Blockade of delta-like ligand 4 signaling inhibits both growth and angiogenesis of pancreatic cancer

Objectives: The Notch signaling pathway is evolutionarily conserved and regulates cell-fate decisions in a variety of organ development. Previous studies have shown that delta-like ligand 4 (DLL4), one of transmembranous Notch ligands, is up-regulated at the site of tumor growth, especially of tumor angiogenesis. In this study, we examined the effects of the DLL4-Notch signaling on tumor angiogenesis using the neutralizing monoclonal antibodies against DLL4. Methods: The neutralizing monoclonal antibodies against murine DLL4 (HMD4-2) were newly established, and their effects on tumor growth and angiogenesis were evaluated using the mice subcutaneously implanted human pancreatic cancer cells (PK-1) in the dorsal flank area. To further assess the effects on tumor angiogenesis, PK-1 cells were implanted in skinfold chambers inserted on the dorsal area of the mice. Results: Treatment (intraperitoneally) with HMD4-2 suppressed the in vivo tumor growth with marked decrease of tumor vasculature and had no direct inhibitory effect on PK-1 cells in vitro. Real-time sequential analysis using the skinfold chamber model revealed the antiangiogenic effect of HMD4-2. Conclusions: These results suggests that cell-to-cell interaction via DLL4-Notch signaling pathway has been implicated in tumor angiogenesis, and control of this pathway can be a new therapeutic approach to solid tumor.