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 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. Coleman & 1 others Anil 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
Externally publishedYes

Fingerprint

Ovarian Neoplasms
Endothelial Cells
Ligands
Neoplasms
Vascular Endothelial Growth Factor A
delta protein
Tumor Microenvironment
Therapeutics
Growth
RNA Interference
Methylation
Small Interfering RNA
Down-Regulation
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. / Hu, Wei; Lu, Chunhua; Han, Hee Dong; Huang, Jie; Shen, De Yu; Stone, Rebecca; Nick, Alpa M.; Shahzad, Mian M K; Mora, Edna; Jennings, Nicholas B.; Lee, Sun Joo; Roh, Ju Won; Matsuo, Koji; Nishimura, Masato; Goodman, Blake W.; Jaffe, Robert B.; Langley, Robert R.; Deavers, Michael T.; Lopez-Berestein, Gabriel; Coleman, Robert L.; Sood, Anil K.

In: Cancer Research, Vol. 71, No. 18, 15.09.2011, p. 6030-6039.

Research output: Contribution to journalArticle

Hu, W, Lu, C, Han, HD, Huang, J, Shen, DY, Stone, R, Nick, AM, Shahzad, MMK, Mora, E, Jennings, NB, Lee, SJ, Roh, JW, Matsuo, K, Nishimura, M, Goodman, BW, Jaffe, RB, Langley, RR, Deavers, MT, Lopez-Berestein, G, Coleman, RL & Sood, AK 2011, 'Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer', Cancer Research, vol. 71, no. 18, pp. 6030-6039. https://doi.org/10.1158/0008-5472.CAN-10-2719
Hu, Wei ; Lu, Chunhua ; Han, Hee Dong ; Huang, Jie ; Shen, De Yu ; Stone, Rebecca ; Nick, Alpa M. ; Shahzad, Mian M K ; Mora, Edna ; Jennings, Nicholas B. ; Lee, Sun Joo ; Roh, Ju Won ; Matsuo, Koji ; Nishimura, Masato ; Goodman, Blake W. ; Jaffe, Robert B. ; Langley, Robert R. ; Deavers, Michael T. ; Lopez-Berestein, Gabriel ; Coleman, Robert L. ; Sood, Anil K. / Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. In: Cancer Research. 2011 ; Vol. 71, No. 18. pp. 6030-6039.
@article{98805a0eef0840cfa2ec7ace07a6cc5b,
title = "Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer",
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.",
author = "Wei Hu and Chunhua Lu and Han, {Hee Dong} and Jie Huang and Shen, {De Yu} and Rebecca Stone and Nick, {Alpa M.} and Shahzad, {Mian M K} and Edna Mora and Jennings, {Nicholas B.} and Lee, {Sun Joo} and Roh, {Ju Won} and Koji Matsuo and Masato Nishimura and Goodman, {Blake W.} and Jaffe, {Robert B.} and Langley, {Robert R.} and Deavers, {Michael T.} and Gabriel Lopez-Berestein and Coleman, {Robert L.} and Sood, {Anil K.}",
year = "2011",
month = "9",
day = "15",
doi = "10.1158/0008-5472.CAN-10-2719",
language = "English (US)",
volume = "71",
pages = "6030--6039",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "18",

}

TY - JOUR

T1 - Biological roles of the delta family notch ligand Dll4 in tumor and endothelial cells in ovarian cancer

AU - Hu, Wei

AU - Lu, Chunhua

AU - Han, Hee Dong

AU - Huang, Jie

AU - Shen, De Yu

AU - Stone, Rebecca

AU - Nick, Alpa M.

AU - Shahzad, Mian M K

AU - Mora, Edna

AU - Jennings, Nicholas B.

AU - Lee, Sun Joo

AU - Roh, Ju Won

AU - Matsuo, Koji

AU - Nishimura, Masato

AU - Goodman, Blake W.

AU - Jaffe, Robert B.

AU - Langley, Robert R.

AU - Deavers, Michael T.

AU - Lopez-Berestein, Gabriel

AU - Coleman, Robert L.

AU - Sood, Anil K.

PY - 2011/9/15

Y1 - 2011/9/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80052816881&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052816881&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-10-2719

DO - 10.1158/0008-5472.CAN-10-2719

M3 - Article

VL - 71

SP - 6030

EP - 6039

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 18

ER -