Research Papers:

The protective role of sphingosine-1-phosphate against the action of the vascular disrupting agent combretastatin A-4 3-O-phosphate

Joanna Shepherd, Matthew Fisher, Abigail Welford, Donald M. McDonald, Chryso Kanthou and Gillian M. Tozer _

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Oncotarget. 2017; 8:95648-95661. https://doi.org/10.18632/oncotarget.21172

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Joanna Shepherd1, Matthew Fisher2, Abigail Welford2, Donald M. McDonald3, Chryso Kanthou2 and Gillian M. Tozer2

1Current/Present address: School of Clinical Dentistry, The University of Sheffield, Claremont Crescent, Sheffield, UK

2Tumour Microcirculation Group, The University of Sheffield, Department of Oncology and Metabolism, School of Medicine, Sheffield, UK

3UCSF Comprehensive Cancer Center, Cardiovascular Research Institute, and Department of Anatomy, University of California, San Francisco, CA, USA

Correspondence to:

Gillian M. Tozer, email: [email protected]

Keywords: sphingosine-1-phosphate; combretastatin; VE-cadherin; tumour microcirculation; adherens junctions

Received: April 27, 2017    Accepted: August 17, 2017    Published: September 21, 2017


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 CA4P-induced (30mg/kg) blood flow shut-down in fibrosarcoma tumours in SCID mice (n≥7 per group), as measured by tumour retention of an intravenously administered fluorescent lectin. A trend towards in vivo protection was also found using laser Doppler flowmetry. 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 filaments 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.

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