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

doi:10.1242/dmm.019927

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 language	English
Pages (from-to)	1105-1119
Number of pages	15
Journal	Disease Models & Mechanisms
Volume	8
DOIs	https://doi.org/10.1242/dmm.019927
Publication status	Published - 1 Sep 2015

Keywords

Integrin
Neuropilin-1
Angiogenesis
Tumour
Focal adhesion

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1242/dmm.019927Licence: CC BY

Dis. Model. Mech.-2015-Ellison-1105-19
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed
Final published version, 2.26 MBLicence: CC BY

Dylan Edwards
- Dylan.Edwardsuea.acuk
- Norwich Medical School - Emeritus Professor
- Norwich Institute for Healthy Aging - Member
- Cancer Studies - Member
Person: Honorary, Research Group Member, Research Centre Member
Stephen Robinson
- Stephen.Robinsonuea.acuk
- School of Biological Sciences - Research Leader
- Norwich Institute for Healthy Aging - Member
- Cells and Tissues - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching & Research

Elucidating how avB3-integrin regulates Neuropilin-1's role in tumour angiogenesis in order to improve anti-angiogenic therapy
Robinson, S.
The Big C Appeal
1/01/12 → 31/03/15
Project: Training

Cite this

Ellison, T. S., Atkinson, S. J., Steri, V., Kirkup, B. M., Preedy, M. E. J., Johnson, R. T., Ruhrberg, C., Edwards, D. R., Schneider, J. G., Weilbaecher, K., & Robinson, S. D. (2015). Suppression of β3-integrin in mice triggers a neuropilin-1- dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis. Disease Models & Mechanisms, 8, 1105-1119. https://doi.org/10.1242/dmm.019927

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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 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{\textquoteright}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.",

keywords = "Integrin, Neuropilin-1, Angiogenesis, Tumour, Focal adhesion",

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

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doi = "10.1242/dmm.019927",

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Ellison, TS, Atkinson, SJ, Steri, V, Kirkup, BM, Preedy, MEJ, Johnson, RT, Ruhrberg, C, Edwards, DR, Schneider, JG, Weilbaecher, K & Robinson, SD 2015, 'Suppression of β3-integrin in mice triggers a neuropilin-1- dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis', Disease Models & Mechanisms, vol. 8, pp. 1105-1119. https://doi.org/10.1242/dmm.019927

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T1 - Suppression of β3-integrin in mice triggers a neuropilin-1- dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis

AU - Ellison, Tim S.

AU - Atkinson, Samuel J.

AU - Steri, Veronica

AU - Kirkup, Benjamin M.

AU - Preedy, Michael E. J.

AU - Johnson, Robert T.

AU - Ruhrberg, Christiana

AU - Edwards, Dylan R.

AU - Schneider, Jochen G.

AU - Weilbaecher, Katherine

AU - Robinson, Stephen D.

N1 - This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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.

KW - Integrin

KW - Neuropilin-1

KW - Angiogenesis

KW - Tumour

KW - Focal adhesion

U2 - 10.1242/dmm.019927

DO - 10.1242/dmm.019927

M3 - Article

VL - 8

SP - 1105

EP - 1119

JO - Disease Models & Mechanisms

JF - Disease Models & Mechanisms

SN - 1754-8403

ER -

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

Keywords

UN SDGs

Access to Document

Profiles

Dylan Edwards

Stephen Robinson

Projects

Elucidating how avB3-integrin regulates Neuropilin-1's role in tumour angiogenesis in order to improve anti-angiogenic therapy

Cite this