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The Basics of Epithelial-Mesenchymal Transition Amendment history: Corrigendum (May 2010) The basics of epithelial-mesenchymal transition Raghu Kalluri, Robert A. Weinberg J Clin Invest. 2009;119(6):1420-1428. https://doi.org/10.1172/JCI39104. Review Series The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial- mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions. Find the latest version: https://jci.me/39104/pdf Review series The basics of epithelial-mesenchymal transition Raghu Kalluri1,2 and Robert A. Weinberg3 1Division of Matrix Biology, Beth Israel Deaconess Medical Center, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. 2Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA. 3Whitehead Institute for Biomedical Research, Ludwig Center for Molecular Oncology, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibro- sis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithe- lial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropri- ated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions. What is epithelial-mesenchymal transition? this concept was an understanding that all cells in a body derive An epithelial-mesenchymal transition (EMT) is a biologic process from other cells and the resulting deduction that ultimately all are that allows a polarized epithelial cell, which normally interacts derived from a single cell, the fertilized egg. An additional level of with basement membrane via its basal surface, to undergo mul- complexity came from the realization that cells can assume various tiple biochemical changes that enable it to assume a mesenchymal phenotypic states during development, that is, they can undergo cell phenotype, which includes enhanced migratory capacity, inva- the process of differentiation. As was learned more recently, dur- siveness, elevated resistance to apoptosis, and greatly increased ing specific steps of embryogenesis and organ development, the production of ECM components (1). The completion of an EMT cells within certain epithelia appear to be plastic and thus able to is signaled by the degradation of underlying basement membrane move back and forth between epithelial and mesenchymal states and the formation of a mesenchymal cell that can migrate away via the processes of EMT and MET (7). Upon completion of the from the epithelial layer in which it originated. development of epithelial tissues, the epithelial cells typically exert A number of distinct molecular processes are engaged in order to tissue-specific function, while the mesenchymal cells in such tis- initiate an EMT and enable it to reach completion. These include sue play a supporting role. Implied in this notion was the further activation of transcription factors, expression of specific cell-sur- idea that a state of terminal differentiation is necessary to carry face proteins, reorganization and expression of cytoskeletal pro- out such specialized functions and that cells are maintained in a teins, production of ECM-degrading enzymes, and changes in the permanent state of differentiation once development is complete. expression of specific microRNAs. In many cases, the involved fac- This concept has been challenged by numerous observations that tors are also used as biomarkers to demonstrate the passage of a the cells within a terminally differentiated epithelium can indeed cell through an EMT (Figure 1). change their phenotype through activation of an EMT program, The pioneering work of Elizabeth Hay first described an “epithelial- which enables transdifferentiation, resulting in the conversion of mesenchymal transformation” using a model of chick primitive streak epithelial cells to mesenchymal derivatives during development formation (2). In the intervening time, the term “transformation” has and adulthood. These programs can also be activated in associa- been replaced with “transition,” reflecting in part the reversibility of tion with tissue repair and pathological stresses, including those the process and the fact that it is distinct from neoplastic transforma- creating various types of inflammation and high-grade carcino- tion (1). The phenotypic plasticity afforded by an EMT is revealed by mas. Accordingly, EMTs now constitute recognized mechanisms the occurrence of the reverse process — a mesenchymal-epithelial tran- for dispersing cells in embryos, forming mesenchymal cells in sition (MET), which involves the conversion of mesenchymal cells to injured tissues, and initiating the invasive and metastatic behavior epithelial derivatives. Relatively little is known about this process; the of epithelial cancers. best-studied example is the MET associated with kidney formation, which is driven by genes such as paired box 2 (Pax2), bone morphoge- Classification of EMT into three different subtypes netic protein 7 (Bmp7), and Wilms tumor 1 (Wt1) (3–5). EMTs are encountered in three distinct biological settings that carry very different functional consequences (Figure 2). While the Why does EMT occur? specific signals that delineate the EMTs in the three discrete set- The concept of cell division as a way to generate more cells and tings are not yet clear, it is now well accepted that functional dis- expand tissue size emerged about 150 years ago (6). Central to tinctions are apparent. A proposal to classify EMTs into three dif- ferent biological subtypes based on the biological context in which they occur was discussed at a 2007 meeting on EMT in Poland Conflict of interest: The authors have declared that no conflict of interest exists. and a subsequent meeting in March 2008 at Cold Spring Harbor Nonstandard abbreviations used: BMP, bone morphogenetic protein; EMT, Laboratories. The EMTs that are associated with implantation, epithelial-mesenchymal transition; EndMT, endothelial-mesenchymal transition; FSP1, fibroblast-specific protein 1; LEF, lymphoid enhancer binding factor; MET, embryo formation, and organ development are organized to gen- mesenchymal-epithelial transition. erate diverse cell types that share common mesenchymal pheno- Citation for this article: J. Clin. Invest. 119:1420–1428 (2009). doi:10.1172/JCI39104. types. This class of EMTs, which we and others (8) propose to term 1420 The Journal of Clinical Investigation http://www.jci.org Volume 119 Number 6 June 2009 review series Figure 1 EMT. An EMT involves a functional transition of polarized epithelial cells into mobile and ECM component–secreting mesenchymal cells. The epithelial and mesenchymal cell markers commonly used by EMT researchers are listed. Colocalization of these two sets of distinct markers defines an intermediate phenotype of EMT, indicating cells that have passed only partly through an EMT. Detection of cells expressing both sets of markers makes it impossible to identify all mesenchymal cells that originate from the epithelia via EMT, as many mesenchymal cells likely shed all epithelial markers once a transition is completed. For this reason, most studies in mice use irreversible epithelial cell–lineage tagging to address the full range of EMT-induced changes. ZO-1, zona occludens 1; MUC1, mucin 1, cell surface associated; miR200, microRNA 200; SIP1, survival of motor neuron protein interacting protein 1; FOXC2, forkhead box C2. “type 1,” neither causes fibrosis nor induces an invasive phenotype future, we will learn more regarding the similarities and differ- resulting in systemic spread via the circulation. Among other out- ences among the three classes of EMTs. comes, these type 1 EMTs can generate mesenchymal cells (prima- ry mesenchyme) that have the potential to subsequently undergo Type 1 EMT: EMT during implantation, embryogenesis, a MET to generate secondary epithelia. and organ development The EMTs associated with wound healing, tissue regeneration, Following the earliest stages of embryogenesis, the implantation and organ fibrosis are of a second type. In these type 2 EMTs, the of the embryo and the initiation of placenta formation are both program begins as part of a repair-associated event that normally associated with an EMT that involves the parietal endoderm (9). In generates fibroblasts and other related cells in order to reconstruct particular, the trophoectoderm cells, which are precursors of the tissues following trauma and inflammatory injury. However,
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