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Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model

Oncogene volume 22, pages 1795–1806 (2003)Cite this article

Abstract

We and others have shown that members of the Ets family of transcription factors are involved in morphogenic properties of endothelial cells in vitro. To investigate the role of these factors in the transcriptional regulation of angiogenesis in vivo, we set up a nontraumatic model that allows daily macroscopic examination of both growth factor- and tumor-induced angiogenesis in mouse ears. In the same animal, we were thus able to record variations in the patterns of neovessels induced and cell populations recruited by the angiogenic factors FGF-2 and VEGF. In this model, inhibition of FGF-2-induced angiogenesis by the pharmacological compound TNP-470 was readily observed, demonstrating that the mouse ear model is also useful in the evaluation of antiangiogenic strategies. Our functional analysis of Ets transcription factors activity utilized a competitor protein, Ets1-DB, a dominant negative Ets1 mutant lacking the transactivation domain. Retrovirus-mediated expression of Ets1-DB inhibited FGF-2-induced angiogenesis, while the expression of Ets1-DB in cancerous and stromal cells disturbed tumor-induced angiogenesis. These results illustrate the value of the ear model and highlight the role of Ets family members in the transcriptional regulation of tumor angiogenesis.

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Acknowledgements

We thank Takeda Chemical Industries for the kind supply of TNP-470. We thank Professor Christophe Bauters for constant interest, stimulating discussions and support. Intravital fluorescence microscopy analysis was performed with the help of Eric Maire. Retroviral vectors were prepared with the assistance of Agnès Bègue, Patrick Martin and Thierry Calmels. We thank Professor Marie Madeleine Ruchoux for her help in the analysis of histological sections. We are grateful to Emile Fleurbaix for taking care of the mice. We thank Fabrice Soncin, Corinne Abbadie, David Bernard and Véronique Fafeur for helpful discussions and Jose Meija for a critical reading of the manuscript. This work was supported by grants from CNRS, Association pour la Lutte contre le Cancer, la Ligue Nationale contre le Cancer, la Fondation pour la Recherche Médicale, l'Université de Lille 2 and l'Institut Pasteur de Lille. Albin Pourtier-Manzanedo was a postdoctoral fellow of the Centre Hospitalier Régional et Universitaire de Lille.

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  1. Albin Pourtier-Manzanedo

    Present address: Laboratoire de Biologie du Développement UPRES EA 1033, Bâtiment SN3, Université des Sciences et Technologies de Lille 1, F-59655, Villeneuve d'Ascq Cedex, France

Authors and Affiliations

  1. FRE 2353 CNRS/Institut Pasteur de Lille/Université Lille 2, Institut de Biologie de Lille, 1 Rue Calmette, Lille, F-59021, Cedex, France

    Albin Pourtier-Manzanedo, Chantal Vercamer & Bernard Vandenbunder

  2. UMR 8526 CNRS/Institut Pasteur de Lille/Université Lille 2, Institut de Biologie de Lille, 1 Rue Calmette, Lille, F-59021, Cedex, France

    Virginie Mattot

  3. Service de Cardiologie B et Hémodynamique, Hôpital Cardiologique, Université de Lille 2, Avenue Oscar Lambret, Lille, F-59037, France

    Eric Van Belle & Frederic Mouquet

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  1. Albin Pourtier-Manzanedo
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Correspondence to Bernard Vandenbunder.

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Pourtier-Manzanedo, A., Vercamer, C., Van Belle, E. et al. Expression of an Ets-1 dominant-negative mutant perturbs normal and tumor angiogenesis in a mouse ear model. Oncogene 22, 1795–1806 (2003). https://doi.org/10.1038/sj.onc.1206215

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