DLL4

The Notch pathway has been identified as one of the most commonly activated pathways in cancer. This signaling cascade is crucial for cell growth, differentiation, and survival. Notch signaling has been identified as possibly having an impact in survival in those who have a diagnosis of cancer and thus makes this a pathway of interest.
The Notch pathway is activated when a Notch receptor binds to a ligand. The mammalian Notch family contains five ligands, delta-like ligand 1 (DLL1), deltalike ligand 3 (DLL3), delta-like ligand 4 (DLL4), Jagged-1 (JAG1), and Jagged-2 (JAG2), and four receptors, Notches 1–4. For the purpose of this review, we will focus on DLL4, which has been studied in SCLC and implicated in activating NF-κβ leading to enhanced VEGF secretion and promotion of metastases.

During tumorigenesis, induction of DLL4 expression by VEGF in endothelial cells of the tumor leads to improved angiogenesis. Interruption of DLL4-Notch signaling led to suppression of tumor growth via nonproductive angiogenesis and hypoxia of tumors. High levels of DLL4 are expressed in cancer stem cells in preclinical models using SCLC cell lines. In human tumor xenografts, targeting DLL4-Notch with anti-DLL4 monoclonal antibodies as a single agent or in combination with cisplatin/etoposide or topotecan resulted in reduction of cancer stem cells.