| Autor: |
Kabir AU; Department of Pathology and Immunology and.; Molecular and Cell Biology Program, Washington University School of Medicine, St. Louis, Missouri, USA., Lee TJ; Department of Pathology and Immunology and., Pan H; Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA., Berry JC; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Krchma K; Department of Pathology and Immunology and., Wu J; Department of Pathology and Immunology and., Liu F; Department of Pathology and Immunology and., Kang HK; Department of Pharmacology, School of Medicine, Jeju National University, Jeju, South Korea., Hinman K; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA., Yang L; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Hamilton S; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Zhou Q; Department of Pharmaceutical Science, College of Pharmacy, University of South Florida, Tampa, Florida, USA., Veis DJ; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Mecham RP; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA., Wickline SA; Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA., Miller MJ; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA., Choi K; Department of Pathology and Immunology and.; Molecular and Cell Biology Program, Washington University School of Medicine, St. Louis, Missouri, USA.; Graduate School of Biotechnology, Kyung Hee University, Yongin, South Korea. |
| Abstrakt: |
Angiogenesis, new blood vessel formation from preexisting vessels, is critical for solid tumor growth. As such, there have been efforts to inhibit angiogenesis as a means to obstruct tumor growth. However, antiangiogenic therapy faces major challenges to the selective targeting of tumor-associated-vessels, as current antiangiogenic targets also disrupt steady-state vessels. Here, we demonstrate that the developmentally critical transcription factor Etv2 is selectively upregulated in both human and mouse tumor-associated endothelial cells (TAECs) and is required for tumor angiogenesis. Two-photon imaging revealed that Etv2-deficient tumor-associated vasculature remained similar to that of steady-state vessels. Etv2-deficient TAECs displayed decreased Flk1 (also known as Vegfr2) expression, FLK1 activation, and proliferation. Endothelial tube formation, proliferation, and sprouting response to VEGF, but not to FGF2, was reduced in Etv2-deficient ECs. ROS activated Etv2 expression in ECs, and ROS blockade inhibited Etv2 expression in TAECs in vivo. Systemic administration of Etv2 siRNA nanoparticles potently inhibited tumor growth and angiogenesis without cardiovascular side effects. These studies highlight a link among vascular oxidative stress, Etv2 expression, and VEGF response that is critical for tumor angiogenesis. Targeting the ETV2 pathway might offer a unique opportunity for more selective antiangiogenic therapies. |
