Efficacy of Tie2 Receptor Antagonism in Angiosarcoma
Efficacy of Tie2 Receptor Antagonism in Angiosarcoma
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DOI：
10.1593/neo.111770
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发表时间：
2012-02-01
期刊：
影响因子：
4.8
通讯作者：
Kozak, Kevin R.
中科院分区：
文献类型：
--
作者：
Hasenstein, Jason R.;Kasmerchak, Kelsey;Kozak, Kevin R.
血管内皮细胞瘤是一种恶性内皮细胞肿瘤，很少有有效的系统治疗。尽管具有独特的内皮来源，但靶向治疗干预的分子候选物一直难以捉摸。在这项研究中，我们探讨了图尼卡内内皮细胞激酶2（Tie 2）受体作为一个潜在的治疗血管肉瘤的目标。来自不同部位的人血管瘤显示出对Tie 2的普遍免疫反应性。Tie 2和血管内皮生长因子受体（VEGFR）拮抗剂在体外抑制SVR和MS 1-VEGF血管肉瘤细胞存活。在高级别SVR细胞系中，Tie 2和VEGF拮抗剂协同抑制细胞存活，而在低级别MS 1-VEGF细胞系中的作用主要是相加的。使用这些细胞系进行的异种移植建模密切地概括了人类疾病。在体内，Tie 2和VEGFR抑制导致显著的血管肉瘤生长延迟。该组合被证明比单独使用任何一种药物更有效。Tie 2抑制似乎通过增加肿瘤细胞凋亡引起肿瘤生长延迟，而VEGFR抑制通过降低肿瘤细胞增殖减少肿瘤生长。这些数据将Tie 2拮抗作用确定为血管瘤的潜在新型靶向治疗，并为进一步研究Tie 2抑制（单独或联合）在该疾病管理中的作用提供了基础。
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.