Dll4 is an endothelium-specific ligand expressed at sites of vascular development and angiogenesis. Dll4 expression has previously been shown to be upregulated within the vasculature of breast, renal, and bladder cancers. It has been suggested that VEGF induces Dll4/Notch signaling while Dll4/Notch signaling modulates the VEGF pathway, that Dll4 and VEGF merge to be the "yin and yang" of angiogenesis. Patients with tumors responding to anti-VEGF therapy had lower levels of DLL4 than patients with stable or progressive disease. Under hypoxic conditions, VEGF increased DLL4 expression in the tumor vasculature. Immobilized DLL4 also downregulated VEGFR2 expression in endothelial cells directly through methylation of the VEGFR2 promoter. RNAi-mediated silencing of DLL4 in ovarian tumor cells and tumor-associated endothelial cells inhibited cell growth and angiogenesis, accompanied by induction of hypoxia in the tumor microenvironment. Combining DLL4-targeted siRNA with bevacizumab resulted in greater inhibition of tumor growth, compared to control or treatment with bevacizumab alone. Together, our findings establish that DLL4 plays a functionally important role in both the tumor and endothelial compartments of ovarian cancer, and that targeting DLL4 in combination with anti-VEGF treatment might improve outcomes of ovarian cancer treatment.
Hu W, et al. Biological roles of the Delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer research. 2011;71(18):6030-6039.