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• W3137803078 abstract "Epithelial cells repress epithelial characteristics and elaborate mesenchymal characteristics to migrate to other locations and acquire new properties. Epithelial plasticity responses are directed through cooperation of signaling pathways, with TGF-β and TGF-β-related proteins playing prominent instructive roles. Epithelial-mesenchymal transitions (EMTs) directed by activin-like molecules, bone morphogenetic proteins, or TGF-β regulate metazoan development and wound healing and drive fibrosis and cancer progression. In carcinomas, diverse EMTs enable stem cell generation, anti-cancer drug resistance, genomic instability, and localized immunosuppression. This review discusses roles of TGF-β and TGF-β-related proteins, and underlying molecular mechanisms, in epithelial plasticity in development and wound healing, fibrosis, and cancer. Epithelial cells repress epithelial characteristics and elaborate mesenchymal characteristics to migrate to other locations and acquire new properties. Epithelial plasticity responses are directed through cooperation of signaling pathways, with TGF-β and TGF-β-related proteins playing prominent instructive roles. Epithelial-mesenchymal transitions (EMTs) directed by activin-like molecules, bone morphogenetic proteins, or TGF-β regulate metazoan development and wound healing and drive fibrosis and cancer progression. In carcinomas, diverse EMTs enable stem cell generation, anti-cancer drug resistance, genomic instability, and localized immunosuppression. This review discusses roles of TGF-β and TGF-β-related proteins, and underlying molecular mechanisms, in epithelial plasticity in development and wound healing, fibrosis, and cancer. Epithelial cell differentiation and formation of polarized epithelial cell sheets are hallmarks of metazoan organisms. Epithelia act as barriers with the environment, allowing for a physiological internal environment for tissue and organ function, and metabolism. In development, they define compartmentalization, patterning, organization, and functions of many organs. They also enable polarized presentation or secretion of proteins, uptake of nutrients, and exchange of metabolites, as they organize themselves into surfaces of tubes and cavities, e.g., in the gastro-intestinal tract (Rodriguez-Boulan and Macara, 2014Rodriguez-Boulan E. Macara I.G. Organization and execution of the epithelial polarity programme.Nat. Rev. Mol. Cell Biol. 2014; 15: 225-242Crossref PubMed Scopus (334) Google Scholar). These functions require epithelial integrity, in which the cells tightly interact with each other using specialized junctions and thus prevent interstitial passage of liquids or proteins, and allow a fully controlled barrier function through transcellular transport. Essential in the maintenance of the integrity are homotypic cell-cell junctions, multiprotein transmembrane complexes that communicate through interactions with the cortical cytoskeletal infrastructure and help define the apical-basal polarity of epithelia. The epithelial sheets position themselves, again through specialized protein complexes, on extracellular matrices, often organized as a basal lamina (Yurchenco, 2011Yurchenco P.D. Basement membranes: cell scaffoldings and signaling platforms.Cold Spring Harb. Perspect. Biol. 2011; 3a004911Crossref PubMed Scopus (450) Google Scholar). In epithelial sheets, the cells receive instructive information from not only neighboring cells but also the extracellular matrix (ECM), thus defining epithelial functions and integrity. While epithelial integrity requires highly controlled maintenance of the epithelial phenotype, differentiation plasticity is also essential for cell division and continued remodeling of epithelial structures, wound repair following injury, and generation of structures, e.g., during branching morphogenesis. Thus, epithelial cells transiently disassemble their cell junctions, reorganize their cytoskeleton, and change shape, as required for epithelial modeling and remodeling (Takeichi, 2014Takeichi M. Dynamic contacts: rearranging adherens junctions to drive epithelial remodelling.Nat. Rev. Mol. Cell Biol. 2014; 15: 397-410Crossref PubMed Scopus (290) Google Scholar). Transient epithelial plasticity responses occur from the most primitive metazoans to mammalian development. In Hydra, the two epithelial cell layers in the body column, i.e., ectoderm and endoderm, continuously undergo self-renewing divisions that result in epithelial displacement toward the lower regions of the stalk or into the tentacles and generation of cell types with diverse functions. Hydra’s remarkable regeneration capacity in response to injury results from the inherent differentiation plasticity of epithelial cells, which have stem-cell-like properties, acquire increased motility, and rapidly regenerate different cell types (Vogg et al., 2019Vogg M.C. Galliot B. Tsiairis C.D. Model systems for regeneration: hydra.Development. 2019; 146: dev177212Crossref Scopus (7) Google Scholar). In Drosophila, the dorsal closure of the embryo provides a model of epithelial wound healing, with epidermal cell sheets migrating to seal a hole in the epidermis. In this process, the cells at the leading edge form actin-rich filopodial protrusions, deconstructing their apical-basal polarity and epithelial junctions. When the two epithelial sheets meet upon closure at the dorsal midline, the cells re-establish themselves as bona fide polarized epithelial cells with junctional integrity (Belacortu and Paricio, 2011Belacortu Y. Paricio N. Drosophila as a model of wound healing and tissue regeneration in vertebrates.Dev. Dyn. 2011; 240: 2379-2404Crossref PubMed Scopus (0) Google Scholar). A similar loss of epithelial cell properties is also apparent in vertebrate epithelial repair. Upon injury, the epithelial cells extend lamellipodia, alter integrin expression and actin organization, and acquire a motile behavior, aimed at re-establishing epithelial integrity. In these and other wound healing systems, the epithelial cells dynamically loose epithelial properties, display increased motility, and then re-establish their cell-cell junctions, epithelial cytoskeletal architecture, and apical-basolateral polarity (Arwert et al., 2012Arwert E.N. Hoste E. Watt F.M. Epithelial stem cells, wound healing and cancer.Nat. Rev. Cancer. 2012; 12: 170-180Crossref PubMed Scopus (268) Google Scholar). Accordingly, transient loss of epithelial characteristics represents an essential aspect of epithelial cell behavior and a prerequisite for epithelial repair, integrity, and homeostasis. While epithelial plasticity allows for remodeling and changes in organization, epithelial cells can also separate from existing structures to migrate collectively, as a group, in response to attractive cues and gradients, and thus give rise to new cell populations with distinct characteristics. In collective cell migration toward a new location, the rear cells often maintain epithelial characteristics with connected cell-cell junctions, whereas cells at leading edges loosen their cell-cell interactions and reorient epithelial polarity toward a front-rear polarity (Friedl and Mayor, 2017Friedl P. Mayor R. Tuning collective cell migration by cell-cell junction regulation.Cold Spring Harb. Perspect. Biol. 2017; 9: a029199Crossref PubMed Scopus (106) Google Scholar). This transition toward the mesenchymal state is marked by not only a loss of epithelial junctions and repressed epithelial gene expression but also expression of proteins that are found in mesenchymal cells, an elongated cell shape with actin reorganization into stress fibers, and motile and invasive behavior (Nieto et al., 2016Nieto M.A. Huang R.Y. Jackson R.A. Thiery J.P. EMT: 2016.Cell. 2016; 166: 21-45Abstract Full Text Full Text PDF PubMed Google Scholar). Migration is facilitated by epithelial-to-mesenchymal transition (EMT), which in collective cell migration is incomplete and restricted to the leading edge of the migrating cell population (Figure 1). Border cell migration in Drosophila represents an example of collective cell migration. Border cells derive from the follicular epithelium of the egg chamber and migrate as a tight cluster of 6–8 cells that alter their relative positions as they move toward the developing oocyte (Montell et al., 2012Montell D.J. Yoon W.H. Starz-Gaiano M. Group choreography: mechanisms orchestrating the collective movement of border cells.Nat. Rev. Mol. Cell Biol. 2012; 13: 631-645Crossref PubMed Scopus (124) Google Scholar). The development of the lateral line in zebrafish provides another example of collective cell migration, with directed migration of a cluster of one to several hundreds of epithelial-like cells. The anterior cells show mesenchymal properties and act as leaders that move toward the attractant chemokine and provide directional information. They remain in close contact with each other and the epithelial-like cells in the rear of this population (Nieto et al., 2016Nieto M.A. Huang R.Y. Jackson R.A. Thiery J.P. EMT: 2016.Cell. 2016; 166: 21-45Abstract Full Text Full Text PDF PubMed Google Scholar; Friedl and Mayor, 2017Friedl P. Mayor R. Tuning collective cell migration by cell-cell junction regulation.Cold Spring Harb. Perspect. Biol. 2017; 9: a029199Crossref PubMed Scopus (106) Google Scholar). Directed migration of cell populations also occurs in gastrulation and neural crest cell migration. In gastrulation of amniotes, the epithelial precursor cells of the mesendoderm move into the midline of the embryo to form the primitive streak and partially or completely lose epithelial characteristics with acquisition of at least some mesenchymal properties, followed by ingression of the mesendoderm between the extra-embryonic and embryonic regions (Friedl and Mayor, 2017Friedl P. Mayor R. Tuning collective cell migration by cell-cell junction regulation.Cold Spring Harb. Perspect. Biol. 2017; 9: a029199Crossref PubMed Scopus (106) Google Scholar). In neural crest delamination, streams of cells migrate from the neural tube to give rise to a diversity of differentiated cells. In this process, many cells remain in contact with each other, yet these contacts are loosely and dynamically organized, and the cells often elongate with mesenchymal characteristics (Piacentino et al., 2020Piacentino M.L. Li Y. Bronner M.E. Epithelial-to-mesenchymal transition and different migration strategies as viewed from the neural crest.Curr. Opin. Cell Biol. 2020; 66: 43-50Crossref Scopus (5) Google Scholar). As illustrated with these examples, epithelial cells often lose epithelial characteristics and transition into mesenchymal cells when they need motility and invasive behavior to reach distant sites. At these sites, they may revert to an epithelial phenotype or not, and acquire new differentiation fates, as shown with the many cell types that originate from the neural crest cells that acquired mesenchymal properties (Bhatt et al., 2013Bhatt S. Diaz R. Trainor P.A. Signals and switches in mammalian neural crest cell differentiation.Cold Spring Harb. Perspect. Biol. 2013; 5: a008326Crossref PubMed Scopus (98) Google Scholar). Besides roles in epithelial wound repair, EMT processes are integral in normal development, enabling neuro-ectodermal and epithelial cells to migrate to different locations and give rise to functionally different cell types. EMTs also occur pathologically in fibroses and cancers from epithelial and neuro-ectodermal origin and are increasingly seen as essential in the initiation and progression of fibrosis and carcinomas. With EMTs occurring in divergent contexts and being studied by scientists and clinicians with diverse interests, much discussion has been dedicated to singularly and simply define the EMT phenotype. A concerted attempt to reach consensus on this subject has recently been summarized (Yang et al., 2020Yang J. Antin P. Berx G. Blanpain C. Brabletz T. Bronner M. Campbell K. Cano A. Casanova J. Christofori G. et al.Guidelines and definitions for research on epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2020; 21: 341-352Crossref PubMed Scopus (98) Google Scholar). EMT initiates with the disassembly of epithelial cell-cell and cell-ECM junctions and of apical-basal cell polarity, hallmarks of the epithelial phenotype. In vertebrate epithelia, three types of junctions mediate cell-cell adhesion, apical tight junctions, lateral adherens junctions, and desmosomes (Rodriguez-Boulan and Macara, 2014Rodriguez-Boulan E. Macara I.G. Organization and execution of the epithelial polarity programme.Nat. Rev. Mol. Cell Biol. 2014; 15: 225-242Crossref PubMed Scopus (334) Google Scholar; Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar), while in invertebrates, specifically in Drosophila, apical adherens junctions and lateral septate junctions mediate epithelial cell adhesion (Belacortu and Paricio, 2011Belacortu Y. Paricio N. Drosophila as a model of wound healing and tissue regeneration in vertebrates.Dev. Dyn. 2011; 240: 2379-2404Crossref PubMed Scopus (0) Google Scholar). These complexes also control apical-basal cell polarity, through interactions with Crumbs, Par3-Par6-aPKC and Scribble complexes. The former two associate apically with tight junctions and define the apical compartment, while regulating the tight junction integrity, and the latter ones localize with adherens junctions in vertebrate cells, or septate junctions in Drosophila epithelia, and define the basolateral compartment (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar; Nieto et al., 2016Nieto M.A. Huang R.Y. Jackson R.A. Thiery J.P. EMT: 2016.Cell. 2016; 166: 21-45Abstract Full Text Full Text PDF PubMed Google Scholar). During epithelial plasticity responses, attenuation of epithelial cell adhesion accompanies impaired apical-basal polarity, both enabling increased motility (Rodriguez-Boulan and Macara, 2014Rodriguez-Boulan E. Macara I.G. Organization and execution of the epithelial polarity programme.Nat. Rev. Mol. Cell Biol. 2014; 15: 225-242Crossref PubMed Scopus (334) Google Scholar) (Figure 1). Upon induction of an epithelial plasticity response, cells activate a transcription program that results in repression of genes for proteins that characterize the epithelial phenotype, and, when cells transition into EMT, additionally activate genes that characterize mesenchymal cells. These changes in transcription, sometimes seen as gene reprogramming, involve three transcription factor families, Snail (Snail1) and Slug/Snail2, ZEB1 and ZEB2, and Twist transcription factors (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar; Dongre and Weinberg, 2019Dongre A. Weinberg R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer.Nat. Rev. Mol. Cell Biol. 2019; 20: 69-84Crossref PubMed Scopus (481) Google Scholar). They are seen as “master” drivers of the EMT process and cooperate to ensure downregulation of adhesion junctions and apical-basal cell polarity. Other transcription factors, such as GATA4 and GATA6 (Campbell et al., 2011Campbell K. Whissell G. Franch-Marro X. Batlle E. Casanova J. Specific GATA factors act as conserved inducers of an endodermal-EMT.Dev. Cell. 2011; 21: 1051-1061Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), HMGA2 (Thuault et al., 2006Thuault S. Valcourt U. Petersen M. Manfioletti G. Heldin C.H. Moustakas A. Transforming growth factor-β employs HMGA2 to elicit epithelial-mesenchymal transition.J. Cell Biol. 2006; 174: 175-183Crossref PubMed Scopus (382) Google Scholar), Goosecoid (Hartwell et al., 2006Hartwell K.A. Muir B. Reinhardt F. Carpenter A.E. Sgroi D.C. Weinberg R.A. The Spemann organizer gene, Goosecoid, promotes tumor metastasis.Proc. Natl. Acad. Sci. USA. 2006; 103: 18969-18974Crossref PubMed Scopus (0) Google Scholar), FoxC2 (Mani et al., 2007Mani S.A. Yang J. Brooks M. Schwaninger G. Zhou A. Miura N. Kutok J.L. Hartwell K. Richardson A.L. Weinberg R.A. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers.Proc. Natl. Acad. Sci. USA. 2007; 104: 10069-10074Crossref PubMed Scopus (420) Google Scholar), Lbx1 (Yu et al., 2009Yu M. Smolen G.A. Zhang J. Wittner B. Schott B.J. Brachtel E. Ramaswamy S. Maheswaran S. Haber D.A. A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression.Genes Dev. 2009; 23: 1737-1742Crossref PubMed Scopus (83) Google Scholar), Six1 (Micalizzi et al., 2009Micalizzi D.S. Christensen K.L. Jedlicka P. Coletta R.D. Barón A.E. Harrell J.C. Horwitz K.B. Billheimer D. Heichman K.A. Welm A.L. et al.The Six1 homeoprotein induces human mammary carcinoma cells to undergo epithelial-mesenchymal transition and metastasis in mice through increasing TGF-β signaling.J. Clin. Invest. 2009; 119: 2678-2690Crossref PubMed Scopus (176) Google Scholar), Sox9 (Sakai et al., 2006Sakai D. Suzuki T. Osumi N. Wakamatsu Y. Cooperative action of Sox9, Snail2 and PKA signaling in early neural crest development.Development. 2006; 133: 1323-1333Crossref PubMed Scopus (145) Google Scholar), and Prrx1(Ocaña et al., 2012Ocaña O.H. Córcoles R. Fabra A. Moreno-Bueno G. Acloque H. Vega S. Barrallo-Gimeno A. Cano A. Nieto M.A. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1.Cancer Cell. 2012; 22: 709-724Abstract Full Text Full Text PDF PubMed Scopus (555) Google Scholar) also contribute to the EMT program, depending on the physiological context. Phosphorylation, glycosylation, and ubiquitylation control the subcellular localization, activity, and/or stability of the EMT transcription factors (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar). Alternative splicing and microRNAs also play key roles in EMT, as illustrated later (Lamouille et al., 2013Lamouille S. Subramanyam D. Blelloch R. Derynck R. Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs.Curr. Opin. Cell Biol. 2013; 25: 200-207Crossref PubMed Scopus (195) Google Scholar). The gene reprogramming during EMT alters the cell adhesion protein repertoire; repression of adherens junction protein E-cadherin expression accompanies expression of the homophilic adhesion proteins N-cadherin and/or N-CAM (Friedl and Mayor, 2017Friedl P. Mayor R. Tuning collective cell migration by cell-cell junction regulation.Cold Spring Harb. Perspect. Biol. 2017; 9: a029199Crossref PubMed Scopus (106) Google Scholar). E-cadherin and N-cadherin both connect via α- and β-catenin to the cytoskeleton, but the associated signaling complexes differ in composition, function, and regulation by Rho-like GTPases and their regulators (Friedl and Mayor, 2017Friedl P. Mayor R. Tuning collective cell migration by cell-cell junction regulation.Cold Spring Harb. Perspect. Biol. 2017; 9: a029199Crossref PubMed Scopus (106) Google Scholar). Changes in cell adhesion proteins also control mechanical force generation to drive cell migration. E-cadherin at the leading edge promotes direction sensing, and E-cadherin-mediated cell-cell adhesion is required for collective border cell migration (Cai et al., 2014Cai D. Chen S.C. Prasad M. He L. Wang X. Choesmel-Cadamuro V. Sawyer J.K. Danuser G. Montell D.J. Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration.Cell. 2014; 157: 1146-1159Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar). Switching from E-cadherin to N-cadherin expression during EMT initiates cell dissociation and migration in neural crest cells (Scarpa et al., 2015Scarpa E. Szabó A. Bibonne A. Theveneau E. Parsons M. Mayor R. Cadherin switch during EMT in neural crest cells leads to contact inhibition of locomotion via repolarization of forces.Dev. Cell. 2015; 34: 421-434Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Transition into a mesenchymal phenotype also changes cell-ECM interactions through integrins. EMT induces changes in ECM protein expression, with increased fibronectin expression and differences in collagen and integrin expression (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar). For example, Snail activates the expression of αvβ3 integrin, which facilitates pro-invasive functions (Haraguchi et al., 2008Haraguchi M. Okubo T. Miyashita Y. Miyamoto Y. Hayashi M. Crotti T.N. McHugh K.P. Ozawa M. Snail regulates cell-matrix adhesion by regulation of the expression of integrins and basement membrane proteins.J. Biol. Chem. 2008; 283: 23514-23523Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). Increased αvβ6 expression during EMT enhances activation of latent TGF-β1 that is stored in the ECM, resulting in increased autocrine TGF-β responses (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar). Consequently, EMT substantially changes cell adhesion to ECM and instructive signaling from ECM. Cells undergoing EMT show drastic changes in morphology and elongate. Upon epithelial junction dissolution, the actin cytoskeleton remodels from a cortical architecture to longitudinal stress fibers, which is driven by Rho GTPases and associated guanine nucleotide exchange factors, GTPase activating proteins, and guanine nucleotide dissociation factors (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar). Changes in Rho GTPase activities during EMT consequently redirect cytoskeletal organization and dynamics, cell-cell adhesion, and microtubule-mediated interactions of cells with the ECM and basement membrane (Lawson and Ridley, 2018Lawson C.D. Ridley A.J. Rho GTPase signaling complexes in cell migration and invasion.J. Cell Biol. 2018; 217: 447-457Crossref PubMed Scopus (133) Google Scholar). Increased vimentin expression during EMT additionally provides an intermediate filament cytoarchitecture with enhanced flexibility and contributes to the cytoskeletal integrity (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar). The EMT-associated relaxation of cytoskeletal organization enables formation of membrane protrusions, such as membrane ruffles, lamellipodia, and filopodia. Lamellipodia allow for adhesion through integrins and cadherins and promote increased motility, whereas filopodia may have more of a sensory function with key roles in directing migration (Ridley, 2011Ridley A.J. Life at the leading edge.Cell. 2011; 145: 1012-1022Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar). As cells move directionally, RhoA regulates cell de-adhesion and retraction at the trailing rear (Lawson and Ridley, 2018Lawson C.D. Ridley A.J. Rho GTPase signaling complexes in cell migration and invasion.J. Cell Biol. 2018; 217: 447-457Crossref PubMed Scopus (133) Google Scholar). Finally, EMT is often accompanied by increased protease expression to facilitate invasion through ECM or basement membrane, in particular of MMP-2, MMP-9, and MT1-MMP (Lamouille et al., 2014Lamouille S. Xu J. Derynck R. Molecular mechanisms of epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2014; 15: 178-196Crossref PubMed Scopus (3744) Google Scholar). These proteases are concentrated at the surface of invadopodia; these protrusions mediate matrix degradation, are enriched with β1 and αvβ3 integrins that interact with ECM proteins, and regulate Rho GTPase activity and actin remodeling (Ridley, 2011Ridley A.J. Life at the leading edge.Cell. 2011; 145: 1012-1022Abstract Full Text Full Text PDF PubMed Scopus (595) Google Scholar). Endothelial-mesenchymal transition (EndMT) largely resembles EMT, in phenotypic changes and underlying molecular mechanisms. EndMT results in loss of endothelial junctions and polarity, activation of EMT transcription factors that repress endothelial junction protein expression, upregulation of mesenchymal markers, and alterations in cytoarchitecture, cell shape, and motility. Cell-type-specific changes distinguish EndMT from EMT. Rather than repressing epithelial E-cadherin, endothelial cells downregulate the expression of vascular endothelial (VE)-cadherin, a key component of adherens junctions (Medici and Kalluri, 2012Medici D. Kalluri R. Endothelial-mesenchymal transition and its contribution to the emergence of stem cell phenotype.Semin. Cancer Biol. 2012; 22: 379-384Crossref PubMed Scopus (127) Google Scholar), and repress expression of CD31/PECAM-1, another adherens junction protein that controls endothelial cell-cell adhesion, and claudin 5, an endothelial tight junction protein. As is apparent from the many EMT-associated changes, epithelial and endothelial cells can repress their characteristic differentiation programs and concomitantly activate cellular and gene expression changes that are seen as mesenchymal. Substantial diversity is apparent among EMT programs, depending on cell origin and signals and cells in the microenvironment. Furthermore, EMT programs often seem to be partially executed, resulting in hybrid EMT that maintains epithelial properties with activated mesenchymal properties, including changes in gene expression and cell migration (Nieto et al., 2016Nieto M.A. Huang R.Y. Jackson R.A. Thiery J.P. EMT: 2016.Cell. 2016; 166: 21-45Abstract Full Text Full Text PDF PubMed Google Scholar; Pastushenko and Blanpain, 2019Pastushenko I. Blanpain C. EMT transition states during tumor progression and metastasis.Trends Cell Biol. 2019; 29: 212-226Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar). Considering the diversity of EMT programs and often incomplete EMTs, it is not possible or even appropriate to characterize EMTs, seen in normal physiological and pathological contexts, as a singular set of changes following a well-defined scenario. Additionally, some previously accepted characteristics should no longer be seen as EMT defining. Clearly, no universal set of EMT markers can and should be proposed, even though upregulation of one or another EMT transcription factor and (partial) repression of epithelial junctions are common (Derynck and Weinberg, 2019Derynck R. Weinberg R.A. EMT and cancer: more than meets the eye.Dev. Cell. 2019; 49: 313-316Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar; Yang et al., 2020Yang J. Antin P. Berx G. Blanpain C. Brabletz T. Bronner M. Campbell K. Cano A. Casanova J. Christofori G. et al.Guidelines and definitions for research on epithelial-mesenchymal transition.Nat. Rev. Mol. Cell Biol. 2020; 21: 341-352Crossref PubMed Scopus (98) Google Scholar). Additionally, that EMT gives rise to mesenchymal cells that migrate individually is a common misperception. Even following full-fledged EMT, cells still adhere to other cells and ECM, and adhesion is required for cell migration. Ameboid cell migration of single carcinoma cells has been observed, but it is unclear how ameboid phenotype and behavior relate to EMT (Madsen and Sahai, 2010Madsen C.D. Sahai E. Cancer dissemination--lessons from leukocytes.Dev. Cell. 2010; 19: 13-26Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Finally, cells that undergo EMT are generally thought to retain the ability to revert to the epithelial phenotype. While this is indeed often the case, in vivo and cell culture observations support the notion that in some developmental and cancer contexts EMT does not revert and that cell populations may retain or even enhance their mesenchymal properties. Hence, withdrawal of EMT-inducing signals may in many cases not be sufficient to revert cells to an epithelial phenotype; rather, instructive signals may additionally be required for reverse, mesenchymal-to-epithelial transitions (METs) (Gregory et al., 2011Gregory P.A. Bracken C.P. Smith E. Bert A.G. Wright J.A. Roslan S. Morris M. Wyatt L. Farshid G. Lim Y.-Y. et al.An autocrine TGF-β/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition.Mol. Biol. Cell. 2011; 22: 1686-1698Crossref PubMed Scopus (384) Google Scholar; Katsuno et al., 2019Katsuno Y. Meyer D.S. Zhang Z. Shokat K.M. Akhurst R.J. Miyazono K. Derynck R. Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition.Sci. Signal. 2019; 12eaau8544Crossref PubMed Scopus (48) Google Scholar; Zhang et al., 2014Zhang J. Tian X.J. Zhang H. Teng Y. Li R. Bai F. Elankumaran S. Xing J. TGF-β-induced epithelial-to-mesenchymal transition proceeds through stepwise activation of multiple feedback loops.Sci. Signal. 2014; 7: ra91Crossref PubMed Scopus (188) Google Scholar). The complexity of EMT responses inherently suggests that multiple signaling pathways need to cooperate (Dongre and Weinberg, 2019Dongre A. Weinberg R.A. New insights into the mechanisms of epithelial-mesenchymal tran" @default.
• W3137803078 created "2021-03-29" @default.
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• W3137803078 date "2021-03-01" @default.
• W3137803078 modified "2023-10-18" @default.
• W3137803078 title "Epithelial plasticity, epithelial-mesenchymal transition, and the TGF-β family" @default.
• W3137803078 cites W1215049722 @default.
• W3137803078 cites W1536072591 @default.
• W3137803078 cites W1565561072 @default.
• W3137803078 cites W1678482413 @default.
• W3137803078 cites W1752721376 @default.
• W3137803078 cites W1896587447 @default.
• W3137803078 cites W1921522108 @default.
• W3137803078 cites W1964847767 @default.
• W3137803078 cites W1966701340 @default.
• W3137803078 cites W1974645044 @default.
• W3137803078 cites W1976324983 @default.
• W3137803078 cites W1977376400 @default.
• W3137803078 cites W1977746306 @default.
• W3137803078 cites W1978317917 @default.
• W3137803078 cites W1978785485 @default.
• W3137803078 cites W1980157632 @default.
• W3137803078 cites W1980484515 @default.
• W3137803078 cites W1981656841 @default.
• W3137803078 cites W1983562016 @default.
• W3137803078 cites W1983575915 @default.
• W3137803078 cites W1983628734 @default.
• W3137803078 cites W1983661286 @default.
• W3137803078 cites W1983991097 @default.
• W3137803078 cites W1984413324 @default.
• W3137803078 cites W1986991531 @default.
• W3137803078 cites W1988947063 @default.
• W3137803078 cites W1992949513 @default.
• W3137803078 cites W1993913242 @default.
• W3137803078 cites W1995700570 @default.
• W3137803078 cites W1999133914 @default.
• W3137803078 cites W2002697796 @default.
• W3137803078 cites W2006305177 @default.
• W3137803078 cites W2007634515 @default.
• W3137803078 cites W2009410973 @default.
• W3137803078 cites W2010030796 @default.
• W3137803078 cites W2010672807 @default.
• W3137803078 cites W2014691022 @default.
• W3137803078 cites W2014835250 @default.
• W3137803078 cites W2017341363 @default.
• W3137803078 cites W2019214567 @default.
• W3137803078 cites W2022896763 @default.
• W3137803078 cites W2023213297 @default.
• W3137803078 cites W2023906705 @default.
• W3137803078 cites W2024460791 @default.
• W3137803078 cites W2026260372 @default.
• W3137803078 cites W2026759417 @default.
• W3137803078 cites W2028415754 @default.
• W3137803078 cites W2028919524 @default.
• W3137803078 cites W2029470215 @default.
• W3137803078 cites W2031334428 @default.
• W3137803078 cites W2032646886 @default.
• W3137803078 cites W2033550998 @default.
• W3137803078 cites W2034955793 @default.
• W3137803078 cites W2035409136 @default.
• W3137803078 cites W2036496674 @default.
• W3137803078 cites W2039161118 @default.
• W3137803078 cites W2039214381 @default.
• W3137803078 cites W2040834336 @default.
• W3137803078 cites W2042773343 @default.
• W3137803078 cites W2043797012 @default.
• W3137803078 cites W2052870089 @default.
• W3137803078 cites W2053785572 @default.
• W3137803078 cites W2054364834 @default.
• W3137803078 cites W2058536420 @default.
• W3137803078 cites W2060126259 @default.
• W3137803078 cites W2060928333 @default.
• W3137803078 cites W2064050439 @default.
• W3137803078 cites W2064209144 @default.
• W3137803078 cites W2068087430 @default.
• W3137803078 cites W2068337731 @default.
• W3137803078 cites W2068517905 @default.
• W3137803078 cites W2069202441 @default.
• W3137803078 cites W2069266255 @default.
• W3137803078 cites W2073554410 @default.
• W3137803078 cites W2076636899 @default.
• W3137803078 cites W2079210215 @default.
• W3137803078 cites W2080627387 @default.
• W3137803078 cites W2081601075 @default.
• W3137803078 cites W2082239705 @default.
• W3137803078 cites W2086324671 @default.
• W3137803078 cites W2086338128 @default.
• W3137803078 cites W2088106349 @default.
• W3137803078 cites W2089556804 @default.
• W3137803078 cites W2092513068 @default.
• W3137803078 cites W2093028734 @default.
• W3137803078 cites W2093157637 @default.
• W3137803078 cites W2093441706 @default.
• W3137803078 cites W2097829282 @default.
• W3137803078 cites W2099950968 @default.
• W3137803078 cites W2102707911 @default.
• W3137803078 cites W2103328690 @default.

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