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 Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 2  |  Page : 77-84

Epithelial-mesenchymal transition - A fundamental mechanism in cancer progression: An overview


Department of Oral Pathology and Microbiology, KLE VK Institute of Dental Sciences and Hospital, Belgaum, Karnataka, India

Date of Web Publication17-Jan-2016

Correspondence Address:
Punnya V Angadi
Department of Oral Pathology and Medicine, KLE VK Institute of Dental Sciences and Hospital, Belgaum - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2349-5006.174233

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  Abstract 

The epithelial-mesenchymal transition (EMT) has a significant role in embryogenesis. EMT is also implicated as a fundamental step development of invasive phenotypes associated with progression of cancer. EMT confers the cancer cells with migratory and invasive properties that allow them to come into the stroma, which creates a conducive environment for cancer progression and metastasis. Moreover, acquisition of EMT is linked with resistance to chemotherapy that could lead to recurrences and enhance the morbidity and mortality related to cancers. Consequently, EMT has been associated with carcinogenesis, invasion, metastasis, recurrence, and chemoresistance. Research into EMT and its role in cancer pathogenesis has advanced in a rapid pace, but since its participation shows considerable variation among different cancer types and the exact mechanism operative in different cancers remains ambiguous; EMT continues to be a significant issue for research. In this review, we present an overview of EMT, its role in cancer progression and the clinical implication of its identification.

Keywords: Cancer progression, epithelial mesenchymal transition, invasion, metastasis


How to cite this article:
Angadi PV, Kale AD. Epithelial-mesenchymal transition - A fundamental mechanism in cancer progression: An overview. Indian J Health Sci Biomed Res 2015;8:77-84

How to cite this URL:
Angadi PV, Kale AD. Epithelial-mesenchymal transition - A fundamental mechanism in cancer progression: An overview. Indian J Health Sci Biomed Res [serial online] 2015 [cited 2017 Dec 12];8:77-84. Available from: http://www.ijournalhs.org/text.asp?2015/8/2/77/174233


  Introduction Top


Cancer is exemplified as a disease that is characterized by unhindered proliferation of cells. The enormous bulk of human malignancies are carcinomas, and the incidence of metastases owing to tumor progression is the reason attributed to the majority of cancer-associated mortality. [1],[2] Since, cancer development is a multistep process characterized by the accumulation of genetic defects and mutations reflected by changes evident at the molecular level, the mechanisms involved in the development of cancer and subsequent metastases are crucial questions in comprehending cancer. Understanding of this process will aid in the detection of novel therapeutic strategies in the management of cancers and for designing future therapies. [3],[4] This highlights the requirement to recognize molecular conduits that could give a added accuracy and reliability to predict disease aggressiveness and clinical course. Epithelial-mesenchymal transition (EMT) is one such multifaceted molecular program in malignant transformation which causes loss of epithelial characteristics and gain in mesenchymal phenotype. [3] EMT is believed to be a vital mechanism for carcinoma progression and is associated with aggressive behavior of cancer cells. [3],[4] EMT is involved in morphogenesis during embryonic development, is attracting increasing attention as an important mechanism for the initial step of metastasis. Here, we present an overview of EMT, its role in cancer progression and the clinical implication of its identification.


  Epithelial Mesenchymal Transition Top


An EMT is a molecular program that allows the cell to go through multiple biochemical modification to attain a mesenchymal phenotype associated with enhanced migration, invasiveness and increased ability to resist apoptosis and considerably amplified secretion of extracellular matrix (ECM) components. [3],[4] The achievement of EMT is indicated by the breakdown of the basement membrane and formation of mesenchymal cell which migrates away from the epithelial layer of its origin [Figure 1]. [3],[4],[5]
Figure 1: Epithelial mesenchymal transition[3]

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Discovery and terminology

Elizabeth Hay in 1968 first demonstrated the epithelial cell plasticity and their ability to convert between epithelial and mesenchymal states via EMT and mesenchymal-epithelial transition (MET). [3] She proposed that epithelial cells undergo dramatic phenotypic changes that reflect their "transformation" to epithelial cells using a chick primitive streak model. It was agreed at the first meeting of the EMT International Association in Port Douglas, Australia (2003), that the term "EMT" was coined. This terminology is favored terminology as it reflects in part the reversibility of the process and the fact that this process is distinct from neoplastic transformation. [3],[4]

Defining the epithelial and mesenchymal phenotypes to decipher the concept of epithelial-mesenchymal transition

Epithelial cells

Epithelial cells are adherent cells that form attached layers as they are held together by intracellular adhesion complexes on their lateral surfaces. They exhibit an apicobasal polarity located on the basement membrane that separates them from the underlying connective tissues. They cannot migrate and contain keratin intermediate filaments. [6],[7]

Mesenchymal cells

Mesenchymal cells are usually individually present as spindle-shaped cells that have end-end polarity, do not have intercellular junctions, and have migratory capacity. They express mesenchymal proteins such as vimentin, fibronectin, alpha-smooth muscle actin (α-SMA). [6],[7]

EMT thus involves development of motile cells from the epithelial cells that by themselves do not have the ability to move [Table 1]. [3]
Table 1: Criteria for epithelial-mesenchymal transition[4]

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Classification of epithelial-mesenchymal transition

EMT's arise in three diverse settings with dissimilar functional consequences. [4]

Type 1 epithelial-mesenchymal transition

EMT associated with embryogenesis produces primary mesenchymal cells that can go through consequent MET to give rise to secondary epithelia. It has been demonstrated during implantation of embryo, placental development, during gastrulation for the creation of three germ layers and during the development of migratory neural crest cells. [3],[4]

Type 2 epithelial-mesenchymal transition

EMT linked to wound healing; repair and regeneration and in organ fibrosis. Here, the EMT program commences as a repair linked event generating fibroblasts and other cells for tissue reconstruction after trauma and inflammatory damage. This program generally ends once inflammation subsides, but in fibrosis, Type 2 EMT leads to organ damage due to its relentless response to continual inflammation. [3],[4]

Type 3 epithelial-mesenchymal transition

EMT in neoplastic cells is connected to genetic and epigenetic events, particularly involving genes that support clonal proliferation and formation of localized tumors. These changes affect the tumor suppressor genes and oncogenes that connive with the EMT regulatory system; leading to invasion through basement membrane and ensuing metastasis to distant locations signifying the beginning of the terminal stages in the multistep process of carcinogenesis. Type 3 EMT activation is projected to be the fundamental mechanism for achieving malignant phenotype by the cancer cells with life-threatening consequences. An obvious contradiction is the observation that the EMT-derived carcinoma cells typically set up secondary colonies at distant sites which resemble histopathologically the primary tumor from which they originated from, i.e., they no longer exhibit the mesenchymal phenotype seen in metastasizing carcinoma cells. Thus, EMT facilitates metastatic dissemination but requires that these cells should get rid of their mesenchymal phenotype via MET for generation of secondary tumor colonies at distant sites [Figure 2]. [3],[4],[5]
Figure 2: Types of epithelial mesenchymal transition[3]

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  Steps in Epithelial-Mesenchymal Transition Top


The process of EMT can be described into several steps, some of which may overlap and occur concurrently.

Numerous environmental factors can induce EMT such as growth factors, ECM constituents, proteases, and hypoxia. Once the epithelial cells become capable to react to these EMT-inducing signals, they promote loss of the cell-cell adhesion molecules and intervene to bring about loss of typical apicobasal polarity of the epithelial cells that leads to alteration in the shape. In addition, several cytoskeletal changes including development of apical constriction, disorganization of basal cytoskeleton, and expression of mesenchymal proteins permits the cells to gain migratory ability. [3] There is concurrent elevation in the protease activity leading to disruption of the basement membrane which leads to invasion of the cells into the ECM. Thus, upon experiencing EMT, the cells acquire migratory and invasive capacity that lets them to move away from the epithelium of their origin and pass through the ECM. [3],[4],[5],[6]

Biomarkers for epithelial-mesenchymal transition [Figure 3]

Cell surface markers

A change in expression of E-cadherin is the typical epithelial marker for EMT. Its expression is reduced during EMT in embryonic development, tissue fibrosis, and cancer.
Figure 3: Biomarkers of epithelial-mesenchymal transition

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Cadherin switch from E-cadherin to N-cadherin which is expressed in mesenchymal cells, fibroblasts, cancer cells and neural tissue has been used as a marker for EMT.

EMT has also been associated with relocation of cells from the basement membrane microenvironment into the fibrillar ECM, which is reflected by the change in the level of expression of different integrins (integrin switch).

Collagen-specific receptor tyrosine kinase (RTK) (DDR2) is a marker that reflects adaptation to the altered ECM environment associated with EMT. Its expression mediates up the regulation of matrix metalloproteinase (MMP) and cell motility and correlates with increased invasiveness of the cancer cells. [4],[5],[7],[8]

Cytoskeletal markers

Fibroblast-specific protein-1 (FSP-1) is a member of the family of calcium binding S-100 protiens and is a marker for detection of EMT in cancer and fibrosis. In tissue fibrosis, FSP-1 expression is demonstrable early in the transition to fibroblast as reported in kidney and liver fibrosis. [4],[10] In cancer, ectopic expression of FSP-1 facilitates EMT-Type 3 in cancer cells.

Vimentin is an intermediate filament protein expressed in various cells including fibroblasts, endothelial cells, cells of hemopioetic lineage and glial cells. This marker is often used to identify cells undergoing Type 3 EMT in cancer-based on the positive correlation of vimentin expression with increased invasiveness and metastases.

De novo expression of α-SMA has been demonstrated in the EMT that gives rise to endocardial cushion during embryonic development. Further, in tissue fibrosis, Type 2 EMT is associated with myofibroblasts which express α-SMA. In cancer, evidence related to α-SMA exists in breast cancers where this molecule has been detected predominantly in breast tumors of the basal phenotype. [12]

Beta-catenin is a cytoplasmic plaque protein that links cadherins to the cytoskeleton and serves as cotranscriptional activator thus playing a dual role in EMT. β-catenin has been used as a marker of EMT in various studies of embryonic development, cancer and tissue fibrosis as it directly controls the expression of genes associated with EMT. [4],[5],[7],[8]

Extracellular matrix proteins

Fibronectin is has been used as an indicator of Type 1 EMT associated with gastrulation, palate fusion, and neural crest migration. In addition, both Type 2 and Type 3 EMT are associated with increased fibronectin expression.

The basement membrane constituents such as Type 4 collagen, laminin, and nidogen are downregulated during EMT suggestive of the invasive and migratory capacity of cells undergoing EMT.

Laminin, especially laminin-1 is shown to be downregulated during gastrulation and palate fusion as well as in fibrotic diseases. Its upregulation has been linked with Type 3 EMT. [4],[5],[7],[8]

Transcription factors

Fibroblast transcription site-1 is a cis-acting regulatory element present in the various EMT-associated genes that encode key players such as FSP-1, twist, snail-1, E-cadherin, β-catenin, vimentin, and α-SMA.

Snail transcription factors are a prominent example of a common downstream target of various signaling pathways that regulate EMT. All known EMT events during development, fibrosis, and cancer appear to be associated with Snail activation.

Twist is a basic helix loop-helix protein that is transcriptionally active during lineage determination and cell differentiation. It is up-regulated in all three types of EMT.

Forkhead box C2 (FOXC2) is another transcription factor that induces EMT. During embryogenesis, FOXC2 expression is required for angiogenesis, musculogenesis, and organogenesis of kidney, heart, and urinary tract as well as in Type 3 EMT. [4],[5],[7],[8]


[Figure 4]">  Molecular Signaling Pathways of Epithelial-Mesenchymal Transition [Figure 4] Top


EMT is a highly complex process requiring extensive changes in adhesion, cell shape and gene expression. Therefore, its regulation is also multifaceted and various mechanisms have been identified leading to specific gene repression and activation, transduction signaling pathways, and a numerous mediator molecules conspire in controlling EMT. There is extensive cross-talking between numerous pathways leading to complex biochemical circuits. The key molecular change involved in EMT is down-regulation of E-cadherin that represents the critical step of reduction in cell-cell adhesion leading to disruption of epithelial architecture and is thus regarded as the "master regulator" of EMT phenotype switch.
Figure 4: Signaling pathways in epithelial-mesenchymal transition[8]

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E-cadherin expression regulation

E-cadherin gene expression can be altered by gene mutation, hypermethylation of E-cadherin promoter or by a change in cadherin expression, i.e., cadherin switch. This is characterized by gain in N-cadherin, which is typically expressed in mesenchymal cells. Direct transcriptional repression can also affect the E-cadherin. [8]

Receptor tyrosine kinases and their pathways

Phosphorylation and dephosphorylation of the RTK in response to binding of growth factors to their receptors enhances EMT. The important growth factors concerned are epidermal growth factor, fibroblast growth factor, hepatocyte growth factor, etc., which activate the tyrosine kinase receptors and downstream signaling pathway including Ras/MAPK, p13/Akt, Rho/Rac, Src, and Wnt-β-catenin signaling. [8]

Transforming growth factor-beta

Transforming growth factor-beta (TGF-β) is the most potent and best-characterized inducer of all three types of EMT. TGF-β signaling pathway is mediated by Type 1 and 2 transmembrane serine - theonine kinase receptors, which on phosphorylation, can act either by Smad-dependent or Smad-independent pathways.

Smad dependent pathway

TGF-β on binding activates Smad 2 and 3 that bind to Smad 4 which translocates to the nucleus to activate lymphoid enhancer-binding factor 1/T-cell factor transcription factor which release β-catenin and Smad leading to EMT. TFG-β also regulates E-cadherin expression by activation of Snail and slug through Smad signaling. It increases the expression of ZEB1 and SIP1 that promote repression of E-cadherin. In addition, TGF-β associated Smad complexes are known to increase N-cadherin, fibronectin and α-SMA expression.

Smad independent pathway

TGFβ can activate Ras/MAPK, p13 K/Akt, Rho/Rac and integrin-linked kinase (ILK), and Wnt/β-catenin pathways for induction of EMT.

In general, most of the downstream mediators of RTK, i.e., MAPK, p13k, and Rho GTPases cooperate with TFG-β to affect EMT. Thus, TGF-β is considered as the archetypal cytokine for induction of EMT as different isoforms mediate various aspects of EMT through diverse cellular mechanisms. [8]

Wnt/β-catenin pathway

Beta-catenin binds to E-cadherin and also transduces to the nucleus and is involved in transcription via the Wnt signaling pathway.

In absence of Wnt signal, β-catenin is associated with E-cadherin at the adherens junction and nonsequestered cytoplasmic β-catenin is rapidly phosphorylated by GSK3β in APC/GSK3β/Axin complex leading to its subsequent degradation by the ubiquitin-proteosome pathway. Wnt glycoprotein binds to frizzled receptor and inhibits GSK-3β degradation of β-catenin leading to its cytoplasmic accumulation. This may translocate to the nucleus and bind to LCF/TEF receptor leading to transcription of down-stream effector genes including Ets, jun, fos, slug, fibronectin, and vimentin for the development of EMT phenotype.

The Wnt signaling can also be activated by down-regulation of E-cadherin, which increases the β-catenin levels in the cytoplasm, or activation of ILK/p13 k/Akt pathway. MAP K/ERK can also bind GSK-3β and inactivate it, leading to increase β-catenin or can cause loss of E-cadherin leading to activation of β-catenin pathway. [6]

Extra cellular matrix components

The extra cellular matrix components, the matrix degrading proteases and integrins play important roles in EMT. Matrix-degrading proteases such as MMP 2, 9, 3, and uPA play an important role in the breakdown of basement membrane and interstitial matrix to create routes for migration of invading tumor cells. They modify the ECM microenvironment by its degradation and promoting the release of growth factors and cytokines which in turn affect cell behavior, release of survival and motility factor that induces cell scattering and migration. They can proteolyse the extracellular domain of E-cadherin leading to loss of cell-cell adhesion and β-catenin and activation of its signaling and E-cadherin derived invasion - promoting fragments. Increased deposition of collagen and structural changes of ECM due to fibrosis affect the mechanical environment of the cells leading to mechanical disruption of cell-cell contacts undergoing EMT to become motile and invasive; mostly, via integrin signaling. The epithelial cells on binding to ECM lead to integrin clustering at the adhesion and subsequent recruitment and activation of signaling proteins, including FAK, Src, Ras, p13k, and ILK. Especially, FAk is recruited to the focal adhesion sites either directly or by cytoskeletal proteins such as talin and paxillin. Upon activation, FAK undergoes phosphorylation, leading to binding and activation of Src which further phophorylates FAK. This results in activation of p13k/Akt pathway and Ras-MAPk signaling. FAK also activates paxillin which in turn can activate Rac-Rho pathway. [6-8]

MiRNA

MicroRNA's are noncoding RNAs involved in EMt and development of metastaisis. MiR10b overexpression is associated with invasiveness and metastatic potential in breast cancer and up-regulated by EMT transcription factor twist. Further, miR-200 family play critical roles in regulating EMT, leading to E-cadherin down regulation. [8-10]

Microenvironment and epithelial-mesenchymal transition

The tumor microenvironment is composed of the ECM, cancer-associated fibroblasts, myofibroblasts, immune cells, and soluble factors required for cancer progression and metastasis. Interaction among cancer cells in the tumor microenvironment can induce EMT by auto-and/or paracrine secretion of mediators such as growth factors, cytokines, and ECM proteins. TME associated EMT signaling pathways are numerous, complex and interrelated. They include - TGF-β, cytokines and NFK-β, Wnt-β-catenin, and notch pathways discussed earlier in the molecular regulation of EMT. [11]


[Figure 5]">  Epithelial Mesenchymal Transition in Cancer Progression [Figure 5] Top


Development and progression of normal mucosa to carcinoma involve numerous phases. The carcinoma with invasive capacity consists of epithelial cells that have lost their polarity and escaped through the basement membrane barrier. This is facilitated by the alteration in the basement membrane components, enhanced cell, and ECM connections that activate numerous signaling pathways that make the microenvironment conducive for the migration of the tumor cells in the connective tissue as a part of EMT. [8],[9],[10]
Figure 5: Epithelial-mesenchymal transition in cancer progression[2]

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Following invasion, EMT comes into play along with increased angiogenesis that facilitates development of metastatic phenotype. EMT enables the tumor cells to intravasate into the blood vessels and gain entry into the and also aids the tumor cells to egress from the blood stream to deposit themselves in a distant location where they can form secondary deposits (micro- and macrometastases). The metastatic deposits are formed by the reverse process, i.e. MET which requires that the cells revert back to the epithelial characteristics to adhere and colonize to form new tumors.

EMT is implicated in the invasion and metastatic behavior of epithelial cancer cells. It contributes in the invasiveness, metastatic spread, and resistance to various therapeutic modalities. MET occurs subsequent to dissemination and favors development of distant metastasis. [10]

Epithelial mesenchymal transition in various cancers

EMT has been identified in various cancers including breast carcinoma, nasopharyngeal carcinoma, hepatocellular carcinoma, esophageal carcinoma, ovarian carcinoma, lung carcinoma, prostate cancer and has been correlated with recurrence, poor prognosis, decreased survival rate, poor histologic differentiation, lymph node metastasis, and resistance to radiotherapy and chemotherapy. [8]

Clinical significance of epithelial mesenchymal transition

EMT is a central element in embryogenesis, wound healing, repair, fibrosis, and cancer progression. There is a lot of interest generated in its use as a pharmaceutical target for individualized therapy. However, most reports on EMT come from in vitro studies, and several results have not been confirmed in vivo, thus the clinical significance remains unclear. [2],[12]

Biomarkers

The commonly used markers that can be clinically used for diagnostic and prognostic purposes include down-regulation of E-cadherin, β-catenin (membrane), claudin, cytokeratins, occludin and up-regulation of β-catenin (nucleus)/ (cytoplasm), epidermal growth factor receptor, N-cadherin, vimentin, fibronectin, Twist, Snail, slug, ZEB1, etc. [2],[12]

Role in tumor cell invasion and metastasis

EMT has been associated with the conversion of premalignancy to malignancy, adenoma to carcinoma and tumor budding/single cell infiltration, invasion in the blood vessels and distant metastasis, presence of circulating tumor cells, and lymphatic and systemic metastasis. Further, it has been suggested that there is reexpression of epithelial markers such as E-cadherin and loss of transcription factor associated with EMT, referred to as MET. This process is essential for the adhesion and colonization of tumor cells in new site. [2],[12]

Enhanced proliferation

Cells that have undergone EMT show enhanced proliferation and resistance to apoptosis. [2],[12]

Resistance to therapy

EMT activation in a cell is linked to acquired resistance to most conventional therapeutic approaches such as chemotherapy, radiotherapy, and hormone withdrawal. [2],[12]

Cancer stem cells

The gene alterations associated with EMT are remarkably similar to that observed in a dedifferentiated state of cells and shows induction of cancer stem cells such as changes i.e., CD44 ++ /CD24. That means EMT can result in stemness making the cells having a self-renewing capacity. The resistance to antineoplastic therapies could be attributed to development of stem cell-like features in the tumor cells following EMT. [2],[12]

Epithelial mesenchymal transition related to patient prognosis

There are numerous studies which have shown a significant association between various EMT markers, i.e., downregulation of E-cadherin, vimentin, Twist, Snail, slug, etc., with poor prognosis and reduced disease-free survival in various/several cancer. [2],[12]

Epithelial mesenchymal transition as a potential target for the neoplasms as well as for fibrosis

Most therapeutic approaches are aiming EMT to slow/block down invasion and metastasis in tumors or impede fibrotic remodeling. [Table 2] shows the existing therapeutic modalities that modulate EMT in various lesions. Most of these approaches target the signaling pathway involved in EMT. Yet in spite of the extensive literature reports on these EMT modulators, there are insufficient data that demonstrate concrete evidence regarding particular compounds in a clinical setting, apart from cell culture information. Consequently, the information related to drugs for EMT must be considered as preliminary and needs further research to develop important pharmacologic targets for induction and progression of EMT. [2],[12]
Table 2: Current therapeutic approaches to combat epithelial mesenchymal transition in cancer[12]

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  Conclusion Top


EMT and cancer progression is a potential field of cancer research. Despite the abundance of evidence for EMT in embryonic development, in vitro, and in model systems, solid evidence of EMT in clinical carcinoma are still sparse, thus making it an important issue in this field. The role of EMT in tumor progression and metastasis provides a fascinating mechanism to explain the initial step of metastasis. However, several areas require additional exploration to expansively appreciate the role of EMT in physiological and pathological processes. Innovative breakthrough will clarify the complex role of EMT and may yield promising information to develop novel therapeutic approaches in the management of cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Lee K, Nelson CM. New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis. Int Rev Cell Mol Biol 2012;294:171-221.  Back to cited text no. 4
    
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Guarino M, Rubino B, Ballabio G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology 2007;39:305-18.  Back to cited text no. 8
    
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Acloque H, Adams MS, Fishwick K, Bronner-Fraser M, Nieto MA. Epithelial - Mmesenchymal transitions: The importance of changing cell state in development and disease. J Clin Invest 2009;119:1438-49.  Back to cited text no. 9
    
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Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002;2:442-54.  Back to cited text no. 10
    
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Jing Y, Han Z, Zhang S, Liu Y, Wei L. Epithelial-Mesenchymal Transition in tumor microenvironment. Cell Biosci 2011;1:29.  Back to cited text no. 11
    
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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