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Epithelial–Mesenchymal Plasticity in Carcinoma Metastasis

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Epithelial–Mesenchymal Plasticity in Carcinoma Metastasis Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Epithelial–mesenchymal plasticity in carcinoma metastasis Jeff H. Tsai1 and Jing Yang1,2,3 1Department of Pharmacology, 2Department of Pediatrics, School of Medicine, University of California at San Diego, La Jolla, California 92093, USA Tumor metastasis is a multistep process by which tumor invade during developmental morphogenesis (Boyer cells disseminate from their primary site and form second- and Thiery 1993; Hay 1995). ary tumors at a distant site. Metastasis occurs through a Although epithelial cells convert into the mesenchy- series of steps: local invasion, intravasation, transport, mal state during developmental EMT, entering the EMT extravasation, and colonization. A developmental program program is not necessarily an irreversible commitment, termed epithelial–mesenchymal transition (EMT) has been as evident during kidney tubule formation. These epithe- shown to play a critical role in promoting metastasis in lial cells can activate a transitory EMT program and then epithelium-derived carcinoma. Recent experimental and undergo a reverse process called mesenchymal–epithelial clinical studies have improved our knowledge of this transition (MET) to continue their differentiation paths dynamic program and implicated EMT and its reverse (Thiery et al. 2009; Lim and Thiery 2012). In many instances, program, mesenchymal–epithelial transition (MET), in the identification of an epithelial versus a mesenchymal the metastatic process. Here, we review the functional state can be relatively fluid, and a partial EMT/MET requirement of EMT and/or MET during the individual frequently occurs to fulfill unique developmental tasks. steps of tumor metastasis and discuss the potential of These dynamic EMT/MET events highlight the enormous targeting this program when treating metastatic diseases. flexibility of presumably differentiated cells during mor- phogenesis. Epithelial and mesenchymal cell types have long been In the past decade, an increasing number of studies recognized by their unique cell morphology and organi- have provided strong evidence for the reinitiation of the zation in tissues. Epithelial cells form polarized sheets or EMT developmental program in carcinoma progression layers of cells that are connected laterally via several and metastasis. This EMT program in tumor metastasis types of cellular junctions, including adherens junctions, possesses many morphological and molecular features desmosomes, and tight junctions. In addition, epithelial similar to those of the developmental EMT program. cells anchor themselves to the underlying basement mem- Importantly, due to the heterogeneity and constantly evolv- brane via hemidesmosomes to maintain apical–basal ing microenvironment in human tumors, the EMT program polarity. Both desmosomes and hemidesmosomes fur- in metastasis adapts to these conditions to allow tumor ther connect with the epithelial-specific cytokeratin cells to successfully metastasize. intermediate filaments. In contrast, mesenchymal cells While EMT has been accepted as a critical program embed themselves inside the extracellular matrix (ECM) during embryogenesis, its role in carcinoma metastasis and rarely establish tight contact with neighboring cells. has been under debate (Tarin et al. 2005; Thomson et al. During specific embryonic morphogenesis processes such 2005; Garber 2008; Ledford 2011; Chui 2013). Many cell as mesoderm formation and neural crest development, culture and mouse tumor model studies have clearly epithelial cells can exhibit enormous plasticity and demonstrated the importance of EMT in tumor progression. transit into a mesenchymal state by activating the However, the EMT process in human cancer, if present, epithelial–mesenchymal transition (EMT) program. Af- remains difficult to identify, since carcinoma cells undergo- ter EMT, these cells lose their epithelial junctions and ing EMT share many similar morphological and molecular switch to producing vimentin filaments. The func- features with surrounding stromal fibroblasts. Further- tional hallmark of the EMT program is to allow sta- more, although primary tumors and circulating tumor tionary epithelial cells to gain the ability to migrate and cells (CTCs) present EMT features, distant metastases are generally epithelial in morphology, suggesting that, [Keywords: epithelial–mesenchymal transition (EMT); mesenchymal– Ó 2013 Tsai and Yang This article is distributed exclusively by Cold epithelial transition (MET); carcinoma metastasis; extravasation; intra- Spring Harbor Laboratory Press for the first six months after the full-issue vasation; invasion; tumor dormancy] publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). 3Corresponding author Aftersixmonths,itisavailableunder a Creative Commons License E-mail [email protected] (Attribution-NonCommercial 3.0 Unported), as described at http:// Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.225334.113. creativecommons.org/licenses/by-nc/3.0/. 2192 GENES & DEVELOPMENT 27:2192–2206 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/13; www.genesdev.org Downloaded from genesdev.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press The dynamic role of EMT in metastasis if functional, the EMT program is likely to be dynami- ECM degradation (Eckert et al. 2011). A number of non- cally regulated during metastasis. In 2002, Jean Paul epithelial cadherins, such as N-cadherin, and cell surface Thiery (2002), proposed the reversible EMT metastasis proteins, such as CD44 (Kuo et al. 2009) and integrin b6 model in which primary epithelial tumor cells activate (Bates et al. 2005), are induced and thought to be critical for EMT to invade and disseminate throughout the body, proper cell migration. All of these proteins have been used while, upon arriving at distant sites, disseminated tumor to define the occurrence of EMT in tumors. cells (DTCs) undergo a reversion process, or MET, to form epithelial metastases. This intriguing hypothesis has EMT core regulators brought EMT research to the forefront of carcinoma Execution of the EMT program involves the transcrip- metastasis study. tional alteration of many genes regulating cell adhesion, mesenchymal differentiation, cell migration, and invasion. In general, three core groups of transcriptional regulators The molecular program of EMT have been consistently shown to be critical during Given that a number of recent reviews have focused on various EMT events, thus being regarded as the core EMT the molecular pathways regulating EMT/MET (Thiery regulators. et al. 2009; De Craene and Berx 2013; Zheng and Kang The first group is the transcription factors of the Snail 2013), this section aims to provide an overview of the zinc finger family, including Snail1 and Snail2, both of cellular and molecular definition for EMT/MET and which are capable of directly binding to the E-boxes of establish a foundation for detailed discussions of these the E-cadherin promoter to repress its transcription (Batlle pathways in the context of tumor metastasis. The com- et al. 2000; Cano et al. 2000; Hajra et al. 2002). The second plex morphological and cellular changes during EMT group is the distantly related zinc finger E-box-binding require the cooperation of a large number of molecular homeobox family proteins Zeb1 and Zeb2, which are also signaling pathways and regulators. Based on their func- able to suppress E-cadherin transcription (Comijn et al. tionalities during EMT, we categorize them into three 2001; Eger et al. 2005) via a double-negative feedback loop groups: the effector molecules that execute the EMT controlling Zeb1/Zeb2 and miRNA-200 family expression program (EMT effectors), the transcription factors that (Christoffersen et al. 2007; Bracken et al. 2008; Burk et al. orchestrate the EMT program (EMT core regulators), and 2008; Gregory et al. 2008; Korpal and Kang 2008; Korpal the extracellular cues that activate the EMT program et al. 2008; Park et al. 2008; Kim et al. 2011b). Both the (EMT inducers). Snail and Zeb families of transcription factors have also been shown to repress the expression of other cellular EMT effectors junction proteins, such as claudins and ZO-1 (Ohkubo and Ozawa 2004; Vandewalle et al. 2005). The third group is Many of the hallmark EMT effector molecules are sub- the basic helix–loop–helix (bHLH) family of transcription cellular structure proteins that demarcate the epithelial factors, including Twist1 (Yang et al. 2004), Twist2 (Fang or mesenchymal identity of a cell. During EMT, key et al. 2011), and E12/E47 (Perez-Moreno et al. 2001), all of molecular components of these structures are subjected which can induce EMT alone or cooperatively. For exam- to various levels of regulation. For example, the genes ple, Twist1 can not only repress E-cadherin through induc- encoding various epithelial junction proteins, such as tion of Snail transcription factors (Li et al. 1995; Yang et al. E-cadherin, a-catenin, and g-catenin, are down-regulated at 2004; Casas et al. 2011) but also activate programs associ- the mRNA and protein levels. Among them, E-cadherin is ated with tumor invasion (Eckert et al. 2011), thus co- regarded as a gatekeeper of the epithelial state in various ordinating two major aspects of the EMT program. epithelial cell types. During EMT, E-cadherin gene tran- scriptional repression (Batlle et al. 2000; Cano et al. 2000;
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