The role of Notch ligand, Delta-like ligand 4 (DLL4), in cancer angiogenesis-implications for therapy

Background It is generally accepted that angiogenesis is a complex and tightly regulated process characterized by the growth of blood vessels from existing vasculature. Activation of the Notch signalling pathway affects multiple aspects of vascular development. One of the components of the Notch signalling pathway, Delta-like ligand 4 (DLL4), has recently appeared as a critical regulator of tumour angiogenesis and thus as a promising therapeutic target. Methods This review article includes available data from peer-reviewed publications associated with the role of DLL4 in cancer angiogenesis. Searches were performed in PubMed, EMBASE, Google Scholar and Web of Science using the terms tumour angiogenesis, DLL4, Notch signalling and anti-cancer therapy. Results The survival curves of cancer patients revealed that the patients with high DLL4 expression levels had significantly shorter survival times than the patients with low DLL4 expression. Moreover, a positive correlation was also identified between DLL4 and VEGF receptors' expression levels. It seems that inhibition of DLL4 may exert potent growth inhibitory effects on some tumours resistant to anti-VEGF therapies. A great number of blocking agents of DLL4/Notch signalling including anti-DLL4 antibodies, DNA vaccination, Notch antibodies and gamma-secretase inhibitors have been studied in preclinical tumour models. Conclusion DLL4 seems to be a promising target in anti-cancer therapy. Nevertheless, the careful evaluation of adverse effects on normal physiological processes in relation to therapeutic doses of anti-DLL4 drugs will be significant for advancement of DLL4 blocking agents in clinical oncology.

Automated summary

DLL4 has emerged as a critical regulator of tumour angiogenesis, with high expression levels associated with shorter survival times and a positive correlation with VEGF receptor expression levels. Inhibiting DLL4 may have potent growth inhibitory effects on tumours resistant to anti-VEGF therapies. Multiple blocking agents of DLL4/Notch signalling have been studied in preclinical tumour models, showing promise for potential clinical applications.