Abstract
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-Pr1 (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-Pr1 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 IIIc subtype of multiple fibroblast growth factor receptors (FGFR) through the TSU-Pr1 series, and targeted abrogation of FGFR2IIIc 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.
Highlights
Cancer metastasis accounts for f90% of cancer deaths [1], yet the mechanisms facilitating progression from benign to invasive, and to metastatic carcinoma, remain largely elusive
We examined the expression of FGFR1 to FGFR3, including splice variants of these receptors involving the third immunoglobulin-like domain (III) that arise from the inclusion of exon 8 (IIIb) or exon 9 (IIIc), and FGFR4 in the TSU-Pr1 series
We observed a series of clones with significantly reduced FGFR2IIIc expression that maintained an epithelial phenotype, and we observed that the two clones with the greatest reduction in FGFR2IIIc expression had acquired a mesenchymal phenotype
Summary
Cancer metastasis accounts for f90% of cancer deaths [1], yet the mechanisms facilitating progression from benign to invasive, and to metastatic carcinoma, remain largely elusive. Extraordinary demands are placed on epithelium-derived carcinoma cells to successfully metastasize, including separation from the epithelial collective, degradation of the surrounding matrix, migration and invasion through the. Doi:10.1158/0008-5472.CAN-06-2044 basement membrane, intravasation and survival in the circulation, extravasation at a secondary site, survival as a micrometastasis, and growth into overt metastases [1]. To successfully complete these complex steps, cancer cells exhibit both mesenchymal- and epithelial-like properties at different times, or even at the same time [2]. Commitment to lineage differentiation in normal and tumor cells is more pliant than first thought, and cellular transition is emerging as a major mechanism of adult tissue homeostasis [3]
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