FGFR4 Promotes Stroma-Induced Epithelial-to-Mesenchymal Transition in Colorectal Cancer
FGFR4 Promotes Stroma-Induced Epithelial-to-Mesenchymal Transition in Colorectal Cancer
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FGFR4 促进结直肠癌基质诱导的上皮间质转化
DOI：
10.1158/0008-5472.can-12-4718
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发表时间：
2013-10-01
期刊：
影响因子：
11.2
通讯作者：
Wei, Yuquan
中科院分区：
文献类型：
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作者：
Liu, Rui;Li, Jingyi;Wei, Yuquan
肿瘤细胞通过与局部微环境相互作用而进化;然而，对控制肿瘤转移的肿瘤-间质相互作用知之甚少。在这项研究中，蛋白质组学分析表明，与肿瘤相关成纤维细胞（TAF）共培养诱导FGFR 4的显着过表达，但不是其他FGFR，在结直肠癌细胞系。机制研究表明，FGFR 4在TAF诱导的结直肠癌细胞系上皮向间充质转化（EMT）中发挥关键作用。细胞膜中积累的FGFR 4磷酸化β-连环蛋白，导致β-连环蛋白易位到细胞核中。此外，TAF衍生的CCL 2及其下游转录因子Ets-1是TAF诱导的FGFR 4上调的先决条件。此外，FGFR 4相关途径显示在结直肠肿瘤样品中优先活化，并在小鼠转移模型中直接肿瘤转移。我们的研究显示了FGFR 4在结直肠癌转移过程中肿瘤-间质相互作用中的关键作用，并为结直肠癌的治疗提供了新的治疗机会。(C)2013年AACR。
Tumor cells evolve by interacting with the local microenvironment; however, the tumor-stroma interactions that govern tumor metastasis are poorly understood. In this study, proteomic analyses reveal that coculture with tumor-associated fibroblasts (TAF) induces significant overexpression of FGFR4, but not other FGFRs, in colorectal cancer cell lines. Mechanistic study shows that FGFR4 plays crucial roles in TAF-induced epithelial-to-mesenchymal transition (EMT) in colorectal cancer cell lines. Accumulated FGFR4 in cell membrane phosphorylates beta-catenin, leading to translocation of b-catenin into the nucleus. Further, TAF-derived CCL2 and its downstream transcription factor, Ets-1, are prerequisites for TAF-induced FGFR4 upregulation. Furthermore, FGFR4-associated pathways are shown to be preferentially activated in colorectal tumor samples, and direct tumor metastasis in a mouse metastasis model. Our study shows a pivotal role of FGFR4 in tumor-stroma interactions during colorectal cancer metastasis, and suggests novel therapeutic opportunities for the treatment of colorectal cancer. (C) 2013 AACR.