Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: Role of fibroblast growth factor receptor-2
Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: Role of fibroblast growth factor receptor-2
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DOI：
10.1158/0008-5472.can-06-2044
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发表时间：
2006-12-01
期刊：
影响因子：
11.2
通讯作者：
Williams, Elizabeth D.
中科院分区：
文献类型：
--
作者：
Chaffer, Christine L.;Brennan, Janelle P.;Williams, Elizabeth D.
上皮-间质转化（EMT）增加了细胞迁移和侵袭，并促进多种癌类型的转移，但掩盖了原发性和继发性肿瘤之间的上皮相似性。本研究强调了间质-上皮转化（MET）在临床显著转移形成中的重要性。在本研究中使用先前描述的膀胱癌TSU-Prl（T24）进展系列的细胞系，所述细胞系在体内选择用于在全身接种后增加转移能力。发现转移性更强的亚系具有获得性上皮特征。通过细胞骨架和形态学分析以及一组体外试验中的表现，在TSU-Prl系列中证实了上皮和间充质表型。在不同部位接种后检查转移能力。心内或胫骨内注射后与骨和软组织定植显著增加相关的上皮特征。相反，更多的上皮细胞亚系显示原位接种后肺转移减少，支持EMT对于肿瘤细胞从原发肿瘤逃逸是重要的概念。我们通过TSU-Prl系列证实了多种成纤维细胞生长因子受体（FGFR）的111c亚型的过表达，并且靶向废除FGFR 2111c逆转了该系统中的MET和相关功能，并增加了严重联合免疫缺陷小鼠体内接种后的存活率。该模型是第一个专门模拟同基因细胞系中转移级联的后半部分步骤的模型，并证实了MET在继发性肿瘤生长中的可疑作用。
Epithelial-to-mesenchymal transition (EMT) increases cell migration and invasion, and facilitates metastasis in multiple carcinoma types, but belies epithelial similarities between primary and secondary tumors. This study addresses the importance of mesenchymal-to-epithelial transition (MET) in the formation of clinically significant metastasis. The previously described bladder carcinoma TSU-Prl (T24) progression series of cell lines selected in vivo for increasing metastatic ability following systemic seeding was used in this study. It was found that the more metastatic sublines had acquired epithelial characteristics. Epithelial and mesenchymal phenotypes were confirmed in the TSU-Prl series by cytoskeletal and morphologic analysis, and by performance in a panel of in vitro assays. Metastatic ability was examined following inoculation at various sites. Epithelial characteristics associated with dramatically increased bone and soft tissue colonization after intracardiac or intratibial injection. In contrast, the more epithelial sublines showed decreased lung metastases following orthotopic inoculation, supporting the concept that EMT is important for the escape of tumor cells from the primary tumor. We confirmed the overexpression of the 111c subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Prl series, and targeted abrogation of FGFR2111c reversed the MET and associated functionality in this system and increased survival following in vivo inoculation in severe combined immunodeficient mice. This model is the first to specifically model steps of the latter part of the metastatic cascade in isogenic cell lines, and confirms the suspected role of MET in secondary tumor growth.