Epithelial-Mesenchymal Transition
2009; Elsevier BV; Volume: 174; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2009.080545
ISSN1525-2191
AutoresMichael W. Klymkowsky, Pierre Savagner,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoEpithelial-mesenchymal transition (EMT) describes a series of rapid changes in cellular phenotype. During EMT, epithelial cells down-modulate cell-cell adhesion structures, alter their polarity, reorganize their cytoskeleton, and become isolated, motile, and resistant to anoikis. The term EMT is often applied to distinct biological events as if it were a single conserved process, but in fact EMT-related processes can vary in intensity from a transient loss of cell polarity to the total cellular reprogramming, as found by transcriptional analysis. Based on clinical observations, it is more appropriate in most cases to describe the emergence of an EMT-like phenotype during tumor progression. Although EMT implies complete trans-differentiation, EMT-like emphasizes the intermediary phenotype associated with tumor cell renewal and adaptation to specific microenvironments. Here, we categorize the various EMT-like phenotypes found in human carcinomas that, depending on the tumor type, may or not represent analogous stages in tumor progression. We based these categories on the global tumor phenotype. The tumor microenvironment, which is associated with stromal reactions, hypoxia, paucity of nutrients, impaired differentiation, and activation of various EMT-associated pathways, modulates overall tumor phenotype and leads to tumor heterogeneity. Epithelial-mesenchymal transition (EMT) describes a series of rapid changes in cellular phenotype. During EMT, epithelial cells down-modulate cell-cell adhesion structures, alter their polarity, reorganize their cytoskeleton, and become isolated, motile, and resistant to anoikis. The term EMT is often applied to distinct biological events as if it were a single conserved process, but in fact EMT-related processes can vary in intensity from a transient loss of cell polarity to the total cellular reprogramming, as found by transcriptional analysis. Based on clinical observations, it is more appropriate in most cases to describe the emergence of an EMT-like phenotype during tumor progression. Although EMT implies complete trans-differentiation, EMT-like emphasizes the intermediary phenotype associated with tumor cell renewal and adaptation to specific microenvironments. Here, we categorize the various EMT-like phenotypes found in human carcinomas that, depending on the tumor type, may or not represent analogous stages in tumor progression. We based these categories on the global tumor phenotype. The tumor microenvironment, which is associated with stromal reactions, hypoxia, paucity of nutrients, impaired differentiation, and activation of various EMT-associated pathways, modulates overall tumor phenotype and leads to tumor heterogeneity. EMT describes a rapid and often reversible change of cell phenotype. EMT was originally defined in the context of the cellular remodeling that occurs during heart morphogenesis,1Bolender D Markwald R Epithelial-mesenchymal transformation in chick atrioventricular cushion morphogenesis.Scan Electron Microsc. 1979; 3: 313-321PubMed Google Scholar but has been applied to a range of events, including mesoderm and neural crest formation.2Savagner P Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition.Bioessays. 2001; 23: 912-923Crossref PubMed Scopus (607) Google Scholar The reverse process, mesenchymal-epithelial transition also occurs during development.3Baum B Settleman J Quinlan M Transitions between epithelial and mesenchymal states in development and disease.Semin Cell Dev Biol. 2008; 19: 294-308Crossref PubMed Scopus (332) Google Scholar During EMT, epithelial cells lose their characteristic cell-cell adhesion structures, change their polarity, modulate the organization of their cytoskeletal systems, switch expression from keratin- to vimentin-type intermediate filaments, and become isolated, motile, and resistant to anoikis.4Stockinger A Eger A Wolf J Beug H Foisner R E-cadherin regulates cell growth by modulating proliferation-dependent beta-catenin transcriptional activity.J Cell Biol. 2001; 154: 1185-1196Crossref PubMed Scopus (277) Google Scholar, 5Valdés F Alvarez A Locascio A Vega S Herrera B Fernández M Benito M Nieto M Fabregat I The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes.Mol Cancer Res. 2002; 1: 68-78PubMed Google Scholar EMT bears at least a superficial resemblance to the metastatic transition of normal cells during epithelial tumor progression. The relevance of EMT to tumor progression was refined and explored in vitro using epithelial cell models, most notably by Greenburg and Hay.6Greenburg G Hay E Cytodifferentiation and tissue phenotype change during transformation of embryonic lens epithelium to mesenchyme-like cells in vitro.Dev Biol. 1986; 115: 363-379Crossref PubMed Scopus (92) Google Scholar Greenburg and Hay transformed epithelial cells into individualized motile cells through manipulations with growth factors or extracellular matrix components.6Greenburg G Hay E Cytodifferentiation and tissue phenotype change during transformation of embryonic lens epithelium to mesenchyme-like cells in vitro.Dev Biol. 1986; 115: 363-379Crossref PubMed Scopus (92) Google Scholar Early EMT models include the transformation of lens epithelial cells growing in collagen gels,7Greenburg G Hay ED Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells.J Cell Biol. 1982; 95: 333-339Crossref PubMed Scopus (515) Google Scholar NBT-II carcinoma cells responding to fibroblast growth factor,8Boyer B Tucker G Valles A Franke W Thiery J Rearrangements of desmosomal and cytoskeletal proteins during the transition from epithelial to fibroblastoid organization in cultured rat bladder carcinoma cells.J Cell Biol. 1989; 109: 1495-1509Crossref PubMed Scopus (185) Google Scholar and MDCK cells responding to hepatocyte growth factor/scatter factor.9Li Y Joseph A Bhargava M Rosen E Nakamura T Goldberg I Effect of scatter factor and hepatocyte growth factor on motility and morphology of MDCK cells.In Vitro Cell Dev Biol. 1992; 28: 364-368Crossref Scopus (23) Google Scholar, 10Uehara Y Kitamura N Expression of a human hepatocyte growth factor/scatter factor cDNA in MDCK epithelial cells influences cell morphology, motility, and anchorage-independent growth.J Cell Biol. 1992; 117: 889-894Crossref PubMed Scopus (43) Google Scholar, 11Weidner K Sachs M Birchmeier W The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells.J Cell Biol. 1993; 121: 145-154Crossref PubMed Scopus (374) Google Scholar Throughout the years, many more models have been described, and a number of genes have been implicated in EMT-like behavior of tumor cells.12Waerner T Alacakaptan M Tamir I Oberauer R Gal A Brabletz T Schreiber M Jechlinger M Beug H ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells.Cancer Cell. 2006; 10: 227-239Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar As is often the case, genes active (and activated) during the course of carcinoma progression and metastasis are also active in other processes, specifically during early embryogenesis, tissue morphogenesis, and wound healing.2Savagner P Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition.Bioessays. 2001; 23: 912-923Crossref PubMed Scopus (607) Google Scholar, 13Thiery JP Sleeman JP Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3223) Google Scholar, 14Berx G Raspe E Christofori G Thiery JP Sleeman JP Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer.Clin Exp Metastasis. 2007; 24: 587-597Crossref PubMed Scopus (205) Google Scholar, 15Dow LE Humbert PO Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis.Int Rev Cytol. 2007; 262: 253-302Crossref PubMed Scopus (102) Google Scholar This has lead to the idea that EMT, as it occurs in the course of developmental events, is reactivated during tumor progression. The popularity of this idea is suggested by the fact that a recent search on epithelial-mesenchymal transition and cancer using PubMed (NCBI, NIH) yielded more than 463 references (accessed 11/26/2008). On the other hand, a number of pathologists have objected to the assumption that EMT is relevant to cancer progression because of the lack of direct clinical evidence and unambiguous molecular markers.16Tarin D Thompson EW Newgreen DF The fallacy of epithelial mesenchymal transition in neoplasia.Cancer Res. 2005; 65: 5996-6001Crossref PubMed Scopus (435) Google Scholar A re-evaluation of the literature suggests that there are good reasons to make a clear distinction between EMT sensu stricto and the EMT-like phenotype observed in carcinoma. By definition, the term EMT applies only to epithelial-derived cancers (carcinomas), which account for 90% of human tumors. To intravasate and metastasize, epithelial cells must, at least transiently, down-regulate their cell-cell adhesion structures.14Berx G Raspe E Christofori G Thiery JP Sleeman JP Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer.Clin Exp Metastasis. 2007; 24: 587-597Crossref PubMed Scopus (205) Google Scholar The loss of cell-cell adhesion, however, does not make an EMT! Perhaps the major obstacle in identifying EMT-specific events is the lack of definitive markers for post-EMT cells. For example, keratin expression is routinely used by pathologists to identify epithelial-derived carcinoma cells,17Barak V Goike H Panaretakis KW Einarsson R Clinical utility of cytokeratins as tumor markers.Clin Biochem. 2004; 37: 529-540Crossref PubMed Scopus (290) Google Scholar but cannot be used to identify post-EMT cells because these cells should (if an actual EMT event were taking place) no longer express keratin. In fact, post-EMT epithelial cells will be phenotypically similar to (normal) vimentin-expressing stromal cells. Several groups have attempted to decipher the clonal origins of the epithelial and mesenchymal components of tumors by comparative genotypic analysis using microsatellite markers.18Halachmi S DeMarzo A Chow N Halachmi N Smith A Linn J Nativ O Epstein J Schoenberg M Sidransky D Genetic alterations in urinary bladder carcinosarcoma: evidence of a common clonal origin.Eur Urol. 2000; 37: 350-357Crossref PubMed Scopus (61) Google Scholar, 19Dacic S Finkelstein S Sasatomi E Swalsky P Yousem S Molecular pathogenesis of pulmonary carcinosarcoma as determined by microdissection-based allelotyping.Am J Surg Pathol. 2002; 26: 510-516Crossref PubMed Scopus (106) Google Scholar, 20Fujii H Yoshida M Gong Z Matsumoto T Hamano Y Fukunaga M Hruban R Gabrielson E Shirai T Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity.Cancer Res. 2000; 60: 114-120PubMed Google Scholar, 21Thompson L Chang B Barsky S Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis.Am J Surg Pathol. 1996; 20: 277-285Crossref PubMed Scopus (317) Google Scholar In fact, some less common tumors such as phyllodes tumors of the prostate were found to combine stromal and epithelial components with distinct clonal origins.22McCarthy R Zhang S Bostwick D Qian J Eble J Wang M Lin H Cheng L Molecular genetic evidence for different clonal origins of epithelial and stromal components of phyllodes tumor of the prostate.Am J Pathol. 2004; 165: 1395-1400Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar This strategy has been problematic, however, when applied to more prevalent mammary invasive ductal carcinomas: transformed stroma cells share chromosomal rearrangements with transformed epithelial cells, suggesting common origin, but also contain stroma-specific rearrangements.23Fukino K Shen L Matsumoto S Morrison C Mutter G Eng C Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets.Cancer Res. 2004; 64: 7231-7236Crossref PubMed Scopus (124) Google Scholar, 24Moinfar F Man YG Arnould L Bratthauer GL Ratschek M Tavassoli FA Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis.Cancer Res. 2000; 60: 2562-2566PubMed Google Scholar, 25Howe JR Roth S Ringold JC Summers RW Jarvinen HJ Sistonen P Tomlinson IP Houlston RS Bevan S Mitros FA Stone EM Aaltonen LA Mutations in the SMAD4/DPC4 gene in juvenile polyposis.Science. 1998; 280: 1086-1088Crossref PubMed Scopus (762) Google Scholar A clearer situation is found in carcinosarcoma, rare tumors mostly described in uterus and lung, which display a mix of epithelial and mesenchymal cell types. Most studies indicate that these tumors are derived from a common epithelial progenitor that gives rise to a mesenchymal subpopulation presumably through an EMT-like process. An important distinction arises because of the poorly differentiated state of many carcinoma cells. Their phenotype may reflect a dedifferentiation rather than a trans-differentiation process, such as occurs during EMT. From this perspective, transformed epithelial progenitors/stem cells may simply fail to differentiate normally, rather than differentiate into mesenchymal cells. If this is the case, the use of the term EMT is inappropriate and confusing, because it is misleading about the origin of the cells (Figure 1). To address this issue, we suggest using the term EMT-like as a more descriptive and accurate term to describe the phenotypes of epithelial cancers, because it does not imply a specific mechanism or the origin of the cells described. We propose three functional criteria to define EMT-like phenotypes in human carcinomas: i) state of cell polarization, ii) state of cell cohesiveness, and iii) intermediate filament protein expression. Based on these criteria we define the following four EMT-like phenotypes: phenotype 0: differentiated tumor cells with preserved epithelial structure and cell polarity; phenotype 1: most tumor cells display loss of cell polarity,15Dow LE Humbert PO Polarity regulators and the control of epithelial architecture, cell migration, and tumorigenesis.Int Rev Cytol. 2007; 262: 253-302Crossref PubMed Scopus (102) Google Scholar but retain cohesive cell-cell contacts and keratin expression; phenotype 2: there is loss of cell-cell adhesion in most tumor cells, but the cells still express keratins; phenotype 3: there is loss of keratin expression and substantial expression of vimentin in most tumor cells. Considering the phenotypic heterogeneity of most human tumors, this classification does not preclude that some tumor area may show distinct phenotypic features. That said, most tumors display a dominant phenotype that can be used by pathologists for typing. We, therefore, applied this scheme to human carcinoma types based on reference works,26Rosai J Ackerman L Surgical Pathology. ed 4. Mosby, New York2004Google Scholar, 27Kufe DW Pollock RE Weichselbaum RR Bast Jr, RC Gansler TS Holland JF Frei III, E Cancer Medicine. 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Some of the criteria we suggest here for EMT-like phenotyping are routinely used by pathologists. For example, expression of E-cadherin, a major player in epithelial cell-cell adhesion, is used to differentiate breast invasive ductal carcinomas that express E-cadherin protein and invasive lobular carcinomas that do not.31Derksen PWB Liu X Saridin F van der Gulden H Zevenhoven J Evers B van Beijnum JR Griffioen AW Vink J Krimpenfort P Peterse JL Cardiff RD Berns A Jonkers J Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis.Cancer Cell. 2006; 10: 437-449Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar, 32Moll R Mitze M Frixen U Birchmeier W Differential loss of E-cadherin expression in infiltrating ductal and lobular breast carcinomas.Am J Pathol. 1993; 143: 1731-1742PubMed Google Scholar In summary, there are limited but therapeutically significant numbers of carcinomas with phenotypes 2 and 3, involving poorly differentiated cells that may remain partially cohesive.Table 1EMT-Like Phenotypes in Human CarcinomasGeneral tumor typeTumor subtypeEMT-like stageBladder cancerTransitional cell carcinoma, papillary3Transitional cell carcinoma, solid3Carcinosarcoma1Breast cancerInvasive ductal carcinoma3Infiltrating lobular carcinoma2Carcinosarcoma1Colon and rectal cancerAdenocarcinomas3aCarcinosarcoma1Anal cancerEpidermoid carcinoma3Endometrial cancerAdenocarcinomas3Carcinosarcoma1Ovarian cancerSerous and mucinous carcinoma3Testicular cancerEmbryonal carcinoma, teratocarcinoma1Gastric cancerDiffuse gastric cancer2Intestinal gastric cancer3Head and neck cancerCarcinoma (squamous cell carcinoma)3Kidney (renal cell) cancerWilms2Renal cell carcinoma3Liver cancerHepatocellular carcinoma3Lung cancerSquamous cell carcinomas3Adenocarcinoma3Small cell lung carcinoma3bSpindle-cell carcinoma2Carcinosarcoma1Pancreatic cancerAdenocarcinomas3Prostate cancerAdenocarcinomas3Carcinosarcoma1Skin cancerBasal cell cancer3Squamous cell cancer3Spindle cell squamous cell1Melanoma3Thyroid cancerAdenocarcinoma3Anaplastic carcinomas2Malignant mesothelioma1We selected three functional criteria to define EMT-like phenotypes in human carcinomas, ranging from partial to total EMT-like phenotype: a) state of cell polarization, b) state of cell cohesiveness, and c) intermediate filament expression. Combination of these criteria helped us define the following four EMT-like phenotypes. Phenotype 0: differentiated tumor cells with preserved epithelial structure and cell polarity; phenotype 1: most tumor cells characterized by cellular depolarization; however, they retain cohesive cell-cell contacts and the expression of keratins; phenotype 2: loss of cell-cell adhesion in most tumor cells still expressing keratins; phenotype 3: loss of keratin and substantial expression of vimentin. Open table in a new tab We selected three functional criteria to define EMT-like phenotypes in human carcinomas, ranging from partial to total EMT-like phenotype: a) state of cell polarization, b) state of cell cohesiveness, and c) intermediate filament expression. Combination of these criteria helped us define the following four EMT-like phenotypes. Phenotype 0: differentiated tumor cells with preserved epithelial structure and cell polarity; phenotype 1: most tumor cells characterized by cellular depolarization; however, they retain cohesive cell-cell contacts and the expression of keratins; phenotype 2: loss of cell-cell adhesion in most tumor cells still expressing keratins; phenotype 3: loss of keratin and substantial expression of vimentin. Most carcinomas display histological heterogeneity. We and others14Berx G Raspe E Christofori G Thiery JP Sleeman JP Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer.Clin Exp Metastasis. 2007; 24: 587-597Crossref PubMed Scopus (205) Google Scholar, 33Côme C Magnino F Bibeau F De Santa Barbara P Becker KF Theillet C Savagner P Snail and slug play distinct roles during breast carcinoma progression.Clin Cancer Res. 2006; 12: 5395-5402Crossref PubMed Scopus (214) Google Scholar have suggested that only a small percentage of tumor cells ever undergo a total transition (corresponding to phenotype 3) and that it is these cells that are presumably the source of actively metastatic cells. Perhaps the best-documented example of this is the invasive front in colorectal carcinomas. Cells in this region usually express a less differentiated progenitor/stem cell phenotype34Brabletz T Jung A Spaderna S Hlubek F Kirchner T Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression.Nat Rev Cancer. 2005; 5: 744-749Crossref PubMed Scopus (1162) Google Scholar together with nuclear β-catenin, indicative of active canonical Wnt signaling. They are thought to play a critical role in the tumor invasion mechanism. A link between progenitor/stem cells and EMT-like grade is expected based on the immature epithelial phenotype of precursor cells.34Brabletz T Jung A Spaderna S Hlubek F Kirchner T Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression.Nat Rev Cancer. 2005; 5: 744-749Crossref PubMed Scopus (1162) Google Scholar Many molecules involved in progenitor/stem cell maintenance also appear to be involved in the regulation of cell motility, EMT, and EMT-like phenotypes. Among these proteins CD24, CD44, CD49/integrin (6, CD29/integrin β1), and Slug (Snail2) constitute good examples.35Brakebusch C Fassler R Beta 1 integrin function in vivo: adhesion, migration and more.Cancer Metastatsis Rev. 2005; 24: 403-411Crossref PubMed Scopus (182) Google Scholar, 36Baumann P Cremers N Kroese F Orend G Chiquet-Ehrismann R Uede T Yagita H Sleeman JP CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis.Cancer Res. 2005; 65: 10783-10793Crossref PubMed Scopus (277) Google Scholar, 37Hamilton SR Fard SF Paiwand FF Tolg C Veiseh M Wang C McCarthy JB Bissell MJ Koropatnick J Turley EA The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells.J Biol Chem. 2007; 282: 16667-16680Crossref PubMed Scopus (215) Google Scholar, 38Savagner P Kusewitt DF Carver EA Magnino F Choi C Gridley T Hudson LG Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes.J Cell Physiol. 2005; 202: 858-866Crossref PubMed Scopus (193) Google Scholar, 39Storci G Sansone P Trere D Tavolari S Taffurellii M Ceccarelli C Guarnieri T Paterini P Pariali M Montanaro L Santini D Chieco P Bonafe M The basal-like breast carcinoma phenotype is regulated by SLUG gene expression.J Pathol. 2008; 214: 25-37Crossref PubMed Scopus (141) Google Scholar Recently, work from R. Weinberg's laboratory40Mani S Guo W Liao M Eaton E Ayyanan A Zhou A Brooks M Reinhard F Zhang C Shipitsin M Campbel IL Polyak K Brisken C Yang J Weinberg R The epithelial-mesenchymal transition generates cells with properties of stem cells.Cell. 2008; 133: 704-715Abstract Full Text Full Text PDF PubMed Scopus (6787) Google Scholar has emphasized molecular links between EMT process and emergence of stemness. This is interesting because stemness is distinct from mesenchymal behavior. Epithelial cells initiate migration by becoming activated. Activation is considered a metastable phenotype,41Lee JM Dedhar S Kalluri R Thompson EW The epithelial-mesenchymal transition: new insights in signaling, development, and disease.J Cell Biol. 2006; 172: 973-981Crossref PubMed Scopus (1709) Google Scholar which combines incomplete differentiation, cell motility, and some cell-cell cohesiveness. It can be considered EMT-like. For example, during wound healing, immature basal keratinocytes are activated by changes in the local microenvironment and express such a metastable phenotype.38Savagner P Kusewitt DF Carver EA Magnino F Choi C Gridley T Hudson LG Developmental transcription factor slug is required for effective re-epithelialization by adult keratinocytes.J Cell Physiol. 2005; 202: 858-866Crossref PubMed Scopus (193) Google Scholar Their migration involves cohort migration, in which cells migrate as groups, not isolated cells. Similarly, during mammary gland tubulogenesis, cells located at the tip of growing tubule terminal end buds (cap cells) migrate as a group entity and express specific cadherins (P-cadherin). Interfering with cell-cell adhesion disrupts rather than enhances the migratory pattern.42Daniel CW Strickland P Friedmann Y Expression and functional role of E- and P-cadherins in mouse mammary ductal morphogenesis and growth.Dev Biol. 1995; 169: 511-519Crossref PubMed Scopus (142) Google Scholar This type of behavior is similar to that displayed by carcinoma cells expressing a metastable phenotype; it explains the cellular chords and partially differentiated tubules found in mammary invasive ductal carcinoma. Total lack of cohesiveness between carcinoma cells, more representative of EMT, represents a distinct mode of invasion present, for example, in infiltrating lobular carcinoma. This type of invasion is more insidious: although not inherently more invasive than invasive ductal carcinomas, it tends to be detected later during tumor progression, resulting in a poorer prognosis. The onset of both EMT and EMT-like events is associated with loss of cellular polarity, partial to total destabilization of cell-cell junctions, remodeling and replacement of cytoskeletal components, the onset of cell motility, and the suppression of apoptosis. In vitro and in vivo model systems have allowed the characterization of various pathways leading to EMT and EMT-like phenotypes. Such pathways are referred to as EMT pathways in this review, without assuming functional specificity. Five main pathways have been found to trigger EMT-associated processes13Thiery JP Sleeman JP Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3223) Google Scholar, 14Berx G Raspe E Christofori G Thiery JP Sleeman JP Pre-EMTing metastasis? 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A distinct EMT pathway has also been recently described involving the protein tyrosine phosphatase Pez.44Wyatt L Wadham C Crocker LA Lardelli M Khew-Goodall Y The protein tyrosine phosphatase Pez regulates TGFbeta, epithelial-mesenchymal transition, and organ development.J Cell Biol. 2007; 178: 1223-1235Crossref PubMed Scopus (71) Google Scholar In direct association with cancer progression, several molecules including ILEI,12Waerner T Alacakaptan M Tamir I Oberauer R Gal A Brabletz T Schreiber M Jechlinger M Beug H ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells.Cancer Cell. 2006; 10: 227-239Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 45Mackenzie NC Raz E Found in translation: a new player in EMT.Dev Cell. 2006; 11: 434-436Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar RKIP,46Beach S Tang H Park S Dhillon AS Keller ET Kolch W Yeung KC Snail is a repressor of RKIP transcription in metastatic prostate cancer cells.Oncogene. 2008; 27: 2243-2248Crossref PubMed Scopus (173) Google Scholar and CXCR447Yoon Y Liang Z Zhang X Choe M Zhu A Cho HT Shin DM Goodman MM Chen ZG Shim H CXC chemokine receptor-4 antagonist blocks both growth of primary tumor and metastasis of head and neck cancer in xenograft mouse models.Cancer Res. 2007; 67: 7518-7524Crossref PubMed Scopus (113) Google Scholar appear to control EMT-like phenotypes and tumor metastasis in mouse models.13Thiery JP Sleeman JP Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3223) Google Scholar, 14Berx G Raspe E Christofori G Thiery JP Sleeman JP Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer.Clin Exp Metastasis. 2007; 24: 587-597Crossref PubMed Scopus (205) Google Scholar Transcriptional down-regulation of junctional components accompanies the EMT process in several systems13Thiery JP Sleeman JP Complex networks orchestrate epithelial-mesenchymal transitions.Nat Rev Mol Cell Biol. 2006; 7: 131-142Crossref PubMed Scopus (3223) Google Scholar, 48Savagner P Yamada KM Thiery JP The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition.J Cell Biol. 1997; 137: 1403-1419Crossref PubMed Scopus (420) Google Scholar and may be either a cause or an effect of EMT-like events. 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These factors appear to be involved in most physiological EMT situations, and their overexpression in epithelial cell lines usually induces an EMT.48Savagner P Yamada KM Thiery JP The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition.J Cell Biol. 1997; 137: 1403-1419Crossref PubMed Scopus (420) Google Scholar, 50Batlle E Sancho E Franci C Dominguez D Monfar M Baulida J Garcia De Herreros A The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells.Nat Cell Biol. 2000; 2: 84-89Crossref PubMed Scopus (2172) Google Scholar, 51Bolós V Peinado H Perez-Moreno MA Fraga MF Esteller M Cano A The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors.J Cell Sci. 2003; 116: 499-511Crossref PubMed Scopus (931) Google Scholar, 52Yang J Mani S Donaher J Ramaswamy S Itzykson R Come C Savagner P Gitelman I Richardson A Weinberg R Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis.Cell. 2004; 117: 927-939Abstract Full Text Full Text PDF PubMed Scopus (3084) Google Scholar At the same time, detailed mechanism(s) of their effects remain unclear; cellular co-expression of Snail and E-cadherin has been described in breast and colon carcinomas by several groups.33Côme C Magnino F Bibeau F De Santa Barbara P Becker KF Theillet C Savagner P Snail and slug play distinct roles during breast carcinoma progression.Clin Cancer Res. 2006; 12: 5395-5402Crossref PubMed Scopus (214) Google Scholar, 53Becker KF Rosivatz E Blechschmidt K Kremmer E Sarbia M Hofler H Analysis of the E-cadherin repressor Snail in primary human cancers.Cells Tissues Organs. 2007; 185: 204-212Crossref PubMed Scopus (114) Google Scholar In addition, specificity of these transcription factors is clearly not restricted to E-cadherin regulation and the EMT process. 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What is clear is that EMT and EMT-like processes are influenced by the origin of the cells under consideration. Based on clinical observations, it appears more appropriate in most cases to describe the emergence of an EMT-like phenotype during tumor progression. This descriptive term does not necessarily imply an active dedifferentiation process but emphasizes an intermediary phenotype resulting from tumor cell renewal and adaptation to specific microenvironments. It clearly emphasizes the importance of better understanding cell population kinetics, survival, and differentiation mechanisms during tumor growth and metastasis.
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