G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation.
G-CSF Promotes Neuroblastoma Tumorigenicity and Metastasis via STAT3-Dependent Cancer Stem Cell Activation.
复制标题
DOI：
10.1158/0008-5472.can-14-2946
复制
发表时间：
2015-06-15
期刊：
影响因子：
11.2
通讯作者：
Shohet JM
中科院分区：
文献类型：
--
作者：
Agarwal S;Lakoma A;Chen Z;Hicks J;Metelitsa LS;Kim ES;Shohet JM
越来越多的证据表明，炎症细胞因子在肿瘤的发生和发展中起着关键作用。我们先前分离出一个癌症干细胞样（CSC）亚群在神经母细胞瘤的基础上差异表达的受体G-CSF（粒细胞集落刺激因子）。在这里，我们证明，G-CSF选择性激活信号转导和转录激活因子3（STAT 3）内神经母细胞瘤CSC亚群，促进其在体外和体内的扩张。外源性G-CSF增强人异种移植瘤和鼠神经母细胞瘤肿瘤模型中的肿瘤生长和转移。响应于G-CSF，STAT 3转录激活G-CSF受体（由CSF 3R编码），产生CSC维持正反馈回路。用抗G-CSF抗体或STAT 3抑制剂阻断G-CSF/STAT 3信号传导环耗尽肿瘤内的CSC亚群，驱动相关的肿瘤消退，阻断转移并增加化学敏感性。总之，这些数据定义G-CSF作为神经母细胞瘤的致瘤生长因子，并建议对G-CSF在这些患者中的临床应用进行全面的重新评估。我们的数据还表明，直接靶向G-CSF/STAT 3信号转导代表了神经母细胞瘤的一种新的治疗方法。
Increasing evidence suggests that inflammatory cytokines play a critical role in tumor initiation and progression. We previously isolated a Cancer Stem Cell-like (CSC) subpopulation in neuroblastoma based on differential expression of the receptor for G-CSF (Granulocyte-Colony Stimulating Factor). Here we demonstrate that G-CSF selectively activates signal transducer and activator of transcription 3 (STAT3) within neuroblastoma CSC subpopulations, promoting their expansion in vitro and in vivo. Exogenous G-CSF enhances tumor growth and metastasis in human xenograft and murine neuroblastoma tumor models. In response to G-CSF, STAT3 transcriptionally activates the G-CSF receptor (encoded by CSF3R), creating a CSC sustaining positive-feedback loop. Blockade of G-CSF/STAT3 signaling loop with either anti-G-CSF antibody or STAT3 inhibitor depletes the CSC subpopulation within tumors, driving correlated tumor regression, blocking metastasis and increasing chemosensitivity. Taken together, these data define G-CSF as a tumorigenic growth factor for neuroblastoma and suggest a comprehensive re-evaluation of the clinical use of G-CSF in these patients. Our data also demonstrate that direct targeting of the G-CSF/STAT3 signaling represents a novel therapeutic approach for neuroblastoma.