Expression of the new CXCL12 receptor, CXCR7, in gliomas
Expression of the new CXCL12 receptor, CXCR7, in gliomas
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DOI：
10.4161/cbt.11.2.13951
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发表时间：
2011-01-15
影响因子：
3.6
通讯作者：
Salmaggi, Andrea
中科院分区：
文献类型：
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作者：
Calatozzolo, Chiara;Canazza, Alessandra;Salmaggi, Andrea
神经胶质瘤是侵袭性很强的脑肿瘤，预后差，因此任何限制肿瘤细胞在脑中扩散的尝试都有望改善神经胶质瘤的治疗。最近CXCR 7作为CXCL 12和CXCL 11的额外受体的去铁化已经提出了关于其与CXCL 12/CXCR 4轴的相互作用作为调节胶质瘤细胞迁移的机制的关键问题。在这项工作中，我们研究了两个趋化因子CXCL 12和CXCL 11，以及它们的受体CXCR 4和CXCR 7在人脑胶质瘤标本和细胞系的蛋白和mRNA的表达，通过免疫组织化学，流式细胞术和定量实时PCR。本研究的主要目的是了解CXCR 4和CXCR 7在胶质瘤细胞中是否以及在何种程度上差异表达。在人脑胶质瘤标本中，与非肿瘤对照或低级别胶质瘤相比，胶质母细胞瘤中CXCL 11和CXCR 4 mRNA的水平显著更高，而CXCL 12和CXCR 7 mRNA的表达没有差异。在细胞系中，流式细胞术和免疫细胞化学实验表明，CXCR 4主要表达，无论其膜或细胞内定位。与此相反，一个主要的细胞内定位与CXCR 7的膜表达可以忽略不计，发现在所有的细胞检查。在体外实验中，CXCR 4和CXCR 7拮抗剂和CXCR 4的沉默显示出完全抑制胶质瘤的增殖，我们的研究结果，与以前的数据一致，表明在人类胶质瘤细胞中，CXCR 7的普遍的细胞内定位可能调节CXCL 11/12的功能，作为这些趋化因子的清道夫或干扰由CXCR 4刺激激活的信号通路。
Gliomas are very invasive brain tumors with poor prognosis and therefore any attempt to limit tumor cell dissemination in the brain is expected to improve glioma treatment. The recent deorphanization of CXCR7 as additional receptor for CXCL12 and CXCL11 has raised key issues on its interaction with the CXCL12/CXCR4 axis as a mechanism to modulate glioma cell migration. In this work we investigated protein and mRNA expression of the two chemokines CXCL12 and CXCL11, together with their receptors CXCR4 and CXCR7 in human glioma specimens and cell lines by immunohistochemistry, flow cytometry and quantitative real-time PCR. The main purpose of this study was to find out whether and at what extent CXCR4 and CXCR7 are differentially expressed in glioma cells. In human glioma specimens the levels of CXCL11 and CXCR4 mRNA were significantly higher in glioblastomas compared to non-tumor controls or low grade gliomas, whilst no difference was found for CXCL12 and CXCR7 mRNA expression. In cell lines, flow cytometry and immunocytochemical experiments showed CXCR4 was mainly expressed irrespective of its membrane or intracellular localization. In contrast, a predominant intracellular localization together with a negligible membrane expression of CXCR7 was found in all cells examined. In in vitro experiments CXCR4 and CXCR7 antagonists and the silencing of CXCR4 showed complete inhibition of glioma proliferation.Our findings, in agreement with previous data, suggest that in human glioma cells the prevalent intracellular localization of CXCR7 might modulate the functionality of CXCL11/12 either acting as a scavenger for these chemokines or interfering with the signaling pathways activated by the stimulation of CXCR4.