Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells

S. A I Adham, Ifat Sher, Brenda L. Coomber

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Human epithelial ovarian cancer (EOC) is the most lethal neoplasm affecting the female genital tract, and is characterized by overexpression of vascular endothelial growth factor (VEGF) and growth as ascites. Anti-VEGF strategies are currently used in EOC therapy with promising results; however, molecular targeting of specific VEGF receptors on the cancer cells themselves has not been explored to date. We previously showed that activation of a VEGF/VEGFR2 signaling loop in EOC cells supports their survival in suspension, and short-term pharmacological inhibition of this loop increased EOC cell apoptosis in vitro. In this study, we stably knocked down VEGFR2 in OVCAR-3 and SKOV-3 EOC cells using short hairpin RNA (shRNA), an RNA interference strategy that could potentially overcome chemoresistance arising with angiogenic inhibitors. Unexpectedly, we observed an induction of more aggressive cellular behavior in transfected cells, leading to increased growth in mouse xenografts, enhanced accumulation of ascites, increased VEGF and neuropilin-1 (NRP-1) expression, and decreased expression of adhesion proteins, notably cadherins and integrins. Sonic hedgehog (SHH) pathways do not seem to be involved in the upregulation of NRP-1 message in VEGFR2 knockdown cells. Supporting our mouse model, we also found a significant increase in the ratio between NRP-1 and VEGFR2 with increasing tumor grade in 80 cases of human EOC. The change in EOC behavior that we report in this study occurred independent of the angiogenic response and shows the direct effect of VEGF blockade on the cancer cells themselves. Our findings highlight the possible confounding events that may affect the usefulness of RNAi in a therapeutic setting for disrupting EOC cell survival in ascites.

Original languageEnglish
Pages (from-to)709-723
Number of pages15
JournalLaboratory Investigation
Volume90
Issue number5
DOIs
Publication statusPublished - May 2010

Fingerprint

Carcinoma
Vascular Endothelial Growth Factor A
Neuropilin-1
Ascites
RNA Interference
Female Genital Neoplasms
Neoplasms
Vascular Endothelial Growth Factor Receptor
Angiogenesis Inhibitors
Hedgehogs
Ovarian epithelial cancer
Cadherins
Growth
Heterografts
Integrins
Small Interfering RNA
Cell Survival
Suspensions
Up-Regulation
Pharmacology

Keywords

  • Adhesion
  • Ascites
  • Cadherin
  • Integrin
  • Neuropilin-1
  • ShRNA

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Pathology and Forensic Medicine

Cite this

Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells. / Adham, S. A I; Sher, Ifat; Coomber, Brenda L.

In: Laboratory Investigation, Vol. 90, No. 5, 05.2010, p. 709-723.

Research output: Contribution to journalArticle

Adham, S. A I ; Sher, Ifat ; Coomber, Brenda L. / Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells. In: Laboratory Investigation. 2010 ; Vol. 90, No. 5. pp. 709-723.
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