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Int. J. Mol. Sci. 2017, 18(11), 2293; https://doi.org/10.3390/ijms18112293

The Effect of Aquaporin 1-Inhibition on Vasculogenic Mimicry in Malignant Mesothelioma

1
Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia
2
Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide 5001, SA, Australia
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 29 September 2017 / Revised: 25 October 2017 / Accepted: 27 October 2017 / Published: 1 November 2017
(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms)
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Abstract

Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes, with poor overall survival and quality of life. Limited targeted treatment strategies exist due to restricted knowledge of pathogenic pathways. Vasculogenic mimicry (VM) is a newly described phenomenon associated with increased aggressiveness in other malignancies, and has been characterized in MM. Normal mesothelium expresses aquaporin 1 (AQP1) and retained expression has been associated with improved survival in MM. AQP1 is expressed by normal vascular endothelium and is involved in mediating MM cell motility and proliferation. We investigated the role of AQP1 in VM, and its interaction with the pro-angiogenic factor vascular endothelial growth factor A (VEGFA), which is variably expressed in MM. Matrigel VM assays were performed using NCI-H226 and NCI-H28 MM cell lines and primary cells in hypoxia and normoxia. The synthetic blocker AqB050 and siRNA were used to inhibit AQP1, and bevacizumab was used to inhibit VEGF. Inhibition of AQP1 resulted in increased VEGFA secretion by MM cells and reduced VM in MM cell lines in hypoxia but not normoxia. No change in VM was seen in MM primary cells. Combined inhibition of AQP1 and VEGF had no effect on VM in normoxia. In a heterotopic xenograft mouse model, AqB050 treatment did not alter vessel formation. AQP1 may interact with VEGFA and play a role in VM, especially under hypoxic conditions, but the heterogeneity of MM cells may result in different dominant pathways between patients. View Full-Text
Keywords: malignant mesothelioma; vasculogenic mimicry; aquaporin 1; vascular endothelial growth factor A (VEGFA); angiogenesis malignant mesothelioma; vasculogenic mimicry; aquaporin 1; vascular endothelial growth factor A (VEGFA); angiogenesis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Pulford, E.; McEvoy, J.; Hocking, A.; Prabhakaran, S.; Griggs, K.; Klebe, S. The Effect of Aquaporin 1-Inhibition on Vasculogenic Mimicry in Malignant Mesothelioma. Int. J. Mol. Sci. 2017, 18, 2293.

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