期刊
INTERNATIONAL JOURNAL OF CANCER
卷 124, 期 5, 页码 1045-1053出版社
WILEY
DOI: 10.1002/ijc.24028
关键词
VEGFR; angiogenesis; ovarian carcinoma
类别
资金
- UTMD Anderson Ovarian Cancer Spore
- National Cancer Institute-DHHS-NIH (T32 Training Grant) [T32 CAI01642]
- ImClone Systems Inc
- NIH [CA110793, CA109298]
- UTMD Anderson Ovarian Cancer Spore [P50 CA083639]
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 HevA8 ovarian cancer cell lines expressed VEGFR-1 and HeyA9 A2774, and SK0V3ip1 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 SK0V3ip1 cells and treated with either human VEGFR-2 specific antibody (112113), 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 112111 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. (c) 2008 Wiley-Liss, Inc.
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