Zadeh Gelareh, Qian Baoping, Okhowat Ali, Sabha Nesrin, Kontos Christopher D, Guha Abhijit
Arthur and Sonia Labatt Brain Tumor Center, Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Pathol. 2004 Feb;164(2):467-76. doi: 10.1016/S0002-9440(10)63137-9.
Tie2 is an endothelial cell-specific receptor tyrosine kinase, whose activation is positively and negatively modulated by angiopoietin-1 and angiopoietin-2, respectively. Angiopoietin-mediated modulation of Tie2 activation contributes to normal vessel development and stability, however, its role in tumor angiogenesis is not well known. We investigated the role of Tie2 activation in malignant astrocytomas, a common and highly vascularized primary human brain tumor. We found that Tie2 expression and activation increases with increasing malignancy grade of astrocytomas. Inhibition of Tie2, using a kinase-deficient Tie2 construct, decreases growth of malignant human astrocytoma subcutaneous and intracranial xenografts. Tie2 inactivation disrupted the tumor vascularity, with a decrease in microvascular density, increased presence of abnormally dilated vessels, and loss of interaction between endothelial cells and surrounding smooth muscle cells, all collectively resulting in increased tumor cell apoptosis. Overall, these findings strongly suggest that Tie2 activation contributes significantly to astrocytoma tumor angiogenesis and growth. We postulate that targeting Tie2 activation, either independently or in conjunction with other anti-angiogenic therapies, such as against vascular endothelial growth factor, is of potential clinical interest.
Tie2是一种内皮细胞特异性受体酪氨酸激酶，其激活分别受到血管生成素-1和血管生成素-2的正向和负向调节。血管生成素介导的Tie2激活调节有助于正常血管发育和稳定，然而，其在肿瘤血管生成中的作用尚不清楚。我们研究了Tie2激活在恶性星形细胞瘤中的作用，恶性星形细胞瘤是一种常见且血管高度丰富的原发性人类脑肿瘤。我们发现，Tie2的表达和激活随着星形细胞瘤恶性程度的增加而增加。使用激酶缺陷型Tie2构建体抑制Tie2可降低恶性人类星形细胞瘤皮下和颅内异种移植物的生长。Tie2失活破坏了肿瘤血管，导致微血管密度降低、异常扩张血管的出现增加以及内皮细胞与周围平滑肌细胞之间的相互作用丧失，所有这些共同导致肿瘤细胞凋亡增加。总体而言，这些发现强烈表明，Tie2激活对星形细胞瘤肿瘤血管生成和生长有显著贡献。我们推测，单独或与其他抗血管生成疗法（如针对血管内皮生长因子的疗法）联合靶向Tie2激活具有潜在的临床意义。
