Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop.
Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop.
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DOI：
10.1158/0008-5472.can-09-1102
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发表时间：
2010-01-01
期刊：
影响因子：
11.2
通讯作者：
Gorelik E
中科院分区：
文献类型：
--
作者：
Levina V;Marrangoni A;Wang T;Parikh S;Su Y;Herberman R;Lokshin A;Gorelik E
肿瘤干细胞(CSC)被认为是肿瘤发生和化疗后肿瘤再生的主要来源。此前，我们发现非小细胞肺癌(NSCLC)细胞株的化疗可以选择生长出高致瘤性和转移性的CSCs。肺CSCs的高度恶性与一个有效的细胞因子网络有关。在这项研究中，我们提供了证据，阻断干细胞因子(SCF)-c-kit信号足以抑制CSC的增殖和化疗促进的生存。在CSC选择的条件下，从NSCLC细胞系中分离出CSCs作为肿瘤球体，并证实了其干细胞特性。与其他肿瘤细胞不同，CSCs表达c-kit受体并产生SCF。干细胞因子中和抗体或c-kit抑制剂伊马替尼(Gleevec)可抑制CSCs的增殖。虽然顺铂治疗消除了大多数肿瘤细胞，但它并没有消除CSCs，而伊马替尼或抗SCF抗体则破坏了CSCs。值得注意的是，将顺铂与伊马替尼或抗SCF抗体联合使用可阻止这两种肿瘤细胞亚群的生长。我们的发现揭示了SCF-c-kit信号轴在肺CSCs自我更新和增殖中的重要作用，提示阻断SCF-c-kit信号通路可以提高人非小细胞肺癌化疗的抗肿瘤效果。
Cancer stem cells (CSC) are thought to be responsible for tumor initiation and tumor regeneration after chemotherapy. Previously, we showed that chemotherapy of non–small cell lung cancer (NSCLC) cells lines can select for outgrowth of highly tumorigenic and metastatic CSCs. The high malignancy of lung CSCs was associated with an efficient cytokine network. In this study, we provide evidence that blocking stem cell factor (SCF)–c-kit signaling is sufficient to inhibit CSC proliferation and survival promoted by chemotherapy. CSCs were isolated from NSCLC cell lines as tumor spheres under CSC-selective conditions and their stem properties were confirmed. In contrast to other tumor cells, CSCs expressed c-kit receptors and produced SCF. Proliferation of CSCs was inhibited by SCF-neutralizing antibodies or by imatinib (Gleevec), an inhibitor of c-kit. Although cisplatin treatment eliminated the majority of tumor cells, it did not eliminate CSCs, whereas imatinib or anti-SCF antibody destroyed CSCs. Significantly, combining cisplatin with imatinib or anti-SCF antibody prevented the growth of both tumor cell subpopulations. Our findings reveal an important role for the SCF–c-kit signaling axis in self-renewal and proliferation of lung CSCs, and they suggest that SCF–c-kit signaling blockade could improve the antitumor efficacy of chemotherapy of human NSCLC.