Overexpression of VEGF 121 in Immortalized Endothelial Cells Causes Conversion to Slowly Growing Angiosarcoma and High Level Expression of the VEGF Receptors VEGFR-1 and VEGFR-2 in Vivo

Arbiser, Jack L.; Larsson, Helena; Claesson‐Welsh, Lena; Bai, Xianhe; LaMontagne, Kenneth R.; Weiss, Sharon W.; Soker, S.; Flynn, Evelyn; Brown, Lawrence F.

doi:10.1016/s0002-9440(10)65015-8

Cited by 112 publications

(74 citation statements)

References 40 publications

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“…Cancer Res 2007; 67: (8 Arbriser et al showed that overexpression of VEGF121 in MS1 endothelial cells resulted in development of slowly growing endothelial tumors in nude mice (37). Moreover, this report underscores the importance of VEGF involvement in ascites development.…”

Section: Cancer Researchmentioning

confidence: 51%

Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells

Schumacher¹,

Dings

Cosin

et al. 2007

Cancer Research

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Vascular endothelial growth factor (VEGF) expression correlates with microvessel density, stage, malignant ascites, metastasis, and survival in ovarian cancer. By transducing VEGF165 into a nontumorigenic rat ovarian surface epithelial cell line (ROSE199), we investigated the direct effect of an angiogenic phenotype on tumor development. The neu oncogene, which is overexpressed in >30% of ovarian cancers, was used in comparison. Neu-transfected ROSE199 cells showed phenotypic characteristics of transformation in vitro with an abundance of focus-forming units in monolayer cultures and anchorage-independent growth in soft agar. In contrast, VEGF-secreting ROSE199 cells (VR) retained normal morphology and in vitro growth characteristics (e.g., proliferation rate) compared with parental ROSE199 cells. Interestingly, injection of VR cells into athymic mice formed malignant ascites in 100% of the animals when injected into the peritoneum and developed vascularized tumors in 85% of the mice when injected s.c. Furthermore, blocking VEGFmediated signaling by the Flk-1/KDR receptor kinase inhibitor SU5416 significantly inhibited the growth of VR tumors. To validate that the proangiogenic switch is responsible for tumor development, the angiogenic phenotype was balanced by the inducible coexpression of endostatin under the control of Tet-activated promoter. Coexpression of endostatin along with VEGF reversed the tumorigenic phenotype of VR cells. These studies show that alterations in the angiogenic characteristics of ovarian surface epithelium may play an important role in the etiology of ovarian cancer, and that inhibition of angiogenesis can be effective in the treatment of epithelial ovarian cancer. [Cancer Res 2007;67(8):3683-90]

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Section: Cancer Researchmentioning

confidence: 51%

Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells

Schumacher¹,

Dings

Cosin

et al. 2007

Cancer Research

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“…The melanoma endothelial cells, liposarcoma endothelial cells, skin endothelial cells, and adipose endothelial cells were purified using FITC-conjugated anti-CD31 antibody and anti-FITC microbeads. Before subculture, diphtheria toxin was used to kill any contaminating human tumor cells because they express human HB-EGF, the diphtheria toxin receptor (17). Diphtheria toxin does not interact with mouse heparin-binding-EGF so that mouse endothelial cell survive this treatment.…”

Section: Resultsmentioning

confidence: 99%

“…CD31-positive cells were sorted and plated onto 1.5% gelatin-coated culture plates and grown in EGM-2MV (Clonetics, Walkersville, MD) and 10% fetal calf serum. Diphtheria toxin (500 ng/mL; Calbiochem, San Diego, CA) was added to tumor endothelial cell cultures to kill human tumor cells that might overgrow the culture (17) and to normal endothelial cell as well so that all of the endothelial cells were consistently treated in the same manner. However, diphtheria toxin treatment was not needed for freshly isolated uncultured endothelial cells.…”

Section: Methodsmentioning

confidence: 99%

Tumor-Associated Endothelial Cells with Cytogenetic Abnormalities

et al. 2004

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Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels have been shown to differ from normal counterparts, for example, by changes in morphology. An important concept in tumor angiogenesis is that tumor endothelial cells are assumed to be genetically normal, although these endothelial cells are structurally and functionally abnormal. However, we hypothesized that given the phenotypic differences between tumor and normal blood vessels, there may be genotypic alterations as well. Mouse endothelial cells were isolated from two different human tumor xenografts, melanoma and liposarcoma, and from two normal endothelial cell counterparts, skin and adipose. Tumor-associated endothelial cells expressed typical endothelial cell markers, such as CD31. They had relatively large, heterogeneous nuclei. Unexpectedly, tumor endothelial cells were cytogenetically abnormal. Fluorescence in situ hybridization (FISH) analysis showed that freshly isolated uncultured tumor endothelial cells were aneuploid and had abnormal multiple centrosomes. The degree of aneuploidy was exacerbated by passage in culture. Multicolor FISH indicated that the structural chromosomal aberrations in tumor endothelial cells were heterogeneous, indicating that the cytogenetic alterations were not clonal. There was no evidence of human tumor-derived chromosomal material in the mouse tumor endothelial cells. In marked contrast, freshly isolated normal skin and adipose endothelial cells were diploid, had normal centrosomes, and remained cytogenetically stable in culture even up to 20 passages. FISH analysis of tumor sections also showed endothelial cell aneuploidy. We conclude that tumor endothelial cells can acquire cytogenetic abnormalities while in the tumor microenvironment.

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“…Pretreatment of ECs with a selective VEGFR-1 and VEGFR-2 inhibitor (VTK; 10 Ϫ5 M, IC 50 ϭ 2.0 and 0.1 ϫ 10 Ϫ6 M, respectively) (18) abrogated by 100 and 90% the synthesis of PGI 2 mediated by VEGF-A 165 and VEGF-A 121 , respectively. Similarly, the blockade of VEGFR-2 activity with SU1498 (selective VEGFR-2 inhibitor; 5 ϫ 10 Ϫ6 M; IC 50 ϭ 7 ϫ 10 Ϫ7 M) (5,19) was sufficient as well to abrogate by 96 and 95% the synthesis of PGI 2 mediated by VEGF-A 165 and VEGF-A 121 , respectively (Fig. 6B).…”

Section: Effect Of Vegf Analogs and Corresponding Receptors Onmentioning

confidence: 85%

Vascular Endothelial Growth Factor (VEGF)-A165-induced Prostacyclin Synthesis Requires the Activation of VEGF Receptor-1 and -2 Heterodimer

Neagoe

Lemieux

Sirois

2005

Journal of Biological Chemistry

111

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We previously reported that vascular endothelial growth factor (VEGF)-A 165 inflammatory effect is mediated by acute platelet-activating factor synthesis from endothelial cells upon the activation of VEGF receptor-2 (VEGFR-2) and its coreceptor, neuropilin-1 (NRP-1). In addition, VEGF-A 165 promotes the release of other endothelial mediators including nitric oxide and prostacyclin (PGI 2 ). However, it is unknown whether VEGF-A 165 is mediating PGI 2 synthesis through VEGF receptor-1 (VEGFR-1) and/or VEGF receptor-2 (VEGFR-2) activation and whether the coreceptor NRP-1 potentiates VEGF-A 165 activity. In this study, PGI 2 synthesis in bovine aortic endothelial cells (BAEC) was assessed by quantifying its stable metabolite (6-keto prostaglandin F 1␣ , 6-keto PGF 1␣

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Overexpression of VEGF 121 in Immortalized Endothelial Cells Causes Conversion to Slowly Growing Angiosarcoma and High Level Expression of the VEGF Receptors VEGFR-1 and VEGFR-2 in Vivo

Cited by 112 publications

References 40 publications

Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells

Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells

Tumor-Associated Endothelial Cells with Cytogenetic Abnormalities

Vascular Endothelial Growth Factor (VEGF)-A165-induced Prostacyclin Synthesis Requires the Activation of VEGF Receptor-1 and -2 Heterodimer

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