title: Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth.
abstract: 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.
authors.affiliation: Departments of Vascular Biology and Thrombosis Research, Ludwig Boltzmann Institute for Clinical and Experimental Oncology, Medical University of Vienna, Lazarettgasse 19, A-1235 Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Lucerna
authors.forename: Jiri
authors.initials: J
authors.lastname: Pomyje
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kadl
authors.forename: Florian
authors.initials: F
authors.lastname: Gruber
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sobanov
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Johannes
authors.initials: J
authors.lastname: Breuss
authors.forename: Oswald
authors.initials: O
authors.lastname: Wagner
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.forename: Matthias
authors.initials: M
authors.lastname: Clauss
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
authors.forename: Erhard
authors.initials: E
authors.lastname: Hofer
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005354:Fibrosarcoma / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D012333:RNA, Messenger