Delta-like ligand 4 (DLL4) (DLL4)

Delta-like ligand 4 (DLL4) is a type I transmembrane protein that serves as a critical ligand for the Notch signaling pathway, specifically interacting with Notch1 and Notch4 receptors [UniProt P57078]. It is a key regulator of angiogenesis, where it mediates the "lateral inhibition" process that determines endothelial cell fate, distinguishing between leader "tip cells" and follower "stalk cells" during vessel sprouting [PubMed: 17110561]. In many solid tumors, DLL4 is upregulated in the vasculature and sometimes on the tumor cells themselves, promoting a functional blood supply and maintaining tumor stem cell populations [PubMed: 21422445]. Therapeutic targeting of DLL4, primarily through monoclonal antibodies or bispecific agents, induces a paradoxical "non-productive" angiogenesis; this results in an increase in vessel density but a decrease in perfusion, effectively starving the tumor of nutrients [PubMed: 17110563]. While the target is often addressed at the protein level, research into DLL4 mRNA-targeted therapies, such as siRNA, is also ongoing to achieve more specific gene silencing [PubMed: 21131563]. Despite its potential, clinical use of DLL4 inhibitors is limited by significant toxicities, most notably hypertension and a risk of congestive heart failure, which are linked to the systemic inhibition of Notch signaling in the cardiovascular system [PubMed: 25538241].

Other names

Delta-like protein 4Drosophila Delta homolog 4hDelta4

Inhibition of Notch signaling by blocking the interaction between DLL4 and Notch receptors, leading to non-productive angiogenesis and reduced tumor growth [PubMed: 17110561, 21422445].