Lin P, Polverini P, Dewhirst M, Shan S, Rao P S, Peters K
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Clin Invest. 1997 Oct 15;100(8):2072-8. doi: 10.1172/JCI119740.
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 for the Tie2 pathway in pathologic angiogenesis, suggesting that targeting this pathway may yield effective antiangiogenic agents for treatment of cancer and other angiogenic diseases.
Tie2是一种新型受体酪氨酸激酶，几乎仅在血管内皮中表达。转基因小鼠中Tie2功能的破坏导致继发于特征性血管缺陷的胚胎致死；Tie2配体被破坏后也出现类似缺陷。这些发现表明，Tie2/Tie2配体途径在胚胎血管系统发育过程中起重要作用。为了确定Tie2途径是否参与成年组织的病理性血管生成，制备了小鼠Tie2细胞外结构域的可溶性形式（ExTek.6His）并用作Tie2抑制剂。将ExTek.6His蛋白单次应用于大鼠皮肤窗小室后，小室内乳腺肿瘤的生长减少了>75%（P<0.005），与对照处理的肿瘤相比，肿瘤血管长度密度降低了40%（P<0.01）。在大鼠角膜中，ExTek.6His阻断了肿瘤细胞条件培养基刺激的血管生成。ExTek.6His蛋白不影响培养的肿瘤细胞的活力，表明ExTek.6His的抗肿瘤作用是由于抑制肿瘤血管生成。这些数据证明了Tie2途径在病理性血管生成中的作用，表明靶向该途径可能产生有效的抗血管生成药物用于治疗癌症和其他血管生成性疾病。
