The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer.
The significance of G-CSF expression and myeloid-derived suppressor cells in the chemoresistance of uterine cervical cancer.
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DOI：
10.1038/srep18217
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发表时间：
2015-12-15
影响因子：
4.6
通讯作者：
Kimura T
中科院分区：
文献类型：
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作者：
Kawano M;Mabuchi S;Matsumoto Y;Sasano T;Takahashi R;Kuroda H;Kozasa K;Hashimoto K;Isobe A;Sawada K;Hamasaki T;Morii E;Kimura T
粒细胞集落刺激因子（G-CSF）产生的恶性肿瘤已报告发生在各种器官，并已与不良的临床结果。本研究旨在探讨肿瘤细胞G-CSF表达在宫颈癌化疗敏感性中的意义。分析复发或晚期宫颈癌患者接受含铂化疗的临床资料。临床样本，宫颈癌细胞系，和宫颈癌的小鼠模型被用来检查负责的机制，在产生G-CSF的宫颈癌的化疗耐药性的发展，重点是骨髓来源的抑制细胞（MDSC）。因此，肿瘤G-CSF表达与MDSC频率增加和生存率降低显著相关。体内外实验表明，肿瘤源性G-CSF诱导的MDSC增加参与了化疗耐药的发展。通过脾切除术或抗Gr-1抗体的管理MDSC耗竭敏感G-CSF产生的宫颈癌顺铂。总之，肿瘤G-CSF表达是化疗宫颈癌患者预后极差的指标。MDSC靶向治疗与目前的标准化疗相结合，可能对产生G-CSF的宫颈癌具有治疗效果。
Granulocyte-colony stimulating factor (G-CSF) producing malignant tumor has been reported to occur in various organs, and has been associated with poor clinical outcome. The aim of this study is to investigate the significance of tumor G-CSF expression in the chemosensitivity of uterine cervical cancer. The clinical data of recurrent or advanced cervical cancer patients who were treated with platinum-based chemotherapy were analyzed. Clinical samples, cervical cancer cell lines, and a mouse model of cervical cancer were employed to examine the mechanisms responsible for the development of chemoresistance in G-CSF-producing cervical cancer, focusing on myeloid-derived suppressor cells (MDSC). As a result, the tumor G-CSF expression was significantly associated with increased MDSC frequencies and compromised survival. In vitro and in vivo experiments demonstrated that the increased MDSC induced by tumor-derived G-CSF is involved in the development of chemoresistance. The depletion of MDSC via splenectomy or the administration of anti-Gr-1 antibody sensitized G-CSF-producing cervical cancer to cisplatin. In conclusion, tumor G-CSF expression is an indicator of an extremely poor prognosis in cervical cancer patients that are treated with chemotherapy. Combining MDSC-targeting treatments with current standard chemotherapies might have therapeutic efficacy as a treatment for G-CSF-producing cervical cancer.