for controlling vessel growth in tumours and other pathological conditions. Our aim was to pursue this by raising a monoclonal antibody to the internal domain of DLL4 and assess its distribution in normal and malignant tissues in comparison with antibodies against the external domain of DLL4.
Methods and results: The anti-DLL4 monoclonal antibody was raised using conventional mouse hybridoma techniques. The antibody has been fully characterized by Western blotting and transfectant immunostaining. It has also been comprehensively compared with other antibodies against both the internal and external domains of DLL4. The antigen is widely expressed on human tissues not only on endothelium but also on epithelium and stromal cells. Indeed, in our comprehensive survey only pulmonary alveoli failed to express DLL4. Of a wide range of malignancies, most also expressed DLL4 on tumour cells with a predominantly cytoplasmic pattern, although a number also displayed nuclear positivity.
Conclusions: Contrary to previous beliefs, DLL4 is widely distributed in tissues other than vessels including many malignancies. Furthermore, the molecule is internalized on binding its receptor and often transported to the nucleus. These findings raise many interesting possibilities for further study of DLL4 and its potential as a therapeutic target.