Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties.
Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties.
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DOI：
10.1371/journal.pone.0003077
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发表时间：
2008-08-27
期刊：
影响因子：
3.7
通讯作者：
Lokshin AE
中科院分区：
文献类型：
--
作者：
Levina V;Marrangoni AM;DeMarco R;Gorelik E;Lokshin AE
癌症干细胞(CSCs)被认为对化疗后的肿瘤再生负责，尽管这一点仍有待直接证实。因此，我们研究了药物治疗是否能够丰富和维持CSCs，以及CSCs的高致瘤和转移能力是否基于其显著的产生生长和血管生成因子并表达其同源受体以刺激肿瘤细胞增殖和间质形成的能力。用阿霉素、顺铂或依托泊苷处理肺肿瘤细胞可选择药物存活细胞(DSCs)。这些细胞表达CD133、CD117、SSEA-3、TRA1-81、OCT-4和核β-连环蛋白，但不表达分化标志物细胞角蛋白8/18(CK8/18)。DSCs能够作为肿瘤球体生长，保持自我更新能力，并分化。分化祖细胞CD133表达缺失，CK8/18增强，获得药物敏感性。在药物存在的情况下，DSC的分化被取消，允许具有CSC样特征的细胞增殖。肺DSCs接种SCID小鼠后显示出较高的致瘤和转移潜能，支持将其归类为CSCs。Luminex对亲代和肿瘤干细胞来源的肿瘤超声裂解物中的人和小鼠细胞因子的分析表明，肿瘤干细胞来源的肿瘤含有两到三倍水平的人血管生成和生长因子(血管内皮生长因子、碱性成纤维细胞生长因子、IL-6、IL-8、肝细胞生长因子、血小板衍生生长因子-BB、G-脑脊液和干细胞生长因子-β)。CSCs中人VEGFR2、FGFR2、CXCR1、2和4受体的表达水平也升高。此外，在SCID小鼠体内生长的人CSCs刺激小鼠基质产生更高水平的血管生成和生长因子。这些发现表明，化疗可以导致CSCs的增殖和阻止其分化。CSCs的高致瘤和转移潜能与有效的细胞因子网络产生有关，这可能是提高癌症治疗效果的一个靶点。
Cancer stem cells (CSCs) are thought to be responsible for tumor regeneration after chemotherapy, although direct confirmation of this remains forthcoming. We therefore investigated whether drug treatment could enrich and maintain CSCs and whether the high tumorogenic and metastatic abilities of CSCs were based on their marked ability to produce growth and angiogenic factors and express their cognate receptors to stimulate tumor cell proliferation and stroma formation. Treatment of lung tumor cells with doxorubicin, cisplatin, or etoposide resulted in the selection of drug surviving cells (DSCs). These cells expressed CD133, CD117, SSEA-3, TRA1-81, Oct-4, and nuclear β-catenin and lost expression of the differentiation markers cytokeratins 8/18 (CK 8/18). DSCs were able to grow as tumor spheres, maintain self-renewal capacity, and differentiate. Differentiated progenitors lost expression of CD133, gained CK 8/18 and acquired drug sensitivity. In the presence of drugs, differentiation of DSCs was abrogated allowing propagation of cells with CSC-like characteristics. Lung DSCs demonstrated high tumorogenic and metastatic potential following inoculation into SCID mice, which supported their classification as CSCs. Luminex analysis of human and murine cytokines in sonicated lysates of parental- and CSC-derived tumors revealed that CSC-derived tumors contained two- to three-fold higher levels of human angiogenic and growth factors (VEGF, bFGF, IL-6, IL-8, HGF, PDGF-BB, G-CSF, and SCGF-β). CSCs also showed elevated levels of expression of human VEGFR2, FGFR2, CXCR1, 2 and 4 receptors. Moreover, human CSCs growing in SCID mice stimulated murine stroma to produce elevated levels of angiogenic and growth factors. These findings suggest that chemotherapy can lead to propagation of CSCs and prevention of their differentiation. The high tumorigenic and metastatic potentials of CSCs are associated with efficient cytokine network production that may represent a target for increased efficacy of cancer therapy.
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