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The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization

Oncogene volume 19, pages 6043–6052 (2000)Cite this article

Abstract

Eph receptor tyrosine kinases and their ephrin ligands have been implicated in embryonic vascular development and in in vivo models of angiogenesis. Eph proteins may also regulate tumor neovascularization, but this role has not been previously investigated. To screen for Eph proteins expressed in tumor blood vessels, we used tumor xenografts grown in nude mice from MDA-MB-435 human breast cancer cells or KS1767 human Kaposi's sarcoma cells. By immunohistochemistry, the ephrin-A1 ligand and one of its receptors, EphA2, were detected throughout tumor vasculature. Double-labeling with anti-CD34 antibodies demonstrated that both ephrin-A1 and EphA2 were expressed in xenograft endothelial cells and also tumor cells. Furthermore, EphA2 was tyrosine-phosphorylated in the xenograft tumors, indicating that it was activated, presumably by interacting with ephrin-A1. Ephrin-A1 and EphA2 were also detected in both the vasculature and tumor cells of surgically removed human cancers. In an in vitro angiogenesis model, a dominant negative form of EphA2 inhibited capillary tube-like formation by human umbilical vein endothelial cells (HUVECs), demonstrating a requirement for EphA receptor signaling. These data suggest that ephrin-A1 and EphA2 play a role in human cancers, at least in part by influencing tumor neovascularization. Eph proteins may represent promising new targets for antiangiogenic cancer treatments.

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Acknowledgements

The authors thank David Scadden for providing the human EphB4 cDNA; Patricia Menzel for the preparation of antibodies used in this study and Vincent Dodelet for helpful discussions and advice. This work was supported by NIH grants HD26351 and CA82713 (EB Pasquale).

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Author notes

  1. Renata Pasqualini

    Present address: GU Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, 77030, Texas, USA

Authors and Affiliations

  1. The Burnham Institute, La Jolla, CA 92037, California, USA

    Kazushige Ogawa, Renata Pasqualini, Andrew L Freeman & Elena B Pasquale

  2. Department of Veterinary Anatomy, Faculty of Agriculture, Iwate University, 202-8550, Morioka, Japan

    Kazushige Ogawa

  3. Amgen Inc., Amgen Center, Thousand Oaks, CA 91320, California, USA

    Richard A Lindberg

  4. Institute for Clinical Pathology, University of Wien/AK Hospital, A-1090, Wien, Austria

    Renate Kain

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Ogawa, K., Pasqualini, R., Lindberg, R. et al. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19, 6043–6052 (2000). https://doi.org/10.1038/sj.onc.1204004

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