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.
Highlights
Malignant mesothelioma is an aggressive malignancy of the serosal membranes, primarily attributable to asbestos exposure
Limited targeted treatments exist for malignant mesothelioma (MM) due to the lack of definitive driver mutations, predictive markers and incomplete understanding of pathogenic pathways
Traditional pathways of angiogenesis have been suggested as targets for therapy due to adverse prognostication associated with increased serum and pleural effusion levels of the pro-angiogenic marker vascular endothelial growth factor A (VEGFA)
Summary
Malignant mesothelioma is an aggressive malignancy of the serosal membranes, primarily attributable to asbestos exposure. Limited targeted treatments exist for malignant mesothelioma (MM) due to the lack of definitive driver mutations, predictive markers and incomplete understanding of pathogenic pathways. Traditional pathways of angiogenesis have been suggested as targets for therapy due to adverse prognostication associated with increased serum and pleural effusion levels of the pro-angiogenic marker vascular endothelial growth factor A (VEGFA). Intratumoural microvessel density is associated with poor prognosis [3]. Clinical inhibition of this pathway utilises bevacizumab (AvastinTM, Genentech, South San Francisco, CA, USA) and tyrosine kinase inhibitors of VEGF receptors; improvements to overall survival have been limited [4,5,6,7,8,9]
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