Zadeh Gelareh, Koushan Keyvan, Pillo Lisa, Shannon Patrick, Guha Abhijit
From Arthur and Sonia Labatts Brain Tumor Center, Hospital for Sick Children, University of Toronto, Toronto, Canada.
J Neuropathol Exp Neurol. 2004 Sep;63(9):978-89. doi: 10.1093/jnen/63.9.978.
Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.
血管生成素（Ang1和Ang2）可调节内皮细胞（EC）特异性受体酪氨酸激酶Tie2的活性，Tie2与血管内皮生长因子（VEGF-A）及其EC特异性受体VEGFR1和VEGFR2共同调节正常的生理性血管发育。血管生成素在肿瘤血管生成，尤其是星形细胞瘤血管生成中的功能作用仍不清楚。在本研究中，我们聚焦于Ang1对多形性胶质母细胞瘤（GBM）血管生长的具体贡献及其与VEGF-A的相互作用。使用3种已建立的星形细胞瘤细胞系（U87、U373和U343）生成皮下和颅内GBM异种移植瘤，这些细胞系经转染后稳定过表达Ang1。还生成了表达低水平VEGF-A和高水平Ang1的GBM异种移植瘤。我们发现，Ang1可使GBM皮下和颅内异种移植瘤的血管生长增加约3倍。然而，血管生长增加仅在VEGF-A同时升高的异种移植瘤中可见，因为降低VEGF-A表达会导致Ang1所具有的促血管生成生长优势丧失。总体而言，我们的数据表明，Ang1以VEGF-A依赖的方式调节GBM血管生成，协同由VEGF-A触发的初始促血管生成反应，并促进GBM的血管生长。
