Shepherd, J. orcid.org/0000-0001-7661-0698, Fisher, M., Welford, A. et al. (3 more authors) (2017) The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3-O-phosphate. Oncotarget, 2017 (8). pp. 95648-95661. ISSN 1949-2553
Abstract
Solid tumours vary in sensitivity to the vascular disrupting agent combretastatin A-4 3-O-phosphate (CA4P), but underlying factors are poorly understood. The signaling sphingolipid, sphingosine-1-phosphate (S1P), promotes vascular barrier integrity by promoting assembly of VE-cadherin/β-catenin complexes. We tested the hypothesis that tumour pre-treatment with S1P would render tumours less susceptible to CA4P. S1P (1μM) pretreatment attenuated an increase in endothelial cell (HUVEC) monolayer permeability induced by 10μM CA4P. Intravenously administered S1P (8mg/kg/hr for 20 minutes then 2mg/kg/hr for 40 minutes), reduced CA4Pinduced (30mg/kg) blood fow shut-down in fbrosarcoma tumours in SCID mice (n≥7 per group), as measured by tumour retention of an intravenously administered fuorescent lectin. A trend towards in vivo protection was also found using laser Doppler fowmetry. Immunohistochemical staining of tumours ex vivo revealed disrupted patterns of VE-cadherin in vasculature of mice treated with CA4P, which were decreased by pretreatment with S1P. S1P treatment also stabilized N-cadherin junctions between endothelial cells and smooth muscle cells in culture, and stabilized tubulin flaments in HUVEC monolayers. We conclude that the rapid shutdown of tumour microvasculature by CA4P is due in part to disruption of adherens junctions and that S1P has a protective effect on both adherens junctions and the endothelial cell cytoskeleton.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Shepherd et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
Keywords: | sphingosine-1-phosphate; combretastatin; VE-cadherin; tumour microcirculation; adherens junctions |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Clinical Dentistry (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 02 Oct 2017 08:44 |
Last Modified: | 10 Nov 2023 13:29 |
Status: | Published |
Publisher: | Impact Journals |
Refereed: | Yes |
Identification Number: | 10.18632/oncotarget.21172 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:121759 |