Endothelial Dll4/notch signaling as a target for cancer and wound healing therapy

Notch signalling is an evolutionarily conserved pathway that metazoan use to regulate cell-fate determination during development and maintain adult tissue homeostasis. Numerous mutations in Notch pathway components have been shown to produce embryonic lethal phenotypes, notably linked to endothelial function. Our laboratory has studied the vascular function of the Notch pathway ligand Dll4 and used it as a target for novel therapeutic strategies. The study of Dll4 function by genetic manipulation revealed its importance for arterial endothelial cell specification and branching angiogenesis. Dll4 is highly expressed in tumoral vasculature and blocking Dll4 function with a novel biopharmaceutical, Dll4-Fc, was effective in reducing tumour growth in various in vivo cancer models. This effect resulted from an exaggerated vascular response to tumoral proangiogenic stimuli, that leads to an increased proportion of poorly functional tumoral blood vessels and thus reduced tumour blood supply. It was also found that Dll4 exerts angiocrine effects over neighbouring tumour cells, regulating cancer stem cell biology, differentiation, and epithelial-to-mesenchymal transition, with the end result being an effect on metastasis onset. All these effects on cancer establishment, growth and progression into metastasis, regulated by Dll4, makes this a relevant target for cancer therapy.