期刊
CANCER RESEARCH
卷 71, 期 18, 页码 6030-6039出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-2719
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资金
- NIH [CA 110793, 109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599, U54 CA 151668]
- Ovarian Cancer Research Fund, Inc.
- DOD [OC073399, OC093146, BC085265]
- Zarrow Foundation
- Marcus Foundation
- Betty Anne Asche Murray Distinguished Professorship
- NCI [CA16672]
- Laura and John Arnold Foundation
- NCI-DHHS-NIH [T32 CA101642]
- NIH/NICHD [HD050128]
- GCF
- GCF/Florence & Marshall Schwid Ovarian
- Phi Beta Psi Sorority
- [NSC-96-3111-B]
Emerging evidence suggests that the Notch/Delta-like ligand 4 (Dll4) pathway may offer important new targets for antiangiogenesis approaches. In this study, we investigated the clinical and biological significance of Dll4 in ovarian cancer. Dll4 was overexpressed in 72% of tumors examined in which it was an independent predictor of poor survival. 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 with 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. Cancer Res; 71(18); 6030-9. (C) 2011 AACR.
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