Epithelial-Mesenchymal Transition and Cancer Stem Cells

Abstract

The epithelial to mesenchymal transition (EMT) is a highly coordinated process and a multistep event during which epithelial cells lose numerous epithelial characteristics and assume properties that are typical of mesenchymal cells, which requires complex changes in cell architecture and behavior. The conversion of epithelial cells to mesenchymal cells is critical for the formation of the body plan and in the differentiation of multiple tissues and organs during embryonic development and involves profound phenotypic changes such as the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties (Thiery et al. 2009). EMT is also involved in the physiological response to injury and in the pathological processes such as organ fibrosis. Accumulating evidence suggests that aberrant activation of the EMT developmental program contributes to tumor initiation invasion, metastatic dissemination and acquisition of therapeutic resistance (Yang, et al., 2004; Yang and Weinberg, 2008; Thiery et al., 2009; Singh and Settleman, 2010; Acloque et al., 2009; Kalluri and Weinberg, 2009). EMT induction can participate in cancer initiation to promote the clonal expansion of premalignant epithelial cells (Tellez et al., 2011). Cancer cells undergoing EMT acquire the capacity to migrate, invade the stroma and metastasise. During the process of metastasis, the EMT program enables these cancer cells to disseminate from a primary tumor and also promotes their self-renewal capability to ensure generation of the critical tumor mass required for progression from microto macro-metastases (Ruan et al., 2009a; Ruan et al., 2009c; Ouyang et al., 2010). EMT-inducing signalling pathways, such as TGF-┚, Wnt, Notch and Hedgehog (Hh), along with other tumor microenvironmental cues, induce well-differentiated epithelial cells to convert into motile mesenchymal cells via the activation of multiple EMT transcription factors, including Twist1, Twist2, Snai1, Slug, ZEB1 and ZEB2. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in cancers contributes to tumor progression. For example, developmental EMT regulators including Twist1, Twist2, Snail, Slug and Six1, and Cripto, along with developmental signaling pathways including TGF-┚ and Wnt/┚-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes.