VEGF, VEGFR-1, VEGFR-2, microvessel density and endothelial cell proliferation in tumours of the ovary

Orre, Maxine; Rogers, Peter A. W.

doi:10.1002/(sici)1097-0215(19990420)84:2<101::aid-ijc2>3.0.co;2-5

Cited by 49 publications

(29 citation statements)

References 21 publications

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“…VEGFR-1 and VEGFR-2 have been found expressed in ovarian carcinoma tissues. 2,[47][48][49] However, expression of VEGFR-1 and VEGFR-2 was seldom found in EOC cell lines. We examined the expression of VEGFR-1 and VEGFR-2 in DOV13 cells and found that their constitutive expression is much lower compared to the expression of VEGF121.…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor–regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases

Wang

Reierstad

et al. 2005

Intl Journal of Cancer

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Vascular endothelial growth factor (VEGF) expression is elevated in primary ovarian tumors and metastases. We examined the effect of VEGF on epithelial ovarian cancer (EOC) in vitro invasion and migration and underlying mechanisms. Using the Matrigel invasion assay and colloidal gold phagokinetic track assay, we found that VEGF induced EOC DOV13 invasion and migration in a matrix metalloproteinase (MMP)-dependent manner. Using Western blotting, we show that VEGF, at 20-80 ng/ml, induced secretion of pro-MMP-7 and pro-MMP-9 and activation of pro-MMP-2 in DOV13 conditioned medium in a concentrationdependent manner. However, gelatinolytic activity and total MMP-7 protein in DOV13 conditioned medium reached the maximum upon VEGF treatment at 20-40 ng/ml and decreased at higher-concentration VEGF treatment (80 ng/ml), as shown by DQ-gelatin degradation assay and ELISA. In addition to the effect on MMP secretion/activation, VEGF stimulated secretion of TIMP-2; and blocking TIMP-2 activity by an anti-TIMP-2 MAb significantly increased VEGF (80 ng/ml)-induced DOV13 invasion (p < 0.05), suggesting that VEGF may regulate MMP-2 activity in DOV13 conditioned medium through TIMP-2. Using real-time PCR, we found that VEGF, at 20 ng/ml, significantly increased the expression of VEGFR-1 and VEGFR-2 by approximately 4-fold and 31-fold, respectively, compared to untreated control (p < 0.05). However, the inducing effect of VEGF on VEGFR-2 expression and the internal expression of VEGF121 in DOV13 cells decreased with increasing of VEGF concentration, suggesting the existence of a negative feedback regulatory mechanism. In summary, our results indicate that VEGF may regulate EOC invasion and migration through VEGFR-mediated secretion and activation of MMPs. ' 2005 Wiley-Liss, Inc.Key words: vascular endothelial growth factor; matrix metalloproteinase; gelatinase A/MMP-2; gelatinase B/MMP-9; matrilysin/MMP-7; membrane type 1 matrix metalloproteinase; tissue inhibitor of matrix metalloproteinase; epithelial ovarian cancer; tumor invasion; vascular endothelial growth factor receptor EOC is the leading cause of death among all gynecologic malignancies and the fifth most common cancer in women in the United States.1 At initial diagnosis, the majority of women are diagnosed with advanced-stage EOC, with a resultant poor prognosis because of widespread dissemination throughout the abdomen and pelvis.2,3 Therefore, understanding the mechanisms involved in EOC metastasis may significantly improve women's health care. EOC metastasis and the formation of malignant ascites require a coordinated series of events to support the survival and implantation of disseminated malignant ovarian epithelium. VEGF, also known as vascular permeability factor, has been found to be a potent mediator of those events.

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Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor–regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases

Wang

Reierstad

et al. 2005

Intl Journal of Cancer

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“…Interestingly, Orre and colleagues found that the endothelial proliferation index in high-vessel density regions of ovarian cancers relative to benign tumors was significantly lower. 13 Recent evidence has confounded our understanding of tumor vasculature including reports of "mosaic vessels" (tumor and endothelial-lined vasculature), 6 tumor-lined vasculature [14][15] and tumor cell vasculogenic mimicry. 4,16 In ischemic tissues in vivo, the aggressive melanoma cells were shown to form chimeric vessels during reperfusion.…”

Section: Discussionmentioning

confidence: 99%

The Clinical Significance of Tumor Cell-Lined Vasculature in Ovarian Carcinoma: Implications for Anti-Vasculogenic Therapy

Sood¹,

Fletcher²,

Zahn³

et al. 2002

Cancer Biology & Therapy

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Vasculogenic mimicry reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature; such has been demonstrated in aggressive ovarian carcinoma. This study measured the clinical significance of tumor cell-lined vasculature in ovarian carcinomas (n=77), which was detected in 23 (29.8%) tumors. The data show that tumor cell-lined vasculature was associated with aggressive tumor features and with shorter overall survival (p<0.001). Cox proportional hazards model revealed that tumor cell-lined vasculature (p=0.002) was independently associated with poor survival. This is the first study demonstrating the clinical implications of tumor celllined vasculature in ovarian carcinoma.

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“…VEGFR1 is expressed in a variety of cancer cell lines and tumors (19)(20)(21)(22)(23)(24)(25) and, in colon and pancreatic cancer cells, activation of VEGFR1 results in epithelial to mesenchymal transition, which is linked to increased invasion and migration of tumor cells (23)(24)(25). For example, VEGFB induced phosphorylation of mitogen-activated protein kinase (MAPK) and enhanced migration in pancreatic cancer cells, and VEGFR1-neutralizing antibody inhibited these responses.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells

et al. 2007

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Vascular endothelial growth factor receptor-1 (VEGFR1) is expressed in cancer cell lines and tumors and, in pancreatic and colon cancer cells, activation of VEGFR1 is linked to increased tumor migration and invasiveness. Tolfenamic acid, a nonsteroidal anti-inflammatory drug, decreases Sp protein expression in Panc-1 and L3.6pl pancreatic cancer cells, and this was accompanied by decreased VEGFR1 protein and mRNA and decreased luciferase activity on cells transfected with constructs (pVEGFR1) containing VEGFR1 promoter inserts. Comparable results were obtained in pancreatic cancer cells transfected with small inhibitory RNAs for Sp1, Sp3, and Sp4 and all three proteins bound to GC-rich elements in the VEGFR1 promoter. These results show that VEGFR1 is regulated by Sp proteins and that treatment with tolfenamic acid decreases expression of this critical angiogenic factor. Moreover, in vitro studies in Panc-1 cells show that activation of VEGFR1 by VEGFB to increase mitogen-activated protein kinase 1/2 phosphorylation and cell migration on collagencoated plates is also inhibited by tolfenamic acid. Thus, targeted degradation of Sp proteins is highly effective for inhibiting VEGFR1 and associated angiogenic responses in pancreatic cancer. [Cancer Res 2007;67(7):3286-94]

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VEGF, VEGFR-1, VEGFR-2, microvessel density and endothelial cell proliferation in tumours of the ovary

Cited by 49 publications

References 21 publications

Vascular endothelial growth factor–regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases

Vascular endothelial growth factor–regulated ovarian cancer invasion and migration involves expression and activation of matrix metalloproteinases

The Clinical Significance of Tumor Cell-Lined Vasculature in Ovarian Carcinoma: Implications for Anti-Vasculogenic Therapy

Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells

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