Zadeh Gelareh, Reti Rob, Koushan Keyvan, Baoping Qian, Shannon Patrick, Guha Abhijit
Arthur and Sonia Labatts Brain Tumor Center, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Neoplasia. 2005 Dec;7(12):1081-90. doi: 10.1593/neo.05424.
Malignant astrocytomas are the most common and highly vascularized of all primary adult brain tumors. The histopathological hallmarks of malignant astrocytomas are microvascular proliferation and formation of vascular entities, which are referred to as "glomeruloid bodies." The significance of glomeruloid bodies and the molecular mechanisms driving the abnormal vascular architecture in malignant astrocytomas are not understood. We have observed that overexpression of angiopoietin-1 (Ang1) in both subcutaneous and intracranial xenograft models of malignant astrocytomas reproduces many of the vascular features of these tumors, including glomeruloid bodies. To confirm that the formation of glomeruloid bodies was directly dependent on Ang1, we performed experiments where levels of Ang1 expression were regulated under tetracycline control, and we found a direct correlation between levels of Ang1 expression and the occurrence of glomeruloid bodies in xenografts. Additionally, we inhibited the action of Ang1 by blocking its cognate receptor Tie2, and we found that the formation of glomeruloid bodies was inhibited. Collectively, these results support our hypothesis that Ang1 is a key molecular regulator of pathological vascularization characteristic of malignant astrocytomas.
恶性星形细胞瘤是所有原发性成人大脑肿瘤中最常见且血管高度丰富的肿瘤。恶性星形细胞瘤的组织病理学特征是微血管增殖和血管实体形成，这些血管实体被称为“肾小球样小体”。肾小球样小体的意义以及驱动恶性星形细胞瘤异常血管结构的分子机制尚不清楚。我们观察到，在恶性星形细胞瘤的皮下和颅内异种移植模型中，血管生成素-1（Ang1）的过表达重现了这些肿瘤的许多血管特征，包括肾小球样小体。为了证实肾小球样小体的形成直接依赖于Ang1，我们进行了在四环素控制下调节Ang1表达水平的实验，并且我们发现Ang1表达水平与异种移植中肾小球样小体的出现之间存在直接相关性。此外，我们通过阻断其同源受体Tie2来抑制Ang1的作用，并且我们发现肾小球样小体的形成受到抑制。总体而言，这些结果支持我们的假设，即Ang1是恶性星形细胞瘤病理性血管生成的关键分子调节因子。
