title: Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer.
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.
authors.affiliation: Department of Urology, U.T. M.D. Anderson Cancer Center, P.O. Box 1373, 1515 Holcombe Boulevard, Houston, TX 77030, USA. dmcconke@mdanderson.org
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.forename: Woonyoung
authors.initials: W
authors.lastname: Choi
authors.forename: Lauren
authors.initials: L
authors.lastname: Marquis
authors.forename: Frances
authors.initials: F
authors.lastname: Martin
authors.forename: Michael B
authors.initials: MB
authors.lastname: Williams
authors.forename: Jay
authors.initials: J
authors.lastname: Shah
authors.forename: Robert
authors.initials: R
authors.lastname: Svatek
authors.forename: Aditi
authors.initials: A
authors.lastname: Das
authors.forename: Liana
authors.initials: L
authors.lastname: Adam
authors.forename: Ashish
authors.initials: A
authors.lastname: Kamat
authors.forename: Arlene
authors.initials: A
authors.lastname: Siefker-Radtke
authors.forename: Colin
authors.initials: C
authors.lastname: Dinney
mesh_terms: D015820:Cadherins / Q000502:physiology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor / Q000473:pathology; D054338:Cell Transdifferentiation / Q000502:physiology*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004848:Epithelium / Q000473:pathology*; D066246:ErbB Receptors / Q000502:physiology; D051518:Fibroblast Growth Factor 3 / Q000502:physiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D035683:MicroRNAs / Q000502:physiology; D008954:Models, Biological; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009363:Neoplasm Proteins / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014945:Wound Healing / Q000502:physiology
chemical_list: D015820:Cadherins; C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3; D035683:MicroRNAs; D009363:Neoplasm Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors