title: Efficacy of Tie2 receptor antagonism in angiosarcoma.
abstract: Angiosarcomas are malignant endothelial cell tumors with few effective systemic treatments. Despite a unique endothelial origin, molecular candidates for targeted therapeutic intervention have been elusive. In this study, we explored the tunica internal endothelial cell kinase 2 (Tie2) receptor as a potential therapeutic target in angiosarcoma. Human angiosarcomas from diverse sites were shown to be universally immunoreactive for Tie2. Tie2 and vascular endothelial growth factor receptor (VEGFR) antagonists inhibited SVR and MS1-VEGF angiosarcoma cell survival in vitro. In the high-grade SVR cell line, Tie2 and VEGF antagonists inhibited cell survival synergistically, whereas effects were largely additive in the low-grade MS1-VEGF cell line. Xenograft modeling using these cell lines closely recapitulated the human disease. In vivo, Tie2 and VEGFR inhibition resulted in significant angiosarcoma growth delay. The combination proved more effective than either agent alone. Tie2 inhibition seemed to elicit tumor growth delay through increased tumor cell apoptosis, whereas VEGFR inhibition reduced tumor growth by lowering tumor cell proliferation. These data identify Tie2 antagonism as a potential novel, targeted therapy for angiosarcomas and provide a foundation for further investigation of Tie2 inhibition, alone and in combinations, in the management of this disease.
authors.affiliation: Department of Human Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Hasenstein
authors.forename: Kelsey
authors.initials: K
authors.lastname: Kasmerchak
authors.forename: Darya
authors.initials: D
authors.lastname: Buehler
authors.forename: Gholam Reza
authors.initials: GR
authors.lastname: Hafez
authors.forename: Kevin
authors.initials: K
authors.lastname: Cleary
authors.forename: John S
authors.initials: JS
authors.lastname: Moody
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kozak
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006394:Hemangiosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007211:Indoles / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D011725:Pyridines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: C571408:4-(6-methoxy-2-naphthyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D011758:Pyrroles; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib