title: Blockade of aquaporin 1 inhibits proliferation, motility, and metastatic potential of mesothelioma in vitro but not in an in vivo model.
abstract: BACKGROUND
  Malignant mesothelioma (MM) is an aggressive tumor of the serosal membranes, mostly the pleura. It is related to asbestos exposure and has a poor prognosis. MM has a long latency period, and incidence is predicted to remain stable or increase until 2020. Currently, no biomarkers for a specific targeted therapy are available. Previously, we observed that expression of aquaporin 1 (AQP1) was an indicator of prognosis in two independent cohorts. Here we determine whether AQP1 inhibition has therapeutic potential in the treatment of MM.
  
  
  METHODS
  Functional studies were performed with H226 cells and primary MM cells harvested from pleural effusions. AQP1 expression and mesothelial phenotype was determined by immunohistochemistry. AQP1 function was inhibited by a pharmacological blocker (AqB050) or AQP1-specific siRNA. Cell proliferation, migration, and anchorage-independent cell growth were assessed. A nude mouse heterotopic xenograft model of MM was utilised for the in vivo studies.
  
  
  RESULTS
  Inhibition of AQP1 significantly decreases cell proliferation, metastatic potential, and motility without inducing nonspecific cytotoxicity or increasing apoptosis. In vivo blockade of AQP1 had no biologically significant effect on growth of established tumours.
  
  
  CONCLUSIONS
  Targeted blockade of AQP1 restricts MM growth and migration in vitro. Further work is warranted to fully evaluate treatment potential in vivo.
authors.affiliation: Department of Anatomical Pathology, Flinders University, Adelaide, Bedford, SA 5042, Australia ; SA Pathology, Department of Surgical Pathology, Flinders Medical Centre, Adelaide, Bedford, SA 5042, Australia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Klebe
authors.affiliation: Department of Anatomical Pathology, Flinders University, Adelaide, Bedford, SA 5042, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Griggs
authors.affiliation: Asbestos Diseases Research Institute, Bernie Banton Centre, NSW 2139, Australia.
authors.forename: Yuen
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Anatomical Pathology, Flinders University, Adelaide, Bedford, SA 5042, Australia.
authors.forename: Jack
authors.initials: J
authors.lastname: Driml
authors.affiliation: Department of Anatomical Pathology, Flinders University, Adelaide, Bedford, SA 5042, Australia ; SA Pathology, Department of Surgical Pathology, Flinders Medical Centre, Adelaide, Bedford, SA 5042, Australia.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Henderson
authors.affiliation: Asbestos Diseases Research Institute, Bernie Banton Centre, NSW 2139, Australia ; School of Medicine, University of Sydney, NSW 2006, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Reid
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D051398:Aquaporin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016066:Pleural Effusion, Malignant / Q000188:drug therapy / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C496020:AQP1 protein, human; D000970:Antineoplastic Agents; D051398:Aquaporin 1
references.citation: Int J Cancer. 2011 Aug 15;129(4):1005-17
references.pmid: 20949562
references.citation: Cancer. 2012 Jun 1;118(11):2952-61
references.pmid: 22020536
references.citation: Clin Exp Nephrol. 2009 Apr;13(2):107-17
references.pmid: 19085041
references.citation: Respir Physiol Neurobiol. 2003 Dec 16;139(1):83-8
references.pmid: 14637313
references.citation: J Clin Invest. 1996 May 15;97(10):2183-91
references.pmid: 8636397
references.citation: Am J Pathol. 2006 Apr;168(4):1345-53
references.pmid: 16565507
references.citation: PLoS One. 2009;4(7):e6167
references.pmid: 19584911
references.citation: Anticancer Res. 2014 Jun;34(6):3061-5
references.pmid: 24922673
references.citation: Microvasc Res. 1999 Sep;58(2):89-98
references.pmid: 10458924
references.citation: BMC Physiol. 2002;2:4
references.pmid: 11914159
references.citation: Annu Rev Physiol. 1996;58:619-48
references.pmid: 8815812
references.citation: J Mol Med (Berl). 2008 May;86(5):523-9
references.pmid: 18311471
references.citation: Respiration. 2012;83(6):481-93
references.pmid: 22710421
references.citation: Am J Physiol Cell Physiol. 2000 Dec;279(6):C1744-50
references.pmid: 11078688
references.citation: Expert Rev Anticancer Ther. 2009 Apr;9(4):453-67
references.pmid: 19374599
references.citation: Ann Med. 2002;34(3):192-200
references.pmid: 12173689
references.citation: Nucl Med Biol. 2009 May;36(4):379-88
references.pmid: 19423005
references.citation: Drug News Perspect. 2001 Sep;14(7):412-20
references.pmid: 12813584
references.citation: Neurosurgery. 2005 Feb;56(2):375-81; discussion 375-81
references.pmid: 15670385
references.citation: Pflugers Arch. 2008 Jul;456(4):693-700
references.pmid: 17968585
references.citation: Med Oncol. 2012 Jun;29(2):656-62
references.pmid: 21519870
references.citation: Trends Endocrinol Metab. 2006 Jan-Feb;17(1):1-2
references.pmid: 16309919
references.citation: FASEB J. 2006 Sep;20(11):1892-4
references.pmid: 16818469
references.citation: J Mol Med (Berl). 2013 May;91(5):613-23
references.pmid: 23197380
references.citation: Am J Ind Med. 2002 Mar;41(3):188-201
references.pmid: 11920963
references.citation: Lancet. 2005 Jul 30-Aug 5;366(9483):397-408
references.pmid: 16054941
references.citation: Nature. 2005 Apr 7;434(7034):786-92
references.pmid: 15815633
references.citation: Lancet Oncol. 2006 Feb;7(2):132-40
references.pmid: 16455477