CD133(+)CXCR4(+) colon cancer cells exhibit metastatic potential and predict poor prognosis of patients.
CD133(+)CXCR4(+) colon cancer cells exhibit metastatic potential and predict poor prognosis of patients.
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CD133( )CXCR4( )结肠癌细胞表现出转移潜力并预测患者的不良预后。
DOI：
10.1186/1741-7015-10-85
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发表时间：
2012-08-07
期刊：
影响因子：
9.3
通讯作者：
Wei LX
中科院分区：
文献类型：
--
作者：
Zhang SS;Han ZP;Jing YY;Tao SF;Li TJ;Wang H;Wang Y;Li R;Yang Y;Zhao X;Xu XD;Yu ED;Rui YC;Liu HJ;Zhang L;Wei LX
研究背景结直肠癌(CRC)是世界范围内与癌症相关的死亡的三大原因之一，常转移至肝脏。越来越多的证据表明，在癌症干细胞中存在一种细胞亚群。这种不同的亚群被认为与肝转移有关；然而，它在结直肠癌中还没有得到充分的研究。方法应用流式细胞术分析CD133和CXCR4标记在人原发和转移性结直肠癌组织中的不同亚群。在体外和体内比较了来自结肠癌细胞系HCT116的不同亚群的‘干性’和转移能力。此外，还探讨了上皮-间充质转化(EMT)和基质细胞衍生因子-1(SDF-1)在肿瘤转移过程中的作用。结果肝转移癌组织中CD133+CXCR4+细胞含量明显高于原发结直肠肿瘤组织。克隆和致瘤细胞仅限于HCT116细胞系中的CD133+细胞，而CXCR4的表达对干细胞特性没有影响。我们发现CD133+CXCR4+癌细胞在体外和体内都有很高的转移能力。与CD133+CXCR4-细胞相比，CD133+CXCR4+癌细胞经历了EMT，这在一定程度上与其转移表型有关。我们发现SDF-1/CXCL12可以进一步诱导CD133+CXCR4+癌细胞发生EMT并增强其侵袭行为，而在CD133+CXCR4-癌细胞中未观察到这种作用。在小鼠肝转移模型中，用CXCR4拮抗剂AMD3100(1，10-[1，4-phenylenebis(methylene)]bis-1，4，8，11-四氮杂环十四烷十八烷盐酸盐阻断SDF1/CXCR4的相互作用可抑制转移瘤的生长。结论针对SDF-1/CXCR4相互作用的策略在抑制结肠癌转移方面具有重要的临床应用价值。进一步研究CXCR4和EMT在这一已确定的肿瘤干细胞亚群中的高表达是有必要的，以期为我们对肿瘤生物学的理解提供见解。
BackgroundColorectal cancer (CRC), which frequently metastasizes to the liver, is one of the three leading causes of cancer-related deaths worldwide. Growing evidence suggests that a subset of cells exists among cancer stem cells. This distinct subpopulation is thought to contribute to liver metastasis; however, it has not been fully explored in CRC yet.MethodsFlow cytometry analysis was performed to detect distinct subsets with CD133 and CXCR4 markers in human primary and metastatic CRC tissues. The 'stemness' and metastatic capacities of different subpopulations derived from the colon cancer cell line HCT116 were compared in vitro and in vivo. The roles of epithelial-mesenchymal transition (EMT) and stromal-cell derived factor-1 (SDF-1) in the metastatic process were also investigated. A survival curve was used to explore the correlation between the content of CD133+CXCR4+ cancer cells and patient survival.ResultsIn human specimens, the content of CD133+CXCR4+ cells was higher in liver metastases than in primary colorectal tumors. Clonogenic and tumorigenic cells were restricted to CD133+ cells in the HCT116 cell line, with CXCR4 expression having no impact on the 'stemness' properties. We found that CD133+CXCR4+ cancer cells had a high metastatic capacity in vitro and in vivo. Compared with CD133+CXCR4- cells, CD133+CXCR4+ cancer cells experienced EMT, which contributed partly to their metastatic phenotype. We then determined that SDF-1/CXCL12 treatment could further induce EMT in CD133+CXCR4+ cancer cells and enhance their invasive behavior, while this could not be observed in CD133+CXCR4- cancer cells. Blocking SDF-1/CXCR4 interaction with a CXCR4 antagonist, AMD3100 (1,10-[1,4-phenylenebis(methylene)]bis-1,4,8,11 -tetraazacyclotetradecane octahydrochloride), inhibited metastatic tumor growth in a mouse hepatic metastasis model. Finally, a high percentage of CD133+CXCR4+ cells in human primary CRC was associated with a reduced two-year survival rate.ConclusionsStrategies targeting the SDF-1/CXCR4 interaction may have important clinical applications in the suppression of colon cancer metastasis. Further investigations on how high expression of CXCR4 and EMT occur in this identified cancer stem cell subset are warranted to provide insights into our understanding of tumor biology.
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影响因子：
11.2
作者：
Lo, Jeng-Fan;Yu, Cheng-Chia;Yu, Yau-Hua
通讯作者：
Yu, Yau-Hua
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
11.2
作者：
Johnson JL;Pillai S;Pernazza D;Sebti SM;Lawrence NJ;Chellappan SP
通讯作者：
Chellappan SP
影响因子：
11.2
作者：
Collins, AT;Berry, PA;Maitland, NJ
通讯作者：
Maitland, NJ
影响因子：
1.8
作者：
Ludbrook, J;Dudley, H
通讯作者：
Dudley, H