Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth.
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.
Cao
Yiting
Y
Department of Radiation Oncology, Duke University Medical Center, Research Drive, DUMC 3455, Durham, NC 27710, USA.
Sonveaux
Pierre
P
Liu
Shanling
S
Zhao
Yulin
Y
Mi
Jing
J
Clary
Bryan M
BM
Li
Chuan-Yuan
CY
Kontos
Christopher D
CD
Dewhirst
Mark W
MW
D000230:Adenocarcinoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D042702:Angiopoietin-2 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
D042702:Angiopoietin-2; D040281:Vascular Endothelial Growth Factor Receptor-1