Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer

Wei Hu, Chunhua Lu, Hee Dong Han, Jie Huang, De Yu Shen, Rebecca L. Stone, Alpa M. Nick, Mian M.K. Shahzad, Edna Mora, Nicholas B. Jennings, Sun Joo Lee, Ju Won Roh, Koji Matsuo, Masato Nishimura, Blake W. Goodman, Robert B. Jaffe, Robert R. Langley, Michael T. Deavers, Gabriel Lopez-Berestein, Robert L. ColemanAnil K. Sood

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6030-6039
Number of pages10
JournalCancer Research
Volume71
Issue number18
DOIs
StatePublished - Sep 15 2011

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hu, W., Lu, C., Han, H. D., Huang, J., Shen, D. Y., Stone, R. L., Nick, A. M., Shahzad, M. M. K., Mora, E., Jennings, N. B., Lee, S. J., Roh, J. W., Matsuo, K., Nishimura, M., Goodman, B. W., Jaffe, R. B., Langley, R. R., Deavers, M. T., Lopez-Berestein, G., ... Sood, A. K. (2011). Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Research, 71(18), 6030-6039. https://doi.org/10.1158/0008-5472.CAN-10-2719