Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer

David J. McConkey, Woonyoung Choi, Lauren Marquis, Frances Martin, Michael B. Williams, Jay Shah, Robert Svatek, Aditi Das, Liana Adam, Ashish Kamat, Arlene Siefker-Radtke, Colin Dinney

Research output: Contribution to journalReview article

222 Scopus citations

Abstract

Epithelial-to-mesenchymal transition (EMT) is a process that plays essential roles in development and wound healing that is characterized by loss of homotypic adhesion and cell polarity and increased invasion and migration. At the molecular level, EMT is characterized by loss of E-cadherin and increased expression of several transcriptional repressors of E-cadherin expression (Zeb-1, Zeb-2, Twist, Snail, and Slug). Early work established that loss of E-cadherin and increased expression of MMP-9 was associated with a poor clinical outcome in patients with urothelial tumors, suggesting that EMT might also be associated with bladder cancer progression and metastasis. More recently, we have used global gene expression profiling to characterize the molecular heterogeneity in human urothelial cancer cell lines (n∈=∈20) and primary patient tumors, and unsupervised clustering analyses revealed that the cells naturally segregate into two discrete "epithelial" and "mesenchymal" subsets, the latter consisting entirely of muscle-invasive tumors. Importantly, sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) or type-3 fibroblast growth factor receptor (FGFR3) was confined to the "epithelial" subset, and sensitivity to EGFR inhibitors could be reestablished by micro-RNA-mediated molecular reversal of EMT. The results suggest that EMT coordinately regulates drug resistance and muscle invasion/metastasis in urothelial cancer and is a dominant feature of overall cancer biology.

Original languageEnglish (US)
Pages (from-to)335-344
Number of pages10
JournalCancer and Metastasis Reviews
Volume28
Issue number3-4
DOIs
StatePublished - Dec 14 2009

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Keywords

  • Epidermal growth factor receptor
  • Epithelial-to-mesenchymal transition
  • Micro-RNA-mediated molecular reversal
  • Type-3 fibroblast growth factor receptor
  • Urothelial tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McConkey, D. J., Choi, W., Marquis, L., Martin, F., Williams, M. B., Shah, J., Svatek, R., Das, A., Adam, L., Kamat, A., Siefker-Radtke, A., & Dinney, C. (2009). Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer and Metastasis Reviews, 28(3-4), 335-344. https://doi.org/10.1007/s10555-009-9194-7