Microglial Stimulation of Glioblastoma Invasion Involves Epidermal Growth Factor Receptor (EGFR) and Colony Stimulating Factor 1 Receptor (CSF-1R) Signaling
Microglial Stimulation of Glioblastoma Invasion Involves Epidermal Growth Factor Receptor (EGFR) and Colony Stimulating Factor 1 Receptor (CSF-1R) Signaling
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DOI：
10.2119/molmed.2011.00217
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发表时间：
2012-03-01
影响因子：
5.7
通讯作者：
Segall, Jeffrey E.
中科院分区：
文献类型：
--
作者：
Coniglio, Salvatore J.;Eugenin, Eliseo;Segall, Jeffrey E.
多形性胶质母细胞瘤是一种致命的癌症，目前的治疗选择有限。胶质母细胞瘤细胞浸润周围脑实质的能力严重限制了当前治疗的有效性。我们研究了小胶质细胞（脑内的常驻巨噬细胞）如何刺激胶质母细胞瘤细胞的侵袭。我们首先检测了来自C57BI/6J小鼠的正常小胶质细胞在体外刺激GL261胶质母细胞瘤细胞侵袭的能力。我们发现，在体外侵袭实验中，小胶质细胞可使GL261胶质母细胞瘤细胞的侵袭能力提高约8倍。表皮生长因子受体（EGFR）的药理抑制作用强烈抑制了小胶质细胞刺激的侵袭。此外，使用核糖核酸（RNA）干扰或药理抑制剂阻断集落刺激因子1受体（CSF - 1R）信号传导，完全抑制了小胶质细胞对胶质母细胞瘤侵袭的增强作用。发现GL261细胞组成性地分泌CSF - 1，其水平不受表皮生长因子（EGF）刺激、EGFR抑制或与小胶质细胞共培养的影响。CSF - 1仅刺激小胶质细胞侵袭，而EGF仅刺激胶质母细胞瘤细胞迁移，表明这两种细胞类型之间存在协同相互作用。最后，在活体动物中使用PLX3397（一种可穿过血脑屏障的CSF - 1R抑制剂），我们发现体内阻断CSF - 1R信号传导可减少与肿瘤相关的小胶质细胞数量以及胶质母细胞瘤的侵袭。这些数据表明，由EGF和CSF - 1介导的胶质母细胞瘤与小胶质细胞的相互作用可增强胶质母细胞瘤的侵袭，并证明了通过抑制CSF - 1R靶向与胶质母细胞瘤相关的小胶质细胞来抑制胶质母细胞瘤侵袭的可能性。在线地址：http://www.molmed.org doi:10.2119/molmed.2011.00217
Glioblastoma multiforme is a deadly cancer for which current treatment options are limited. The ability of glioblastoma tumor cells to infiltrate the surrounding brain parenchyma critically limits the effectiveness of current treatments. We investigated how microglia, the resident macrophages of the brain, stimulate glioblastoma cell invasion. We first examined the ability of normal microglia from C57BI/6J mice to stimulate GL261 glioblastoma cell invasion in vitro. We found that microglia stimulate the invasion of GL261 glioblastoma cells by approximately eightfold in an in vitro invasion assay. Pharmacological inhibition of epidermal growth factor receptor (EGFR) strongly inhibited microglia-stimulated invasion. Furthermore, blockade of colony stimulating factor 1 receptor (CSF-1R) signaling using ribonucleic acid (RNA) interference or pharmacological inhibitors completely inhibited microglial enhancement of glioblastoma invasion. GL261 cells were found to constitutively secrete CSF-1, the levels of which were unaffected by epidermal growth factor (EGF) stimulation, EGFR inhibition or coculture with microglia. CSF-1 only stimulated microglia invasion, whereas EGF only stimulated glioblastoma cell migration, demonstrating a synergistic interaction between these two cell types. Finally, using PLX3397 (a CSF-1R inhibitor that can cross the blood-brain barrier) in live animals, we discovered that blockade of CSF-1R signaling in vivo reduced the number of tumor-associated microglia and glioblastoma invasion. These data indicate that glioblastoma and microglia interactions mediated by EGF and CSF-1 can enhance glioblastoma invasion and demonstrate the possibility of inhibiting glioblastoma invasion by targeting glioblastoma-associated microglia via inhibition of the CSF-1R. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00217