TY - JOUR
T1 - Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer
AU - McConkey, David J.
AU - Choi, Woonyoung
AU - Marquis, Lauren
AU - Martin, Frances
AU - Williams, Michael B.
AU - Shah, Jay
AU - Svatek, Robert
AU - Das, Aditi
AU - Adam, Liana
AU - Kamat, Ashish
AU - Siefker-Radtke, Arlene
AU - Dinney, Colin
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Epidermal growth factor receptor
KW - Epithelial-to-mesenchymal transition
KW - Micro-RNA-mediated molecular reversal
KW - Type-3 fibroblast growth factor receptor
KW - Urothelial tumor
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U2 - 10.1007/s10555-009-9194-7
DO - 10.1007/s10555-009-9194-7
M3 - Review article
C2 - 20012924
AN - SCOPUS:76649134077
SN - 0167-7659
VL - 28
SP - 335
EP - 344
JO - Cancer and Metastasis Reviews
JF - Cancer and Metastasis Reviews
IS - 3-4
ER -