Employing an orthotopic model to study the role of epithelial-mesenchymal transition in bladder cancer metastasis

• Published in: Oncotarget Vol. 8; no. 21; pp. 34205 - 34222
• Main Authors: Roth, Beat, Jayaratna, Isuru, Sundi, Debasish, Cheng, Tiewei, Melquist, Jonathan, Choi, Woonyoung, Porten, Sima, Nitti, Giovanni, Navai, Neema, Wszolek, Matthew, Guo, Charles, Czerniak, Bogdan, McConkey, David, Dinney, Colin
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 23.05.2017
• Subjects: Animals; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplastic Cells, Circulating - metabolism; Neoplastic Cells, Circulating - pathology; Research Paper; Signal Transduction - drug effects; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Whole Genome Sequencing; orthotopic xenografts; circulating tumor cells; metastasis; bladder cancer; SNAIL
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.11009

Epithelial-to-mesenchymal transition (EMT) has been implicated in the progression of bladder cancer. To study its contribution to bladder cancer metastasis, we established new xenograft models derived from human bladder cancer cell lines utilizing an orthotopic "recycling" technique that allowed us to isolate and examine the primary tumor and its corresponding circulating tumor cells (CTC's) and metastatic lesions. Using whole genome mRNA expression profiling, we found that a reversible epithelial-to-mesenchymal transition (EMT) characterized by TGFβ pathway activation and SNAIL expression was associated with the accumulation of CTCs. Finally, we observed that conditional silencing of SNAIL completely blocked CTC production and regional/distant metastasis. Using this unique bladder cancer xenograft model, we conclude that metastasis is dependent on a reversible EMT mediated by SNAIL.