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  • Original Paper
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Formation of transformed endothelial cells in the absence of VEGFR-2/Flk-1 by Polyoma middle T oncogene

Oncogene volume 18, pages 4200–4210 (1999)Cite this article

Abstract

The middle T antigen of murine Polyomavirus (PymT) rapidly transforms endothelial cells leading to vascular malformations reminiscent of endothelial tumors or hemangiomas. Flk-1, a receptor tyrosine kinase which is activated upon binding of its ligand VEGF, is predominantly expressed in endothelial cells and essential for the formation of blood vessels since absence of Flk-1 prevents the development of mature endothelial cells in mice and in ES-cell differentiation experiments. To investigate the role of Flk-1 in PymT-induced vascular tumor formation, we studied the expression of Flk-1 and VEGF in PymT-transformed endothelial cells (Endothelioma cells, END. cells). The receptor and its ligand were both expressed in END. cells suggesting that a VEGF/Flk-1 autocrine loop might be causally involved in the formation of vascular tumors. To test this hypothesis, ES cells lacking Flk-1 were generated and the transforming potential of PymT was analysed after in vitro differentiation. Flk-1−/− END. cell lines were established which are morphologically identical to flk-1+/+ END. cells and which express several markers characteristic for endothelial cells. This result suggests that PymT functionally replaces the requirement of Flk-1 in expansion and/or survival of endothelial progenitor cells. Therefore, flk-1−/− END. cells provide a powerful tool to dissect the downstream signaling pathways of Flk-1.

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Acknowledgements

We thank Drs E Ogris and A Ullrich for the generous gift of antibodies; I Mudrak for help with PymT Western blot analysis; Dr P Steinlein for help with FACScan analysis and N Howells for assistance with the tumor induction experiments. We are grateful to Drs FK Kiefer, K Matsuo and MS Pepper for critical reading of the manuscript and helpful comments. Photographic work was done by H Tkadletz. U Mühlner was a recipient of a Boehringer Ingelheim Fonds postgraduate fellowship and part of this work was supported by the Austrian Industrial Research Promotion Fund.

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  1. Werner Risau: This paper is dedicated to the memory of Werner Risau

Authors and Affiliations

  1. Research Institute of Molecular Pathology (I.M.P.), Dr. Bohr-Gasse 7, A-1030, Vienna, Austria

    Ulrich Mühlner, Uta Möhle-Steinlein, Gerhard Christofori & Erwin F Wagner

  2. Department of Molecular and Cell Biology, Max-Planck-Institute for Physiological and Clinical Research, D-61231, Bad Nauheim, Germany

    Susanne Wizigmann-Voos & Werner Risau

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  1. Ulrich Mühlner
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Mühlner, U., Möhle-Steinlein, U., Wizigmann-Voos, S. et al. Formation of transformed endothelial cells in the absence of VEGFR-2/Flk-1 by Polyoma middle T oncogene. Oncogene 18, 4200–4210 (1999). https://doi.org/10.1038/sj.onc.1203014

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