Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.
Angiopoietin-4 promotes glioblastoma progression by enhancing tumor cell viability and angiogenesis.
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DOI：
10.1158/0008-5472.can-09-4125
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发表时间：
2010-09-15
期刊：
影响因子：
11.2
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Brunckhorst MK;Wang H;Lu R;Yu Q
多形性胶质母细胞瘤（GBM）是一种高度侵袭性和血管化的侵袭性脑肿瘤。不到10%的GBM患者在诊断后存活超过5年。血管生成在GBM生长中起重要作用，并且基于抗血管生成的疗法已经证明对GBM患者的临床疗效。不幸的是，在这些患者中通常会产生治疗抗性，这表明GBM细胞能够将其对一种促血管生成信号通路的依赖性转换为另一种。因此，重要的是要确定新的血管生成因子，在肿瘤血管生成和GBM进展中发挥重要作用。血管生成素（angiopoietin-1、-2和-4）是Tie-2受体酪氨酸激酶（RTK）的配体。血管生成素-1和-2（Ang-1和-2）在肿瘤血管生成中的作用已被确定。然而，关于血管生成素-4（Ang-4）如何影响肿瘤血管生成和GBM进展及其作用机制知之甚少。在我们目前的研究中，我们确定了Ang-4在人GBM组织和细胞中上调。我们证明，像内皮细胞，人GBM细胞表达Tie-2 RTK。我们首先确定Ang-4通过促进肿瘤血管生成和直接激活GBM细胞中的Erk 1/2激酶来促进人GBM细胞的体内生长。我们的研究结果确立了Ang-4对肿瘤血管生成和GBM进展的新作用，并表明Ang-4的这种促GBM作用是通过促进肿瘤血管生成和激活GBM细胞中的Erk 1/2激酶介导的。总之，我们的结果表明，Ang-4-Tie-2功能轴是GBM的一个有吸引力的治疗靶点。
Glioblastoma multiforme (GBM) is a highly invasive and vascularized aggressive brain tumor. Less than 10% of GBM patients survive more than 5 years after diagnosis. Angiogenesis plays an important role in GBM growth and anti-angiogenesis based therapies have demonstrated clinical efficacy for GBM patients. Unfortunately, therapeutic resistance often develops in these patients, suggesting GBM cells are capable of switching their dependency on one pro-angiogenic signaling pathway to an alternative one. Therefore, it is important to identify novel angiogenic factors that play essential roles in tumor angiogenesis and GBM progression. Angiopoietins (angiopoietin-1, -2, and -4) are the ligands of Tie-2 receptor tyrosine kinase (RTK). The roles of angiopoietin-1 and -2 (Ang-1 and -2) in tumor angiogenesis have been established. However, little is known about how angiopoietin-4 (Ang-4) affects tumor angiogenesis and GBM progression and the mechanism underlying its effects. In our current study, we establish that Ang-4 is up-regulated in human GBM tissues and cells. We demonstrate that like endothelial cells, human GBM cells express Tie-2 RTK. We first establish that Ang-4 promotes in vivo growth of human GBM cells by promoting tumor angiogenesis and directly activating Erk1/2 kinases in GBM cells. Our results establish the novel effects of Ang-4 on tumor angiogenesis and GBM progression and suggest that this pro-GBM effect of Ang-4 is mediated by promoting tumor angiogenesis and activating Erk1/2 kinase in GBM cells. Together, our results suggest that the Ang-4-Tie-2 functional axis is an attractive therapeutic target for GBM.