Normal tissue expression of DLL3 is highest in fetal brain, and DLL3 plays a key role in somitogenesis in the paraxial mesoderm. Although Notch pathway activation acts as an oncogenic stimulus in some tumor types, Notch activation in neuroendocrine tumors suppresses tumor growth. In the course of normal development, DLL3 inhibits both cis- and transacting Notch pathway activation by interacting with Notch and DLL1 and redirecting or retaining them to late endosomal/lysosomal compartments or the Golgi, respectively, thereby preventing their localization to the cell surface. Moreover, DLL3 is one of several Notch ligands that appear to be direct downstream targets of ASCL1. Together, these observations suggest that DLL3 might be associated with the neuroendocrine phenotype and contributes to neuroendocrine tumorigenesis.
Saunders L R, et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo[J]. Science translational medicine, 2015, 7(302): 302ra136-302ra136.