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Systemic Overexpression of Angiopoietin-2 Promotes Tumor Microvessel Regression and Inhibits Angiogenesis and Tumor Growth

Departments of ¹ Radiation Oncology, ² Surgery, and ³ Medicine, Duke University Medical Center, Durham, North Carolina; ⁴ Unit of Pharmacology and Therapeutics, Université Catholique de Louvain, Brussels, Belgium; ⁵ West China Second University Hospital, Sichuan University, Chengdu, Sichuan, P.R. China; and ⁶ Department of Radiation Oncology, University of Colorado Health Science Center, Aurora, Colorado

Requests for reprints: Mark W. Dewhirst, Department of Radiation Oncology, Duke University Medical Center, MSRB Room 201, Research Drive, DUMC 3455, Durham, NC 27710. Phone: 919-684-4180; Fax: 919-684-8718; E-mail: dewhi001{at}mc.duke.edu.

Angiopoietin-2 (Ang-2) is a conditional antagonist and agonist for the endothelium-specific Tie-2 receptor. Although endogenous Ang-2 cooperates with vascular endothelial growth factor (VEGF) to protect tumor endothelial cells, the effect on tumor vasculature of high levels of exogenous Ang-2 with different levels of VEGF has not been studied in detail. Here, we report that systemic overexpression of Ang-2 leads to unexpected massive tumor vessel regression within 24 h, even without concomitant inhibition of VEGF. By impairing pericyte coverage of the tumor vasculature, Ang-2 destabilizes the tumor vascular bed while improving perfusion in surviving tumor vessels. Ang-2 overexpression transiently exacerbates tumor hypoxia without affecting ATP levels. Although sustained systemic Ang-2 overexpression does not affect tumor hypoxia and proliferation, it significantly inhibits tumor angiogenesis, promotes tumor apoptosis, and suppresses tumor growth. The similar antitumoral, antiangiogenic efficacy of systemic overexpression of Ang-2, soluble VEGF receptor-1, and the combination of both suggests that concomitant VEGF inhibition is not required for Ang-2–induced tumor vessel regression and growth delay. This study shows the important roles of Ang-2–induced pericyte dropout during tumor vessel regression. It also reveals that elevated Ang-2 levels have profound pleiotropic effects on tumor vessel structure, perfusion, oxygenation, and apoptosis. [Cancer Res 2007;67(8):3835–44]

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