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  • Original Paper
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Inhibition of VEGF receptors significantly impairs mammary cancer growth in C3(1)/Tag transgenic mice through antiangiogenic and non-antiangiogenic mechanisms

Oncogene volume 24, pages 790–800 (2005)Cite this article

A Corrigendum to this article was published on 09 June 2005

Abstract

Cancer growth and progression is often critically influenced by the production of vascular endothelial growth factor (VEGF), a key mediator of angiogenesis. VEGF produced by tumor cells stimulates endothelial cell growth through the binding and activation of the KDR/Flk-1 receptor (VEGFR-2) on endothelial cells. Recently, some human breast cancer epithelial cells have been shown to express VEGF receptors, suggesting a potential autocrine-mediated growth stimulation of a subset of cancers by VEGF. We demonstrate that mammary tumors in the C3(1)/Tag transgenic model express VEGF and VEGF receptors and tumor growth is stimulated by this autocrine mechanism. GW654652, an indazolylpyrimidine, is a VEGFRs tyrosine kinase inhibitor that dramatically reduces both angiogenesis and tumor cell growth in this model, as demonstrated using both in vitro and in vivo assays. GW654652 significantly decreased cell proliferation and induced apoptosis in human umbilical vein endothelial cells and M6 mammary tumor cells derived from C3(1)/Tag (Tag: simian virus 40 T-antigen) transgenic mice. A 75% reduction in VEGF-induced angiogenesis was observed with GW654652 using the chick chorioallantoic membrane assay, whereas GW654652 produced an approximately 85% reduction in angiogenesis as assessed by the Matrigelâ„¢ plug assay. A profound inhibitory effect on tumor growth in the C3(1)/Tag transgenic model of human breast cancer was observed with oral administration of GW654652 as measured by delayed tumor onset, decreased multiplicity, reduced tumor volume, and extended animal survival. The antitumor effects of GW654652 were associated with reduced tumor vascularization and no apparent toxicity. Tumor growth, however, rapidly advanced following cessation of treatment. This is the first demonstration that a VEGF receptor inhibitor, GW654652, has a strong inhibitory effect on angiogenesis and tumor progression in a transgenic model of mammary cancer, suggesting that this is a useful approach for preclinical testing of such agents.

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Abbreviations

HUVEC:

human umbilical vein endothelial cells

VEGF:

vascular endothelial growth factor

bFGF:

basic fibroblast growth factor

Tag:

simian virus 40 T-antigen

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Acknowledgements

We appreciate Mizuko Mamura and Sushil G Rane for their assistance and helpful discussion with regard to FACS analyses. We are also grateful to Lisa Birely for her technical assistance with regard to animals.

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Author notes

  1. Alfonso Calvo

    Present address: Division of Oncology, Department of Histology and Pathology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain

  2. Jeffrey Stafford

    Present address: Syrrx Inc., San Diego, CA, USA

  3. Jung-Im Huh and Alfonso Calvo: These two authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Jung-Im Huh, Alfonso Calvo & Jeffrey E Green

  2. Cell Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    Jeffrey Stafford, Mui Cheung & Rakesh Kumar

  3. GlaxoSmithKline, Research Triangle Park, NC, USA

    Deborah Philp & Hynda K Kleinman

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Correspondence to Jeffrey E Green.

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Huh, JI., Calvo, A., Stafford, J. et al. Inhibition of VEGF receptors significantly impairs mammary cancer growth in C3(1)/Tag transgenic mice through antiangiogenic and non-antiangiogenic mechanisms. Oncogene 24, 790–800 (2005). https://doi.org/10.1038/sj.onc.1208221

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