Suppression of β3-integrin in mice triggers a neuropilin-1- dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis

Tim S. Ellison, Samuel J. Atkinson, Veronica Steri, Benjamin M. Kirkup, Michael E. J. Preedy, Robert T. Johnson, Christiana Ruhrberg, Dylan R. Edwards, Jochen G. Schneider, Katherine Weilbaecher, Stephen D. Robinson

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Abstract

Anti-angiogenic treatments against αvβ3-integrin fail to block tumour growth in the long term, which suggests tumour vascular escape through αvβ3-integrin-independent mechanisms. Here, we show that suppression of β3-integrin leads to the activation of a neuropilin-1 (NRP1) dependent cell migration pathway in endothelial cells via a mechanism that depends on NRP1’s mobilisation away from mature focal adhesions following VEGF-stimulation. The simultaneous genetic targeting of both molecules significantly impairs paxillin-1 activation and focal adhesion remodelling in endothelial cells and therefore inhibits tumour angiogenesis and the growth of already established tumours. These findings provide a firm foundation for testing drugs against these molecules in combination to treat patients with advanced cancers.
Original languageEnglish
Pages (from-to)1105-1119
Number of pages15
JournalDisease Models & Mechanisms
Volume8
DOIs
Publication statusPublished - 2015

Keywords

  • Integrin
  • Neuropilin-1
  • Angiogenesis
  • Tumour
  • Focal adhesion

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