Microglial-stimulation of glioma invasion involves the EGFR ligand amphiregulin.
Microglial-stimulation of glioma invasion involves the EGFR ligand amphiregulin.
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DOI：
10.1371/journal.pone.0260252
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Segall JE
中科院分区：
文献类型：
--
作者：
Coniglio SJ;Segall JE
高级别胶质瘤是最致命的人类癌症之一，诊断后的中位生存率仅为一年。高级别胶质瘤的高度运动性和侵袭性使得其难以完全手术切除。因此，增加我们对神经胶质瘤细胞侵入正常脑的机制的了解对于设计新的治疗方法至关重要。我们的实验室先前表明，肿瘤相关小胶质细胞（TAM）刺激胶质瘤细胞侵袭，并且该过程依赖于CSF-1 R信号传导。在这项研究中，我们试图确定在小胶质细胞中以CSF-1 R依赖性方式上调的促侵袭因子。我们分析了用来自鼠神经胶质瘤细胞系GL 261的条件培养基处理的小胶质细胞的cDNA和蛋白质，并发现包括双调蛋白（AREG）在内的几种EGFR配体强烈上调。这种上调通过添加药理学CSF-1 R抑制剂来阻断。使用RNA干扰，我们表明，AREG耗尽的小胶质细胞在促进GL 261细胞侵入Matrigel包被的侵入室中的效果较差。此外，AREG阻断抗体强烈减弱THP-1巨噬细胞激活人神经胶质瘤细胞系U87侵袭的能力。此外，我们已经确定了一个信号通路，涉及CSF-1信号通过ERK上调AREG表达的小胶质细胞。使用药理学抑制剂干扰ERK可防止小胶质细胞中AREG上调和小胶质细胞刺激的GL 261侵袭。这些数据突出了AREG作为肿瘤相关小胶质细胞产生的促进胶质瘤侵袭的关键因子。
High grade glioma is one of the deadliest human cancers with a median survival rate of only one year following diagnosis. The highly motile and invasive nature of high grade glioma makes it difficult to completely remove surgically. Therefore, increasing our knowledge of the mechanisms glioma cells use to invade normal brain is of critical importance in designing novel therapies. It was previously shown by our laboratory that tumor-associated microglia (TAMs) stimulate glioma cell invasion and this process is dependent on CSF-1R signaling. In this study, we seek to identify pro-invasive factors that are upregulated in microglia in a CSF-1R-dependent manner. We assayed cDNA and protein from microglia treated with conditioned media from the murine glioma cell line GL261, and discovered that several EGFR ligands including amphiregulin (AREG) are strongly upregulated. This upregulation is blocked by addition of a pharmacological CSF-1R inhibitor. Using RNA interference, we show that AREG-depleted microglia are less effective at promoting invasion of GL261 cells into Matrigel-coated invasion chambers. In addition, an AREG blocking antibody strongly attenuates the ability of THP-1 macrophages to activate human glioma cell line U87 invasion. Furthermore, we have identified a signaling pathway which involves CSF-1 signaling through ERK to upregulate AREG expression in microglia. Interfering with ERK using pharmacological inhibitors prevents AREG upregulation in microglia and microglia-stimulated GL261 invasion. These data highlight AREG as a key factor in produced by tumor associated microglia in promoting glioma invasion.
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影响因子：
8
作者：
Bonavia, R.;Inda, M. M.;Vandenberg, S.;Cheng, S-Y;Nagane, M.;Hadwiger, P.;Tan, P.;Sah, D. W. Y.;Cavenee, W. K.;Furnari, F. B.
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Furnari, F. B.
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3.3
作者：
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通讯作者：
Fillmore, H. L.
影响因子：
5.7
作者：
Coniglio, Salvatore J.;Eugenin, Eliseo;Segall, Jeffrey E.
通讯作者：
Segall, Jeffrey E.
影响因子：
3.9
作者：
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通讯作者：
Leenstra, Sieger