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

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Anti-angiogenic treatments against αvβ3-integrin fail to block tumour growth in the long term, which suggests that the tumour vasculature escapes from angiogenesis inhibition through αvβ3- integrin-independent mechanisms. Here, we show that suppression of β3-integrin in mice leads to the activation of a neuropilin-1 (NRP1)- dependent cell migration pathway in endothelial cells via amechanism 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 thesemolecules in combination to treat patients with advanced cancers.

Original languageEnglish
Pages (from-to)1105-1119
Number of pages15
JournalDMM Disease Models and Mechanisms
Volume8
Issue number9
DOIs
StatePublished - Sep 1 2015

Keywords

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

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