The NADPH Oxidase Nox4 mediates tumour angiogenesis

V. Helfinger, N. Henke, S. Harenkamp, M. Walter, J. Epah, C. Penski, M. Mittelbronn, K. Schröder*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

Abstract

Aim: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)435-446
Number of pages12
JournalActa Physiologica
Volume216
Issue number4
DOIs
Publication statusPublished - 1 Apr 2016
Externally publishedYes

Keywords

  • Cancer
  • Hypoxia-inducible factor-1α
  • NADPH oxidase Nox4
  • Tumour angiogenesis

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