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

• Published in: Oncogene Vol. 22; no. 12; pp. 1795 - 1806
• Main Authors: POURTIER-MANZANEDO, Albin, VERCAMER, Chantal, VAN BELLE, Eric, MATTOT, Virginie, MOUQUET, Frederic, VANDENBUNDER, Bernard
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 27.03.2003; Nature Publishing Group
• Subjects: Angiogenesis; Animals; Antiangiogenic agents; Biological and medical sciences; Blood vessels; Classical genetics, quantitative genetics, hybrids; Ear; Ear - pathology; Endothelial cells; Endothelial Growth Factors - physiology; Ets-1 protein; Female; Fibroblast growth factor 2; Fibroblast Growth Factor 2 - physiology; Fundamental and applied biological sciences. Psychology; Gene regulation; Genes; Genes, Dominant; Genetic Vectors; Genetics of eukaryotes. Biological and molecular evolution; Growth factors; Intercellular Signaling Peptides and Proteins - physiology; Lymphokines - physiology; Mice; Mice, Nude; Microscopy, Fluorescence; Mutants; Mutation; Neoplasm Transplantation; Neoplasms, Experimental - blood supply; Neoplasms, Experimental - genetics; Neovascularization, Pathologic - genetics; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-ets; Stromal cells; Transcription factors; Transcription Factors - genetics; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vertebrata; France; growth factors; Rodentia; inhibition; Ets-1; Normal; Angiogenesis; Vertebrata; in vivo model; Mammalia; Mouse; Ear; Tumor; Models
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206215

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.