Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway.
Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway.
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DOI：
10.1371/journal.pone.0131059
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kucheryavykh LY
中科院分区：
文献类型：
--
作者：
Rolón-Reyes K;Kucheryavykh YV;Cubano LA;Inyushin M;Skatchkov SN;Eaton MJ;Harrison JK;Kucheryavykh LY
胶质母细胞瘤是最具侵袭性和致命性的脑癌之一，这是由于胶质瘤细胞的高度侵袭性。小胶质细胞浸润大多数胶质瘤肿瘤，因此，构成胶质瘤微环境的重要组成部分。在肿瘤环境中，小胶质细胞释放导致细胞外基质降解的因子，并刺激信号通路以促进胶质瘤细胞侵袭。在本研究中，我们证明了小胶质细胞可以通过一种独立于细胞外基质降解的机制促进胶质瘤的迁移。使用蛋白质印迹分析，我们发现上调富含脯氨酸的酪氨酸激酶2（Pyk 2）蛋白磷酸化的Tyr 579/580在胶质瘤细胞与小胶质细胞条件培养基处理。这种上调发生在啮齿动物C6和GL 261以及具有不同侵袭水平的人神经胶质瘤细胞系（U-87 MG、A172和HS 683）中。Pyk 2蛋白的siRNA敲低和Pyk 2/粘着斑激酶（FAK）抑制剂PF-562，271的药理学阻断逆转了所有细胞系中小胶质细胞对胶质瘤迁移的刺激作用。选择性抑制FAK但不抑制Pyk 2的较低浓度PF-562，271对胶质瘤细胞迁移没有任何影响。此外，通过使用CD 11b-HSVTK小胶质细胞消融小鼠模型，我们证明了通过局部肿瘤内施用更昔洛韦消除植入肿瘤（GL 261胶质瘤细胞用于脑植入）中的小胶质细胞，显著降低了植入肿瘤细胞中Pyk 2在Tyr 579/580处的磷酸化。总之，这些数据表明，小胶质细胞通过胶质瘤细胞中的促迁移Pyk 2信号传导途径激活胶质瘤细胞迁移/分散。
Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells.
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