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Sustained Expression of Early Growth Response Protein-1 Blocks Angiogenesis and Tumor Growth

Departments of ¹ Vascular Biology and Thrombosis Research and ² Dermatology, ³ Clinical Department of Medical and Chemical Laboratory Diagnostics, ⁴ Ludwig Boltzmann Institute for Clinical and Experimental Oncology, Medical University of Vienna, Vienna, Austria and ⁵ Department of Cellular and Integrative Physiology, Indiana Center of Vascular Biology and Medicine, Indianapolis

Requests for reprints: Erhard Hofer, Department of Vascular Biology and Thrombosis Research, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna Competence Center, Lazarettgasse 19, A-1235 Vienna, Austria. Phone: 43-1-40160-33111; Fax: 43-1-40160-933100; E-mail: erhard.hofer{at}meduniwien.ac.at.

Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by recombinant adenoviruses in endothelial cells, however, leads to the specific induction of potent feedback inhibitory mechanisms, including strong up-regulation of transcriptional repressors, negative cell cycle check point effectors, proteins with established antiangiogenic activity, and several proapoptotic genes. Sustained EGR-1 expression consistently leads to an antiangiogenic state characterized by an altered responsiveness to VEGF and bFGF and a striking inhibition of sprouting and tubule formation in vitro. Furthermore, EGR-1–expressing viruses potently inhibit cell invasion and vessel formation in the murine Matrigel model and repress tumor growth in a murine fibrosarcoma model. We propose that gene therapy involving sustained EGR-1 expression may constitute a novel therapeutic principle in the treatment of cancer due to the simultaneous induction of multiple pathways of antiangiogenesis, growth arrest, and apoptosis induction in proliferating cells leading to preferential inhibition of angiogenesis and tumor growth. (Cancer Res 2006; 66(13): 6708-13)

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