title: Suppression of β3-integrin in mice triggers a neuropilin-1-dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis.
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 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.
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Ellison
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Atkinson
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Veronica
authors.initials: V
authors.lastname: Steri
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Kirkup
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Michael E J
authors.initials: ME
authors.lastname: Preedy
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Johnson
authors.affiliation: Institute of Ophthalmology, University College London, London, EC1V 9EL, UK.
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
authors.affiliation: Luxembourg Center for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg & Saarland University Medical Center, Internal Medicine II, L-4362 Homburg, Germany.
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine, Division of Molecular Oncology, Washington University in St Louis, St Louis, MO 63110, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Weilbaecher
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK stephen.robinson@uea.ac.uk.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Robinson
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D003593:Cytoplasm; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology; D005434:Flow Cytometry; D022001:Focal Adhesions; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008168:Lung / Q000503:physiopathology; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D039942:Neuropilin-1 / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D039661:Integrin beta3; D016023:Integrins; D051419:Paxillin; C496062:Pxn protein, mouse; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Focal adhesion; Integrin; Neuropilin-1; Tumour