Epithelial-to-mesenchymal transition | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Epithelial-to-mesenchymal transition

Encyclopedia of Cancer, 2015

List of abbreviations

ECM — Extracellular matrix

EMT — Epithelial-mesenchymal transition

MET — Mesenchymal-epithelial transition

NF-kB — Nuclear factor kB

SMA — Smooth muscle actin

TGF-β1 — Transforming growth factor-β1


Phenotypic alterations in which epithelial cells adopt characteristics of mesenchymal cells. Epithelial-mesenchymal transition (EMT) is a physiological process during normal development and a pathological process during cancer progression and fibrosis.


Epithelial cells line external surfaces and internal cavities of the body. A distinguishing characteristic of epithelial cells is the presence of junctional complexes, such as tight junctions, adherens junctions, and desmosomes, and segregation of plasma membrane into apical and basolateral domains. These features promote adhesion, restrict motility, facilitate intercellular communication, and permit individual cells to function as a cohesive unit. The phenotype of epithelial cells cultured in vitro or in tissues is often described as well differentiated (Fig. 1, left panel).

Mesenchymal cells are spindle shaped with fibroblast-like morphology, lack adhesiveness, and are highly motile. They do not have junctional complexes and specialization of the plasma membrane into apical and basolateral domains. When cells of epithelial origin show a mesenchymal phenotype under in vitro culture conditions or in tissues, they are often described as poorly differentiated (Fig. 1, right panel).

The plasticity of epithelial cells enables them to convert between the epithelial and mesenchymal phenotypes. These phenotypic transformations are highly regulated by specific signaling events and molecules. Conversion of the epithelial cell to a mesenchymal phenotype is known as epithelial-mesenchymal transition (EMT) and vice versa as mesenchymal-epithelial transition (MET). EMT and MET occur during normal development as well as in cancer progression.

EMT provides a mechanism for epithelial cells to overcome the physical constraints imposed upon them by intercellular junctions and to adopt a motile phenotype. The process was originally identified during specific stages of embryogenesis in which epithelial cells migrate and colonize various embryonic territories to form different organs. EMT is critical for the formation of ectoderm, mesoderm, and endoderm during gastrulation as well as for the differentiation of neural crest cells into neurons and glia of the peripheral nervous system. During embryogenesis EMT is spatially and temporally regulated in a subtle manner that is essential for normal organ development. Activation of the EMT program depends on the convergence of multiple cues that are both intrinsic to the cell and received from the microenvironment.

EMT during cancer progression occurs in an aggressive and uncontrolled fashion and might facilitate the invasive and metastatic potentials of cancer cells. The phenotypic conversion of epithelial cells to mesenchymal cells involves a series of events that includes dissolution of tight junctions, adherens junctions, and desmosomes, the suppression of molecules involved in restricting invasiveness and motility, and induction of factors that promote invasiveness and motility and gain of stem cell attributes. EMT can also occur as a partial transition when the phenotypic conversion is not complete. A characteristic feature of cells undergoing EMT in culture is the change in the organization of the actin cytoskeleton. In most cases stress fibers are induced with a concomitant loss of the cortical actin ring. Although it is established that such morphological changes accompany EMT, the chronology of these events is still not deciphered. It is also not known whether all these changes are essential for induction of EMT and the metastatic potential of cancer cells.


EMT is in part achieved by downregulation of epithelial-specific molecules and induction of proteins expressed in mesenchymal cells. One of the epithelial cell molecules extensively studied that change during EMT is the cell-cell adhesion molecule E-cadherin. During epithelial morphogenesis, E-cadherin regulates the establishment of adherens junctions, which form a continuous adhesive belt below the apical surface. The extracellular domain of E-cadherin mediates calcium-dependent homotypic interactions with E-cadherin molecules on adjacent cells, and the intracellular domain binds cytosolic catenins and links the E-cadherin complex to the actin cytoskeleton. A stable E-cadherin complex at the plasma membrane is essential for the cell-cell adhesion function of this protein.

Several studies have shown that expression of E-cadherin is reduced during EMT, associated with the loss of junctional complexes and the induction of a mesenchymal phenotype of carcinoma cells. It is believed that the decrease in adhesive force following reduced expression of E-cadherin facilitates invasion and dispersion of carcinoma cells from the primary tumor mass. Methods to abolish E-cadherin function promote epithelial cell invasion into a variety of substrates, as determined by a number of in vitro and in vivo experimental systems. Loss or reduced expression of E-cadherin is also accompanied by expression of mesenchymal markers such as vimentin, smooth muscle actin (SMA), g-actin, b-filamin, and talin and extracellular matrix (ECM) components such as fibronectin and collagen precursors. Upregulation of these proteins facilitates cytoskeletal remodeling and promotes cell motility (Table 1).

The diverse molecular mechanisms mediated by growth factors and extracellular matrix proteins contribute to EMT. Growth factors such as epidermal growth factor (EGF), hepatocyte growth factor (HGF), or insulin growth factor II (IGF-II) promote signaling cascades through their cognate receptor tyrosine kinases, which in turn signal through various downstream effector molecules such as Ras, Src, phosphatidylinositol- 3-kinase (PI3K), and MAPK leading to EMT. In addition, signaling pathways essential for stem cell function during development such as the Wnt, Notch, and Hedgehog signaling pathways are activated during EMT. The role of Wnt signaling has been well established during normal development as well as in EMT. Binding of the soluble ligand Wnt to its receptor frizzled inhibits b-catenin degradation and facilitates its nuclear translocation together with the TCF/LEF transcription factors to activate transcription of target genes such as cyclin D1 and Myc. The transcriptional activity of b-catenin is increased in a wide variety of cancers as well as in growth factor-induced EMT of cultured cells.

A key molecule involved in the induction of EMT and extensively studied is the transforming growth factor- β1 (TGF-β1). The TGF-β growth factor superfamily comprises TGF-βs, bone morphogenetic proteins (BMPs), activins, and other related proteins. TGF-β induces EMT in epithelia either through transcriptional- or transcription-independent mechanisms. Cooperation between TGF-β and Ras/Raf/MEK/MAPK signaling is involved in the induction and maintenance of EMT. TGF-β has been shown to stimulate ERK1/2 activity in cell culture models of EMT that is required for the disassembly of junctional complexes and the induction of motility. TGF-β also activates phosphatidylinositol-3-kinase (PI3K) in a RhoA-dependent manner, which has been implicated in the disassembly of tight junctions. In keratinocytes and several epithelial cell types, TGF-β treatment activates the Notch pathway by inducing the Notch ligand jagged1 and the Notch target genes TLE3, HEY1, HEY2, and HES1 at the onset of EMT. TGF-β, in cooperation with oncogenic Ras, induces EMT by the activation of the transcription factor nuclear factor k B (NF-kB). Constitutive activation of NF-kB induces EMT and metastasis, whereas inhibition of NF-kB by inhibitory IkBa suppresses EMT and metastasis in a breast tumor model. Although in different cell types TGF-β induces various signaling pathways, these signals subsequently target E-cadherin expression and the disassembly of epithelial junctional complexes to induce EMT. For example, the TGF-β type I receptor is localized to tight junctions through the tight junction protein occludin allowing for efficient TGF-β-dependent dissolution of tight junctions during EMT. The epithelial polarity protein Par-6 interacts with the TGF-β type I receptor and TGF-β binding initiates Par-6 phosphorylation and activation of the E3-ubiquitin ligase, Smurf-1. Activated Smurf-1 promotes degradation of local RhoA resulting in .tight junction dissociation, inhibition of cell adhesion, and transition to a mesenchymal phenotype.

The signaling cascades described above induce two major types of transcriptional regulators that mediate EMT, zinc finger (Snail, Slug, ZEB-1, ZEB-2) and basic helix-loop-helix (Twist, E12/E47) proteins. The transcription suppressors SNAI1 (Snail) and SNAI2 (Slug) play a central role in the induction of EMT. These zincfinger proteins recognize E-box elements in the cognate target promoters, and SNAI1 represses the transcription of the E-cadherin gene during EMT as well as embryonic development. Factors that regulate SNAI1 by phosphorylation, subcellular localization, and transcription have been well described in development and EMT. While phosphorylation of SNAI1 in the two GSK3b phosphorylation consensus motifs targets it for export from the nucleus (motif 2) and ubiquitinylation and degradation (motif 1), phosphorylation of SNAI1 at Ser246 by p21-activated kinase (PAK1) results in its accumulation in the nucleus and induction of EMT. LIV-1, an estrogenregulated member of the LZT subfamily of zinc transporters, is activated by STAT3, which is essential for nuclear localization of SNAI1 and suppression of E-cadherin expression during gastrulation in zebrafish embryos. Further, SNAI1 expression is transcriptionally suppressed by metastasis-associated gene 3 (MTA3), a subunit of the Mi-2/NuRD transcriptional corepressor, thereby establishing a mechanistic link between estrogen receptor status and invasive growth of breast cancers. While there is great deal of knowledge about SNAI1 regulation, much less is known about SNAI2. It has been shown that SNAI2 suppresses E-cadherin expression when ectopically expressed in welldifferentiated epithelial cells. HGF and FGF induce SNAI2 to suppress desmoplakin and desmoglein, thereby destabilizing desmosomes. The SMAD-interacting repressors SIP-1/ZEB2 and dEF1/ZEB1 that can be induced by TGF-β bind to the E-cadherin promoter to suppress its transcription. The basic helix-loop-helix transcription factors involved in the induction of EMT are E12/E47 (E2A gene product) and Twist, both of which have been shown to repress E-cadherin expression and induce EMT. The mechanisms by which these factors suppress E-cadherin expression are not well established but recent work emphasized the importance of microRNAs and epigenetic factors.

Clinical relevance

Although EMT represents a fundamentally important process for tumor dissemination and is widely believed to be an essential event involved in cancer metastasis, there are several lines of evidence to suggest that many invasive and metastatic carcinomas have not undergone a complete transition to a mesenchymal phenotype. Many advanced carcinomas of prostate, breast, squamous cell carcinomas derived from a variety of origins, including the esophagus, oral epithelium, lung, cervix, and salivary neoplasms, possess molecular and morphological characteristics of well-differentiated epithelial cells, with the presence of epithelial junctions and apicalbasolateral plasma membrane asymmetry. High E-cadherin expression was also observed in a wide variety of carcinomas and E-cadherin levels did not correlate with invasiveness and metastasis. These results are consistent with the idea that complete EMT might not be necessary for cancer cell metastasis or that cancer cells redifferentiate to an epithelial phenotype following metastasis. While EMT is well established in cultured cells, there is little evidence for EMT in vivo and if EMT occurs it is not known at what stage of tumor progression. There are several possibilities by which cancer cells could spread without undergoing complete EMT: (1) incomplete EMT by which epithelial cells partially convert to a mesenchymal phenotype acquiring invasive and metastatic potential, (2) cohort migration in which well-differentiated epithelial cells migrate as a cluster and cause metastasis, and (3) reversion of poorly differentiated cells to a well- differentiated phenotype by mesenchymalepithelial transition (MET) at the site of metastasis. These diverse mechanisms might be regulated by the tumor microenvironment and/or signaling pathways distinct from the molecular machinery of EMT. Thus, there are several mechanisms by which cancer cells could metastasize and EMT may represent one of the global changes associated with malignant transformation of epithelial cells. Recognizing EMT as a fundamentally important process for tumor dissemination together with the increasing knowledge about the molecular pathways leading to EMT may offer new targets for therapeutic intervention. Indeed, inhibitors of the TGF-β, ERK1/2, and PI3K/Akt pathways have shown encouraging results in the suppression of tumor progression. Further understanding of the molecular requirements of EMT will allow for more effective approaches for future therapeutic intervention.

Epithelial-to-mesenchymal transition (Энц. канцера 2012)

Fig. 1. Transitions between well-differentiated epithelial cells and poorly differentiated mesenchymal cells during EMT. Left panel, phase contrast microscopy and schematic diagram of well-differentiated polarized epithelial cells with characteristic apical-basolateral polarity and junctional complexes. Right panel, cells that have undergone EMT display mesenchymal morphology with no junctions and are highly motile and invasive. The process of reversion of mesenchymal cells to an epithelial phenotype is called mesenchymal-epithelial transition (MET)

Table 1. Markers of EMT

Increased abundance/activity
Epithelial-mesenchymal markers N-cadherin



Smooth muscle actin




Collagen precursors


Stress fibers

Signal transduction molecules/pathways Epidermal growth factor (EGF)

Fibroblast growth factor (FGF)

Hepatocyte growth factor (HGF)

Insulin growth factor (IGF)

Platelet-derived growth factor (PDGF)

Transforming growth factor (TGF-β)














Transcriptional regulators Snail








DNA methylation

Histone acetylation

Decreased abundance/activity
Epithelial-mesenchymal markers E-cadherin







Actin cytoskeleton — The actin cytoskeleton is a dynamic structure of actin bundles and networks in the cytoplasm that provides a framework to maintain cell shape, protects the cell, and enables cell locomotion. It also plays an important role in intracellular transport.

Epigenetics — Mechanisms that impose a cellular phenotype without a change in its nucleotide sequence and largely achieved by covalent modification of DNA and histone proteins through methylation and acetylation.

Epithelial cell — Epithelial cells line and protect both the outside and the inside cavities and lumen of the body. They regulate selective permeability and transcellular transport between the compartments they separate and are involved in secretion absorption and sensation detection.

Microenvironment — Biophysical and biochemical factors in the immediate vicinity of a cell that directly or indirectly affect the behavior of a cell. The microenvironment is composed of extracellular matrix homotypic and heterotypic cells, soluble factors including cytokines, ormones and other bioactive agents, and mechanical forces.

Stem cell — Undifferentiated cell capable of dividing and renewing itself for long time periods and with the potential to develop into different cell types.


Chapman HA (2011) Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 73:413–435

De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13:97–110

Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428

Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196

Lindsey S, Langhans SA (2014) Crosstalk of oncogenic signaling pathways during epithelial-mesenchymal transition. Front Oncol 4:358

Moreno-Bueno G, Portillo F, Cano A (2008) Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27:6958–6969

Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19:1438–1449

Thiery JP, Acloque H, Huang RY, Nieto MA (2009) — Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890