Journal Article

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

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

2009

Overview

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.

• Publisher: Springer US,Springer Nature B.V
• Subject: Biomedical and Life Sciences / Biomedicine / Bladder cancer / Cadherins - physiology / Cancer Research / Carcinoma, Transitional Cell - drug therapy / Carcinoma, Transitional Cell - genetics / Carcinoma, Transitional Cell - pathology / Cell Line, Tumor - pathology / Cell Transdifferentiation - physiology / Disease Progression / Drug Resistance, Neoplasm / Epithelium - pathology / Fibroblast Growth Factor 3 - physiology / Gene Expression Profiling / Gene Expression Regulation, Developmental / Gene Expression Regulation, Neoplastic / Humans / Mesoderm - pathology / MicroRNAs - physiology / Models, Biological / Neoplasm Invasiveness - genetics / Neoplasm Invasiveness - pathology / Neoplasm Proteins - physiology / Oncology / Receptor, Epidermal Growth Factor - physiology / TNF-Related Apoptosis-Inducing Ligand - physiology / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - pathology / Wound Healing - physiology