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

Emily Kate Pulford, James Hugh McEvoy, Ashleigh J. Hocking, Sarita Prabhakaran, Kim M. Griggs, Sonja Klebe

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    4 Citations (Scopus)

    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.

    Original languageEnglish
    Article number2293
    Number of pages12
    JournalInternational Journal of Molecular Sciences
    Volume18
    Issue number11
    DOIs
    Publication statusPublished - 1 Nov 2017

    Bibliographical note

    This article is an open access
    article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

    Keywords

    • Angiogenesis
    • Aquaporin 1
    • Malignant mesothelioma
    • Vascular endothelial growth factor a (VEGFA)
    • Vasculogenic mimicry

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