CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts
CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts
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DOI：
10.1172/jci39397
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发表时间：
2010-02-01
影响因子：
15.9
通讯作者：
Wicha, Max S.
中科院分区：
文献类型：
--
作者：
Ginestier, Christophe;Liu, Suling;Wicha, Max S.
最近的证据表明，乳腺癌和其他实体瘤拥有罕见的细胞群，能够进行广泛的自我更新，从而导致转移和治疗耐药。我们在此报告了通过阻断 IL-8 受体 CXCR1 来靶向这些乳腺癌干细胞 (CSC) 的策略的开发。使用 CXCR1 特异性阻断抗体或小分子 CXCR1 抑制剂 repertaxin 进行 CXCR1 阻断，可在体外选择性地消除 2 种人乳腺癌细胞系中的 CSC 群。此外，随后通过 FASL/FAS 信号传导在大量肿瘤群体中诱导大量细胞凋亡。 CXCR1 阻断对 CSC 活力和 FASL 产生的影响是由 FAK/AKT/FOXO3A 途径介导的。此外，repertaxin 能够特异性靶向人类乳腺癌异种移植物中的 CSC 群体，延缓肿瘤生长并减少转移。因此，我们的数据表明，CXCR1 阻断可能提供一种靶向和消除乳腺 CSC 的新方法。
Recent evidence suggests that breast cancer and other solid tumors possess a rare population of cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel means of targeting and eliminating breast CSCs.