title: The NADPH Oxidase Nox4 mediates tumour angiogenesis.
abstract: OBJECTIVE
  The aim of this work was to identify the role of the NADPH oxidase Nox4 for tumour angiogenesis in a slow-growing tumour model in mice.
  
  
  METHODS
  Tumour angiogenesis was studied in tumours induced by the carcinogen 3-methylcholanthrene (MCA) in wild-type and Nox knockout mice. Mice were killed when the tumour reached a diameter of 1.5 cm and tumour tissue was used for histological and molecular analysis.
  
  
  RESULTS
  3-methylcholanthrene induced fibrosarcoma in wild-type, Nox1y/-, Nox2y/- and Nox4-/- mice. Histological analysis of vessel density using anti-CD31 staining showed a significant 38% reduction in tumour vascularization in fibrosarcomas of Nox4-/- mice. In contrast, tumour angiogenesis was doubled in Nox1 knockout mice, whereas knockout of Nox2 had no effect on tumour-vessel density. As underlying mechanisms, we identified a defect in hypoxia signalling in Nox4-/- mice. Hypoxia-inducible factor 1-alpha (Hif-1α) accumulation in the tumours was attenuated as was the expression of the Hif-1α-dependent pro-angiogenic genes vascular endothelial growth factor-A, glucose transporter 1 and adrenomedullin.
  
  
  CONCLUSIONS
  By regulating the tumour-vessel density through stabilization of Hif-1α and induction of VEGF expression, Nox4 promotes tumour angiogenesis and may represent a novel target for anti-angiogenic tumour therapy.
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Helfinger
authors.affiliation: Institute for Biochemistry I/Pathobiochemistry, Goethe-University, Frankfurt, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Henke
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Harenkamp
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Walter
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Epah
authors.affiliation: Neurological Institute (Edinger Institute) Goethe-University, Frankfurt, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Penski
authors.affiliation: Neurological Institute (Edinger Institute) Goethe-University, Frankfurt, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schröder
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000172:deficiency / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D016133:Polymerase Chain Reaction
chemical_list: D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse
keywords: NADPH oxidase Nox4; cancer; hypoxia-inducible factor-1α; tumour angiogenesis