Elucidating how αvβ3-integrin regulates neuropilin-1’s role in tumour angiogenesis in order to improve anti-angiogenic therapy

Ellison, Timothy (2015) Elucidating how αvβ3-integrin regulates neuropilin-1’s role in tumour angiogenesis in order to improve anti-angiogenic therapy. Doctoral thesis, University of East Anglia.

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Abstract

αvβ3-integrin expression is vastly upregulated in tumour vasculature, and has long been considered a key molecule in promoting tumour angiogenesis. However, its initial promise as a target in anti-angiogenic therapy has wavered since the αvβ3-integrin antagonist cilengitide did not meet its end point in Phase III clinical trials for the treatment of glioblastoma. This failure corresponds with the enhanced tumour growth and angiogenesis observed in β3-integrin-knockout mice, which potentially occurs via a compensatory upregulation of VEGFR2 and
enhancement in VEGFR2-neuropilin-1 interactions. Here, I show that tumour growth and angiogenesis are sensitive to neuropilin-1 perturbation even with only a 50% reduction in β3-integrin expression. β3-integrin-heterozygous, but not wild-type, mice show an increased dependence on neuropilin-1 that is not related to changes in neuropilin-1-mediated VEGFR2 function. Rather, the suppression of β3-integrin leads to the activation of a neuropilin-1-dependent endothelial cell
migration pathway via a mechanism in which NRP1 is mobilised away from mature focal adhesions following VEGF-stimulation. Concordantly, the simultaneous genetic targeting of both molecules significantly impairs paxillin activation and focal adhesion turnover in endothelial cells, and thus inhibits endothelial cell migration, and tumour growth and angiogenesis, even in established tumours. These findings therefore provide important pre-clinical evidence that pharmacologically targeting both molecules in unison might be an effective anti-angiogenic therapy for patients with advanced cancers.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Biological Sciences
Depositing User: Brian Watkins
Date Deposited: 10 Mar 2016 11:25
Last Modified: 10 Mar 2016 11:25
URI: https://ueaeprints.uea.ac.uk/id/eprint/57412
DOI:

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