{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T13:57:45Z","timestamp":1760623065974,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2017,11,1]],"date-time":"2017-11-01T00:00:00Z","timestamp":1509494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008017","name":"Flinders Medical Centre Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008017","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001785","name":"Flinders University","doi-asserted-by":"publisher","award":["Michael Ely Scholarship"],"award-info":[{"award-number":["Michael Ely Scholarship"]}],"id":[{"id":"10.13039\/501100001785","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms18112293","type":"journal-article","created":{"date-parts":[[2017,11,1]],"date-time":"2017-11-01T16:01:19Z","timestamp":1509552079000},"page":"2293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Effect of Aquaporin 1-Inhibition on Vasculogenic Mimicry in Malignant Mesothelioma"],"prefix":"10.3390","volume":"18","author":[{"given":"Emily","family":"Pulford","sequence":"first","affiliation":[{"name":"Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"McEvoy","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashleigh","family":"Hocking","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3252-2519","authenticated-orcid":false,"given":"Sarita","family":"Prabhakaran","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia"},{"name":"Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide 5001, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Griggs","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8976-4714","authenticated-orcid":false,"given":"Sonja","family":"Klebe","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Flinders University, Adelaide 5000, SA, Australia"},{"name":"Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide 5001, SA, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,11,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/sj.bjc.6690650","article-title":"VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours","volume":"81","author":"Ohta","year":"1999","journal-title":"Br. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1002\/path.824","article-title":"Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma","volume":"193","author":"Strizzi","year":"2001","journal-title":"J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/(SICI)1096-9896(199706)182:2<211::AID-PATH834>3.0.CO;2-D","article-title":"Evaluation of tumour angiogenesis as a prognostic marker in malignant mesothelioma","volume":"182","author":"Vermeulen","year":"1997","journal-title":"J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/S0140-6736(15)01238-6","article-title":"Bevacizumab for newly diagnosed pleural mesothelioma in the mesothelioma avastin cisplatin pemetrexed study (MAPS): A randomised, controlled, open-label, phase 3 trial","volume":"387","author":"Zalcman","year":"2016","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/bjc.2013.368","article-title":"Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma","volume":"109","author":"Ceresoli","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.lungcan.2012.05.111","article-title":"A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma","volume":"77","author":"Dowell","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1200\/JCO.2011.41.5869","article-title":"Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine\/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma","volume":"30","author":"Kindler","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1097\/JTO.0b013e318229586e","article-title":"Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509","volume":"6","author":"Garland","year":"2011","journal-title":"J. Thorac. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1097\/JTO.0b013e31825f22ee","article-title":"A phase II study of intermittent sunitinib malate as second-line therapy in progressive malignant pleural mesothelioma","volume":"7","author":"Nowak","year":"2012","journal-title":"J.Thorac. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/S0002-9440(10)65173-5","article-title":"Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry","volume":"155","author":"Maniotis","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"56408","DOI":"10.18632\/oncotarget.16919","article-title":"Tumor vasculogenic mimicry formation as an unfavorable prognostic indicator in patients with breast cancer","volume":"8","author":"Shen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhu, B., Zhou, L., Yu, L., Wu, S., Song, W., Gong, X., and Wang, D. (2017). Evaluation of the correlation of vasculogenic mimicry, aldh1, kai1 and microvessel density in the prediction of metastasis and prognosis in colorectal carcinoma. BMC Surg., 17.","DOI":"10.1186\/s12893-017-0246-6"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13000-017-0612-9","article-title":"Evaluation of the correlation of vasculogenic mimicry, ALDH1, KISS-1, and MACC1 in the prediction of metastasis and prognosis in ovarian carcinoma","volume":"12","author":"Yu","year":"2017","journal-title":"Diagn. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2408645","DOI":"10.1155\/2016\/2408645","article-title":"Association between tumor vasculogenic mimicry and the poor prognosis of gastric cancer in China: An updated systematic review and meta-analysis","volume":"2016","author":"Guo","year":"2016","journal-title":"Biomed. Res. Int."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/j.pathol.2016.07.009","article-title":"Vasculogenic mimicry in malignant mesothelioma: An experimental and immunohistochemical analysis","volume":"48","author":"Pulford","year":"2016","journal-title":"Pathology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"22191","DOI":"10.18632\/oncotarget.4339","article-title":"Endothelial-like malignant glioma cells in dynamic three dimensional culture identifies a role for VEGF and FGFR in a tumor-derived angiogenic response","volume":"6","author":"Smith","year":"2015","journal-title":"Oncotarget"},{"key":"ref_17","first-page":"29","article-title":"VEGF-sirna silencing induces apoptosis, inhibits proliferation and suppresses vasculogenic mimicry in osteosarcoma in vitro","volume":"30","author":"Mei","year":"2008","journal-title":"Exp. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1158\/0008-5472.CAN-14-1855","article-title":"Induction of vasculogenic mimicry overrides VEGF-A silencing and enriches stem-like cancer cells in melanoma","volume":"75","author":"Schnegg","year":"2015","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1080\/ann.34.3.192.200","article-title":"Physiological importance of aquaporin water channels","volume":"34","author":"Verkman","year":"2002","journal-title":"Ann. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"286719","DOI":"10.1155\/2015\/286719","article-title":"Blockade of aquaporin 1 inhibits proliferation, motility, and metastatic potential of mesothelioma in vitro but not in an in vivo model","volume":"2015","author":"Klebe","year":"2015","journal-title":"Dis. Markers"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Monzani, E., Bazzotti, R., Perego, C., and LA Porta, C.A. (2009). AQP1 is not only a water channel: It contributes to cell migration through lin7\/\u03b2-catenin. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006167"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"C1744","DOI":"10.1152\/ajpcell.2000.279.6.C1744","article-title":"Role of aquaporin water channels in pleural fluid dynamics","volume":"279","author":"Song","year":"2000","journal-title":"Am. J. Physiol. Cell Phys."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Driml, J., Pulford, E., Moffat, D., Karapetis, C., Kao, S., Griggs, K., Henderson, D.W., and Klebe, S. (2016). Usefulness of aquaporin 1 as a prognostic marker in a prospective cohort of malignant mesotheliomas. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071041"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1002\/cncr.26497","article-title":"Aquaporin 1 is an independent prognostic factor in pleural malignant mesothelioma","volume":"118","author":"Kao","year":"2012","journal-title":"Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.gene.2012.12.075","article-title":"Gene expression profile of aquaporin 1 and associated interactors in malignant pleural mesothelioma","volume":"517","author":"Jagirdar","year":"2013","journal-title":"Gene"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nature03460","article-title":"Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption","volume":"434","author":"Saadoun","year":"2005","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"DeCicco-Skinner, K.L., Henry, G.H., Cataisson, C., Tabib, T., Gwilliam, J.C., Watson, N.J., Bullwinkle, E.M., Falkenburg, L., O\u2019Neill, R.C., and Morin, A. (2014). Endothelial cell tube formation assay for the in vitro study of angiogenesis. J. Vis. Exp., e51312.","DOI":"10.3791\/51312"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/j.1365-2613.2008.00633.x","article-title":"A critical analysis of current in vitro and in vivo angiogenesis assays","volume":"90","author":"Staton","year":"2009","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_29","first-page":"F461","article-title":"Aquaporins: A family of water channel proteins","volume":"265","author":"Agre","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1159\/000133639","article-title":"The human gene for water channel aquaporin 1 (AQP1) is localized on chromosome 7p15->p14","volume":"65","author":"Deen","year":"1994","journal-title":"Cytogenet. Cell Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1002\/iub.243","article-title":"Aquaporin-1 activity of plasma membrane affects HT20 colon cancer cell migration","volume":"61","author":"Jiang","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13046-016-0310-6","article-title":"Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro","volume":"35","author":"Dorward","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1074\/jbc.270.3.1230","article-title":"Purification and characterization of hypoxia-inducible factor 1","volume":"270","author":"Wang","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7987","DOI":"10.1073\/pnas.95.14.7987","article-title":"Regulation of hypoxia-inducible factor 1\u03b1 is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway","volume":"95","author":"Huang","year":"1998","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17771","DOI":"10.1074\/jbc.271.30.17771","article-title":"Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1","volume":"271","author":"Jiang","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.lungcan.2005.07.010","article-title":"Expression and prognostic significance of hypoxia-inducible factor 1\u03b1 (HIF-1\u03b1) in malignant pleural mesothelioma (MPM)","volume":"51","author":"Klabatsa","year":"2006","journal-title":"Lung Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.mvr.2007.12.003","article-title":"Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells","volume":"75","author":"Kaneko","year":"2008","journal-title":"Microvasc. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"30207","DOI":"10.1074\/jbc.M702639200","article-title":"Development of cytosolic hypoxia and hypoxia-inducible factor stabilization are facilitated by aquaporin-1 expression","volume":"282","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.rmed.2010.10.010","article-title":"Pleural effusion VEGF levels as a prognostic factor of malignant pleural mesothelioma","volume":"105","author":"Hirayama","year":"2011","journal-title":"Respir. Med."},{"key":"ref_40","first-page":"957","article-title":"Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation","volume":"6","author":"Yano","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1002\/ijc.10996","article-title":"Malignant mesothelioma growth inhibition by agents that target the VEGF and VEGF-c autocrine loops","volume":"104","author":"Masood","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.1158\/1078-0432.CCR-07-0501","article-title":"The therapeutic efficacy of anti vascular endothelial growth factor antibody, bevacizumab, and pemetrexed against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice","volume":"13","author":"Li","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_43","first-page":"693","article-title":"Vasculogenic mimicry is associated with high tumor grade, invasion and metastasis, and short survival in patients with hepatocellular carcinoma","volume":"16","author":"Sun","year":"2006","journal-title":"Oncol. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3914","DOI":"10.1016\/j.ejca.2013.07.148","article-title":"Tumour vasculogenic mimicry is associated with poor prognosis of human cancer patients: A systemic review and meta-analysis","volume":"49","author":"Cao","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/BF00666038","article-title":"Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors","volume":"36","author":"Weidner","year":"1995","journal-title":"Breast Cancer Res. Treat."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/11\/2293\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:49:06Z","timestamp":1760208546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/11\/2293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,1]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2017,11]]}},"alternative-id":["ijms18112293"],"URL":"https:\/\/doi.org\/10.3390\/ijms18112293","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2017,11,1]]}}}