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Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
Functional significance of VEGFR-2 on ovarian cancer cells
Whitney A Spannuth1, Alpa M Nick, Nicholas B Jennings
1Department of Gynecologic Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Abstract:
Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of this study. By protein analysis, A2780-par and HeyA8 ovarian cancer cell lines expressed VEGFR-1 and HeyA8 A2774, and SKOV3ip1 expressed VEGFR-2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR-2 expression, whereas only 15% showed moderate to high VEGFR-1 expression. By immunofluorescence, little or no VEGFR-2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with SKOV3ip1 cells and treated with either human VEGFR-2 specific antibody (1121B), murine VEGFR-2 specific antibody (DC101) or the combination. Treatment with 1121B reduced SKOV3ip1 cell migration by 68% (p < 0.01) and invasion by 72% (p < 0.01), but exposure to VEGFR-1 antibody had no effect. Treatment with 1121B effectively blocked VEGF-induced phosphorylation of p130Cas. In vivo treatment with either DC101 or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ip1 and A2774 models. Decreased tumor burden after treatment with DC101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p < 0.001). We show functionally active VEGFR-2 is present on most ovarian cancer cells. The observed anti-tumor activity of VEGF-targeted therapies may be mediated by both anti-angiogenic and direct anti-tumor effects.
Insights
Vascular endothelial growth factor receptor-2 (VEGFR-2) is active in ovarian cancer cells, driving migration and invasion. Targeting VEGFR-2 with specific antibodies shows significant anti-tumor effects by reducing growth and increasing apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Vascular endothelial growth factor receptor (VEGFR) presence on ovarian cancer cells was noted, but its functional role remained unclear.
- VEGFR-1 and VEGFR-2 expression varies in ovarian cancer cell lines and patient specimens.
Purpose of the Study:
- To investigate the functional significance of VEGFR in ovarian cancer.
- To evaluate the anti-tumor efficacy of VEGFR-2 targeted therapies.
Main Methods:
- Protein analysis and in situ hybridization (ISH) to assess VEGFR expression in cell lines and human specimens.
- Immunofluorescence to detect VEGFR-2 in normal and cancerous ovarian tissues.
- In vivo studies using nude mice xenograft models treated with VEGFR-2 specific antibodies (1121B and DC101).
Main Results:
- VEGFR-2 was highly expressed in 85% of ovarian cancer specimens, unlike VEGFR-1 (15%).
- VEGFR-2 targeted therapy (1121B) significantly reduced ovarian cancer cell migration (68%) and invasion (72%).
- In vivo, VEGFR-2 antibodies (DC101, 1121B) inhibited tumor growth, increased apoptosis, decreased proliferation, and reduced microvessel density.
Conclusions:
- Functionally active VEGFR-2 is present on most ovarian cancer cells.
- VEGF-targeted therapies exhibit anti-tumor activity through both anti-angiogenic and direct anti-tumor mechanisms.
- Targeting VEGFR-2 represents a promising therapeutic strategy for ovarian cancer.
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