Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth
Inhibition of tumor angiogenesis using a soluble receptor establishes a role for Tie2 in pathologic vascular growth
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DOI：
10.1172/jci119740
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发表时间：
1997-10-15
影响因子：
15.9
通讯作者：
Peters, K
中科院分区：
文献类型：
--
作者：
Lin, PN;Polverini, P;Peters, K
Tie2是一种新的受体酪氨酸激酶，几乎完全由血管内皮细胞表达。在转基因小鼠中，Tie2功能的破坏导致了继发于特征性血管缺陷的胚胎死亡；Tie2配体的破坏后也出现了类似的缺陷，这些发现表明Tie2/Tie2配体通路在胚胎血管系统的发育中起着重要的作用。为了确定Tie2通路是否参与成人组织的病理性血管生成，开发了一种可溶性形式的小鼠Tie2胞外区(ExTek.6His)并用作Tie2抑制剂，在将ExTek.6His蛋白应用于大鼠皮肤窗腔后，腔内乳腺肿瘤的生长减少了75%(P<；0.005)，肿瘤血管长度密度与对照组相比降低了40%(P<；在大鼠角膜中，ExTek.6His阻断了肿瘤细胞条件培养液刺激的血管生成，ExTek.6His蛋白不影响培养的肿瘤细胞的活力，表明ExTek.6His的抗肿瘤作用是通过抑制肿瘤血管生成而实现的。这些数据证明了Tie2通路在病理性血管生成中的作用，提示靶向该通路可能会产生有效的抗血管生成药物来治疗癌症和其他血管生成疾病。
Tie2 is a novel receptor tyrosine kinase that is expressed almost exclusively by vascular endothelium. Disruption of Tie2 function in transgenic mice resulted in embryonic lethality secondary to characteristic vascular defects; similar defects occurred after disruption of the Tie2 Ligand, These findings indicate that the Tie2/Tie2 ligand pathway plays important roles during development of the embryonic vasculature. To determine whether the Tie2 pathway was involved in pathologic angiogenesis in adult tissues, a soluble form of the extracellular domain of murine Tie2 (ExTek.6His) was developed and used as a Tie2 inhibitor, After a single application of the ExTek.6His protein into a rat cutaneous window chamber, growth of a mammary tumor inside the chamber was reduced by > 75% (P < 0.005), and tumor vascular length density was reduced by 40% when compared with control-treated tumors (P < 0.01), In the rat cornea, ExTek.6His blocked angiogenesis stimulated by tumor cell conditioned media, ExTek.6His protein did not affect the viability of cultured tumor cells, indicating that the antitumor effect of ExTek.6His was due to the inhibition of tumor angiogenesis. These data demonstrate a role far the Tie2 pathway in pathologic angiogenesis, suggesting that targeting this pathway may yield effective antiangiogenic agents for treatment of cancer and other angiogenic diseases.