Stress-induced CXCR4 promotes migration and invasion of ewing sarcoma.
Stress-induced CXCR4 promotes migration and invasion of ewing sarcoma.
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DOI：
10.1158/1541-7786.mcr-13-0668
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发表时间：
2014-06
期刊：
影响因子：
--
通讯作者：
Lawlor ER
中科院分区：
文献类型：
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作者：
Krook MA;Nicholls LA;Scannell CA;Chugh R;Thomas DG;Lawlor ER
尤文氏肉瘤是儿科患者中第二常见的骨癌。虽然尤文氏肉瘤的主要死亡原因是转移，但肿瘤扩散的机制仍有待阐明。为此，我们研究了CXCR4/SDF-1a趋化因子轴在尤文氏肉瘤转移中的作用。通过免疫组化（IHC）染色检测原发肿瘤标本中CXCR4的表达情况，并通过定量RT-PCR和流式细胞术检测多个细胞系中CXCR4的表达情况。同时也检测了cxcr4阳性尤文氏肉瘤细胞向CXCL12/SDF-1a的迁移和侵袭。有趣的是，虽然CXCR4的状态在尤文氏肉瘤细胞中是不同的，从缺失到高表达；它的表达是高度动态的，对微环境的变化反应灵敏。特别是，CXCR4的上调发生在生长因子剥夺、缺氧和空间限制的细胞中。在去除有害的细胞应激条件后，CXCR4的上调被迅速逆转。功能上，CXCR4阳性细胞向SDF-1a梯度迁移和侵袭，这些侵袭特性受到CXCR4小分子抑制剂AMD3100和CXCR4敲低的阻碍。此外，Cdc42和Rac1的小分子抑制剂抑制了cxcr4依赖的迁移和侵袭，这从机制上暗示了这些rho - gtpase是cxcr4依赖表型的下游介质。
Ewing sarcoma is the second most common bone cancer in pediatric patients. Although the primary cause of death in Ewing sarcoma is metastasis, the mechanism underlying tumor spread needs to be elucidated. To this end, the role of the CXCR4/SDF-1a chemokine axis as a mediator of Ewing sarcoma metastasis was investigated. CXCR4 expression status was measured in primary tumor specimens by immunohistochemical (IHC) staining and in multiple cell lines by quantitative RT-PCR and flow cytometry. Migration and invasion of CXCR4-positive Ewing sarcoma cells towards CXCL12/SDF-1a were also determined. Interestingly, while CXCR4 status was disparate among Ewing sarcoma cells, ranging from absent to high-level expression; its expression was found to be highly dynamic and responsive to changes in the microenvironment. In particular, up-regulation of CXCR4 occurred in cells that were subjected to growth factor deprivation, hypoxia, and space constraints. This up-regulation of CXCR4 was rapidly reversed upon removal of the offending cellular stress conditions. Functionally, CXCR4-positive cells migrated and invaded towards an SDF-1a gradient and these aggressive properties were impeded by both the CXCR4 small molecule inhibitor AMD3100, and by knockdown of CXCR4. In addition, CXCR4-dependent migration and invasion were inhibited by small molecule inhibitors of Cdc42 and Rac1, mechanistically implicating these Rho-GTPases as downstream mediators of the CXCR4-dependent phenotype.