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 “mes-enchymal” 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.

A set of NF-κB–regulated microRNAs induces acquired TRAIL resistance in Lung cancer

“…Epithelial-mesenchymal transition (EMT) is associated with reduced sensitivity to many chemotherapeutic drugs (34). We observed an impressive change in cellular shape of H460R cells from an epithelial phenotype to a spindle-fibroblastoid morphology, which was rescued by the knockdown of NF-κB (Fig.…”

High Motility of Triple-negative Breast Cancer Cells Is Due to Repression of Plakoglobin Gene by Metastasis Modulator Protein SLUG

“…It inhibits PUMA to block the induction of anoikis in the cancer cells (31)(32)(33). Although cancer cells with abnormally high levels of SLUG protein are highly motile (8,(35)(36)(37)(38), direct association of SLUG with cellular motility is not established until our study. Using the isogenic breast cancer cell system, we have shown here that the motility of the SLUG-negative cells is increased significantly with the expression of SLUG in these cells.…”

Let-7c Governs the Acquisition of Chemo- or Radioresistance and Epithelial-to-Mesenchymal Transition Phenotypes in Docetaxel-Resistant Lung Adenocarcinoma

“…EMT has been reported to play vital roles in the resistance of tumor cells to most conventional therapeutics (36,37), and the presence of EMT phenotypic cells in LAD could be one of the reasons that patients with LAD are typically drugresistant, which contributes to high mortality. Therefore, therapeutic benefits such as the restoration of chemosensitivity or suppression of metastasis will be enabled by reversing EMT phenotype.…”