Research Papers:

Targeting Tie-2/angiopoietin axis in experimental mesothelioma confers differential responses and raises predictive implications

Sophia Magkouta _, Apostolos Pappas, Ioannis S. Pateras, Androniki Kollintza, Charalampos Moschos, Maria-Eleni Vazakidou, Vasiliki Karavana, Vassilis G. Gorgoulis and Ioannis Kalomenidis

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Oncotarget. 2018; 9:21783-21796. https://doi.org/10.18632/oncotarget.25004

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Sophia Magkouta1, Apostolos Pappas1, Ioannis S. Pateras2, Androniki Kollintza1, Charalampos Moschos1, Maria-Eleni Vazakidou1, Vasiliki Karavana1, Vassilis G. Gorgoulis2,3,4 and Ioannis Kalomenidis1

1Marianthi Simou Laboratory, 1st Department of Critical Care and Pulmonary Medicine, National and Kapodistrian University of Athens, School of Medicine, Evangelismos Hospital, Athens, 10675, Greece

2Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens, Athens, GR-11527, Greece

3Biomedical Research Foundation of the Academy of Athens, Athens, GR-11527, Greece

4Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M20 4QL, UK

Correspondence to:

Sophia Magkouta, email: [email protected]

Keywords: malignant pleural mesothelioma; angiopoietins; Tie-2; tumor angiogenesis; murine Tek-delta Fc

Received: July 22, 2017     Accepted: February 28, 2018     Published: April 24, 2018


Malignant pleural mesothelioma is resistant to currently used treatment. Angiopoieitn-1 directly promotes mesothelioma cell growth in a Tie-2-dependent fashion. Angiopoietin/Tie-2 axis may thus be valid targets for therapeutic interventions against mesothelioma. We hypothesized that a soluble angiopoietin inhibitor (Murine Tek-deltaFc) would halt mesothelioma progression in vivo by enhancing mesothelioma cell proliferation and inhibiting tumor angiogenesis. Our hypothesis was challenged on two syngeneic mesothelioma in vivo models (AB1 cells-Balb/c mice and AE17 cells-C57BL/6 mice. Even though both mesothelioma cell lines express the Angiopoietin-1/-2 and Tie-2, murine Tek-deltaFc hampered AB1 but not AE17 mesothelioma growth in vivo by enhancing tumor cell apoptosis and limiting tumor angiogenesis. Neither angiopoietins (Angs)-1 and -2 nor the inhibitor affected mesothelioma cell growth in vitro. AB1 (responding) tumors were more vascularized and displayed higher endothelial Tie-2 and lower tumor Ang-1 expression than the (non-responding) AE17 tumors. Angiopoietins-1 and -2 are expressed in tumors and pleural cavity of mesothelioma patients demonstrating the clinical relevance of our experimental observations. In conclusion, disrupting Ang-Tie-2 signaling limits mesothelioma angiogenesis and halts tumor progression. Tumor vascularity, endothelial Tie-2 expression and tumor Ang-1 expression may predict mesothelioma response to Tek-deltaFc.

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