CXCL12 does not attract CXCR4+ human metastatic neuroblastoma cells:: Clinical implications
CXCL12 does not attract CXCR4+ human metastatic neuroblastoma cells:: Clinical implications
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DOI：
10.1158/1078-0432.ccr-05-1376
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发表时间：
2006-01-01
影响因子：
11.5
通讯作者：
Pistoia, V
中科院分区：
文献类型：
--
作者：
Airoldi, I;Raffaghello, L;Pistoia, V
目的：最近提出了 CXCR4 在神经母细胞瘤细胞骨髓定位中的作用。本研究的目的是研究 CXCR4 在从骨髓中分离的人转移性神经母细胞瘤细胞中的表达和趋化功能，并在一组神经母细胞瘤细胞系中进行比较。 实验设计：在从患者骨髓中分离的转移性神经母细胞瘤细胞和神经母细胞瘤细胞系中研究 CXCR4 的表达和趋化功能。通过免疫磁珠操作将前一种细胞分离为CD45(-)或GD2(+)细胞。趋化测定在 Transwell 系统中进行。通过逆转录-PCR 研究 G 蛋白信号表达的调节因子。结果：转移性神经母细胞瘤细胞一致表达 CXCR4，在 10 个神经母细胞瘤细胞系中的 5 个中也检测到了 CXCR4。无论在常氧或缺氧条件下检测到 CXCR4 上调，CXCL12 都不会刺激原发性肿瘤细胞或细胞系的趋化性。因此，神经母细胞瘤细胞在用 CXCL12 处理后无法调节丝状肌动蛋白并激活丝裂原激活蛋白激酶。 RGS16 mRNA在原发性肿瘤细胞和细胞系中一致表达，但RNA干扰引起的下调并不能恢复CXCR4趋化功能。结论：这些结果明确表明人转移性神经母细胞瘤细胞中表达的CXCR4没有功能，不支持临床使用CXCR4拮抗剂预防神经母细胞瘤转移。
Purpose: The role of CXCR4 in bone marrow localization of neuroblastoma cells has been recently proposed. The aim of this study was to investigate the expression and chemotactic functionality of CXCR4 in human metastatic neuroblastoma cells isolated from the bone marrow and, for comparison, in a panel of neuroblastoma cell lines.Experimental Design: CXCR4 expression and chemotactic functionality were investigated in metastatic neuroblastoma cells isolated from patient bone marrow and in neuroblastoma cell lines. The former cells were isolated as CD45(-) or GD2(+) cells by immunomagnetic bead manipulation. Chemotactic assays were done in a transwell system. Regulator of G protein signaling expression was investigated by reverse transcription-PCR.Results: Metastatic neuroblastoma cells consistently expressed CXCR4, which was also detected in 5 of 10 neuroblastoma cell lines. CXCL12 did not stimulate the chemotaxis of primary tumor cells or cell lines in either normoxia or hypoxia, irrespective of CXCR4 up-regulation detected under the latter condition. Accordingly, neuroblastoma cells failed to modulate filamentous actin and to activate mitogen-activated protein kinase upon treatment with CXCL12. RGS16 mRNA was consistently expressed in primary tumor cells and cell lines, but its down-regulation by RNA interference did not restore CXCR4 chemotactic functionality.Conclusions: These results show unambiguously that CXCR4 expressed in human metastatic neuroblastoma cells is not functional and do not support the clinical use of CXCR4 antagonists to prevent neuroblastoma metastasis.