Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway
Mesenchymal stem cells enhance lung cancer initiation through activation of IL-6/JAK2/STAT3 pathway
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DOI：
10.1016/j.lungcan.2011.07.001
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发表时间：
2012-02-01
期刊：
影响因子：
5.3
通讯作者：
Hung, Shih-Chieh
中科院分区：
文献类型：
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作者：
Hsu, Han-Shui;Lin, Jiun-Han;Hung, Shih-Chieh
背景：间充质干细胞（MSCs）和IL-6在肺癌中的作用尚未得到很好的解决。本研究旨在探讨骨髓间充质干细胞（MSCs）是否能增强肺癌细胞的成瘤能力，并将其与IL-6/JAK 2/STAT 3信号通路的激活联系起来。材料与方法：将MSCs直接或间接与肺癌细胞株A549和CL 1 -5共培养。球体定义为具有>50%面积的细胞集落，其显示三维结构和模糊的细胞边缘。将没有和具有MSC的细胞注射到NOD/SCID小鼠中。测定肿瘤形成的百分比。IL-6/JAK 2/STAT 3信号通路在癌细胞球形成和肿瘤生长的影响进行了调查。结果：一个非常小的数目的肺癌细胞，当与其他非致瘤性MSC混合时，获得从头致瘤性时，皮下注射，并允许形成肿瘤异种移植物。从MSC分泌IL-6增加了癌细胞中JAK 2/STAT 3通路的激活，并增强了球体形成和肿瘤起始。A549和CL 1 -5肺癌细胞的肿瘤形成的能力降低时，IL-6被抑制在MSC或STAT 3被沉默在A549和CL 1 -5与MSCs.Conclusions：A549或CL 1 -5肺癌细胞与MSC的培养增加球体形成，耐药性，和多能性标志物的过表达，通过激活IL-6/JAK 2/STAT 3通路。MSC增强了A549和CL 1 -5肺癌细胞在免疫缺陷小鼠中形成肿瘤的能力。阻断IL-6/JAK 2/STAT 3通路减弱了A549和CL 1 -5细胞形成肿瘤的能力。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Background: The role of mesenchymal stem cells (MSCs) and IL-6 in lung cancer has not been well-addressed. We aimed to determine if MSCs can enhance the ability of tumor initiation of lung cancer cells, and link MSCs with activation of the IL-6/JAK2/STAT3 signaling pathway.Materials and methods: Lung cancer cell lines A549 and CL1-5 were directly or indirectly cocultured with MSCs. Spheres were defined as cell colonies with >50% area showing 3-dimensional structure and blurred cell margins. Cells without and with MSCs were injected into NOD/SCID mice. The percentage of tumor formation was determined. The influence of the IL-6/JAK2/STAT3 signaling pathway in cancer cell sphere formation and tumor growth were investigated.Results: A very small number of lung cancer cells, when mixed with otherwise non-tumorigenic MSCs, obtained de novo tumorigenicity when injected subcutaneously and allowed to form a tumor xenograft. Secretion of IL-6 from MSCs increased activation of the JAK2/STAT3 pathway in cancer cells, and enhanced sphere formation and tumor initiation. A reduced capacity of tumor formation of A549 and CL1-5 lung cancer cells when IL-6 was inhibited in MSCs or STAT3 was silenced in A549 and CL1-5 admixed with MSCs.Conclusions: Culture of A549 or CL1-5 lung cancer cells with MSCs increased sphere formation, drug resistance, and overexpression of pluripotency markers through activation of the IL-6/JAK2/STAT3 pathway. MSCs enhanced the capability of A549 and CL1-5 lung cancer cells to form tumors in immunodeficient mice. Blockade of the IL-6/JAK2/STAT3 pathway attenuated the capability of A549 and CL1-5 cells to form tumors. (C) 2011 Elsevier Ireland Ltd. All rights reserved.