Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells.
Imatinib sensitizes endometrial cancer cells to cisplatin by targeting CD117-positive growth-competent cells.
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伊马替尼通过靶向 CD117 阳性生长活性细胞，使子宫内膜癌细胞对顺铂敏感。
DOI：
10.1016/j.canlet.2013.11.020
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Fujiwara H.
中科院分区：
文献类型：
--
作者：
Zhang X;Kyo S;Nakamura M;Mizumoto Y;Maida Y;Bono Y;Takakura M;Fujiwara H.
子宫内膜癌的分子靶向治疗尚未确立。本研究探讨了靶向CD 117阳性癌细胞作为一种新的分子靶向治疗的潜在治疗策略。从子宫内膜癌细胞系（石川或MFE 280细胞）中分离的FACS分选的CD 117+细胞与CD 117+细胞相比，在体外表现出更高的增殖能力和在软琼脂上的集落形成活性，并且对顺铂的敏感性降低。对子宫内膜癌手术标本的免疫组化分析显示，高CD 117表达与晚期FIGO分期、子宫肌层浸润和组织学分级密切相关，并与不良总生存率和无复发生存率显著相关（Kaplan-Meier分析; p< 0.001，对数秩检验）。Cox回归风险模型确定高CD 117表达是生存的独立预后因素（p< 0.05）。体外实验证实，子宫内膜癌CD 117+细胞特异性产生干细胞因子（SCF），加入抗SCF抗体后，SCF的集落形成活性被抑制，表明SCF依赖性生长。伊马替尼在体外被证实选择性靶向CD 117+细胞，并协同增强低剂量顺铂的体内抗肿瘤作用，其在单次使用时仅显示出适度的作用。这些发现表明，CD 117可以作为细胞侵袭行为的标志物，以及子宫内膜癌的独立预后标志物。伊马替尼靶向SCF/CD 117轴使子宫内膜癌细胞对顺铂敏感，为这种肿瘤类型提出了一种新的治疗策略。© 2013 Elsevier爱尔兰有限公司版权所有。
The use of molecular target therapy has not been established for endometrial cancer. The present study investigated the potential therapeutic strategy of targeting CD117-positive cancer cells as a novel molecular target therapy. FACS-sorted CD117+ cells isolated from endometrial cancer cell lines (Ishikawa or MFE280 cells) exhibited higher proliferative capacity in vitro and colony forming activity on soft agar, and decreased sensitivity to cisplatin, compared to CD117À cells. Immunohistochemical analyses with surgical specimens of endometrial cancers showed that high CD117 expression was tightly linked to advanced FIGO stages, myometrial invasion and histological grade, and was significantly associated with poor overall survival and relapse-free survival (Kaplan–Meier analysis; p< 0.001, log-rank test). The Cox-regression hazard model identified high CD117 expression to be an independent prognostic factor for survival (p< 0.05). In vitro assay confirmed that stem cell factor (SCF), a ligand of CD117, was produced specifically in CD117+ cells of endometrial cancer, and the colony-forming activity were abrogated by adding anti-SCF antibody, indicating an SCF-dependent growth property. Imatinib was confirmed to selectively target CD117+ cells in vitro, and synergistically enhanced the anti-tumor effect of low dose cisplatin in vivo, which showed only modest effects when used as a single use. These findings suggest that CD117 can be a marker of aggressive behavior of cells as well as an independent prognostic marker in endometrial cancer. Targeting of the SCF/CD117 axis by imatinib sensitized endometrial cancer cells to cisplatin, proposing a novel therapeutic strategy for this tumor type. Ó 2013 Elsevier Ireland Ltd. All rights reserved.
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