EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase.
EphB2 receptor controls proliferation/migration dichotomy of glioblastoma by interacting with focal adhesion kinase.
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DOI：
10.1038/onc.2012.16
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发表时间：
2012-12-13
期刊：
影响因子：
8
通讯作者：
Xia, S.
中科院分区：
文献类型：
--
作者：
Wang, S. D.;Rath, P.;Lal, B.;Richard, J-P;Li, Y.;Goodwin, C. R.;Laterra, J.;Xia, S.
关键词：
多形性胶质母细胞瘤（GBM）是成人中最常见且侵袭性最强的原发性脑肿瘤。不受控制的增殖和异常细胞迁移是GBM的两个突出的空间和时间分离的特征。在这项研究中，我们研究了受体酪氨酸激酶EphB 2在控制GBM增殖/迁移二分法中的作用。我们研究了EphB 2在胶质母细胞瘤源性干细胞样神经球（GBM-SC）中的功能获得和功能丧失，其体内生长模式与人GBM密切复制。EphB 2的表达刺激GBM神经球细胞的迁移和侵袭，并抑制神经球细胞的增殖。同时，EphB 2沉默增加了肿瘤细胞增殖并减少了肿瘤细胞迁移。使用内部控制的双荧光异种移植模型，发现EphB 2在体内增加肿瘤细胞侵袭。来自过表达EphB 2的GBM神经球的异种移植物也显示细胞增殖减少。发现非受体酪氨酸激酶粘着斑激酶（FAK）与EphB 2表达共相关并被EphB 2高度激活，并且FAK激活促进EphB 2表达的GBM神经球细胞中粘着斑形成、细胞骨架结构改变和细胞迁移。总之，我们的研究结果表明，EphB 2在GBM干细胞样神经球中具有促侵袭和抗增殖作用，部分是由EphB 2受体和FAK之间的相互作用介导的。这些新的发现表明，肿瘤细胞侵袭可以通过抑制EphB 2信号传导来治疗靶向，并且对EphB 2靶向的最佳抗肿瘤应答可能需要同时使用抗增殖剂。
Glioblastoma multiforme (GBM) are the most frequent and aggressive primary brain tumors in adults. Uncontrolled proliferation and abnormal cell migration are two prominent spatially and temporally disassociated characteristics of GBMs. In this study, we investigated the role of the receptor tyrosine kinase EphB2 in controlling the proliferation/migration dichotomy of GBM. We studied EphB2 gain-of-function and loss-of function in glioblastoma-derived stem-like neurospheres (GBM-SCs), whose in vivo growth pattern closely replicates human GBM. EphB2 expression stimulated GBM neurosphere cell migration and invasion, and inhibited neurosphere cell proliferation in vitro. In parallel, EphB2 silencing increased tumor cell proliferation and decreased tumor cell migration. EphB2 was found to increase tumor cell invasion in vivo using an internally controlled dual-fluorescent xenograft model. Xenografts derived from EphB2 overexpressing GBM neurospheres also showed decreased cellular proliferation. The non-receptor tyrosine kinase focal adhesion kinase (FAK) was found to be co-associated with and highly activated by EphB2 expression and FAK activation facilitated focal adhesion formation, cytoskeleton structure change and cell migration in EphB2-expression GBM neurosphere cells. Taken together, our findings indicate that EphB2 has pro-invasive and anti-proliferative actions in GBM stem-like neurospheres mediated, in part, by interactions between EphB2 receptors and FAK. These novel findings suggest that tumor cell invasion can be therapeutically targeted by inhibiting EphB2 signaling and that optimal anti-tumor responses to EphB2 targeting may require the concurrent use of anti-proliferative agents.
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