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Special Issue "Epithelial-Mesenchymal Transition"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (20 November 2015)

Special Issue Editors

Guest Editor
Prof. Dr. David A. Brenner

Vice Chancellor for Health Sciences, Dean, School of Medicine, University of California, San Diego, 1318 Biomedical Sciences Building, 9500 Gilman Drive, La Jolla, CA 92093-0602, USA
Website | E-Mail
Fax: +1 858 822 0084
Interests: liver fibrosis; origin of hepatic myofibroblasts; EMT; hepatic stellate cells; NOX; treatment of liver fibrosis; reversibility of liver fibrosis
Guest Editor
Dr. Tatiana Kisseleva

Department of Surgery, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Website | E-Mail
Fax: +1 858 822 0084
Interests: fibrocytes; EMT; hepatic stellate cells; portal fibroblasts; the role of IL-17 signaling in pathogenesis of liver fibrosis
Guest Editor
Dr. Jonas Fuxe

Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Website | E-Mail
Phone: +46 8 52487275
Interests: cancer cell migration and metastasis; EMT; TGF-beta signaling; vascular biology; inflammation

Special Issue Information

Dear Colleagues,

The last decade has seen an explosion in studies that have examined the role of EMT in various contexts of physiology and disease. EMT has convincingly been proven to play an important role in the trans-differentiation of epithelial cells into mesenchymal cells during embryonic development. Also, despite of debates regarding the best methodology for tracing EMT, the data obtained from cancer patients and mouse models of different types of epithelial cancers suggest that epithelial cells may undergo EMT in response to a dynamically changing tumor microenvironment and obtain markers of mesenchymal cells. However, although several studies have utilized different models of fibrogenic injury in mice, and also immunocytochemistry-based analysis of adult human tissues has implicated EMT in the pathogenesis of liver fibrosis, this topic remains controversial. Here, we would like to reinitiate the discussion on the role of EMT in embryonic development, fibrosis, and cancer, and invite scientists whose intellectual contribution to this field is immense, and whose insightful opinions, acquired throughout years of superb research, may advance our understanding of this process.

Prof. Dr. David A. Brenner
Dr. Tatiana Kisseleva
Dr. Jonas Fuxe
Guest Editor
s

Manuscript Submission Information

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Keywords

  • epithelial cells
  • myofibroblasts
  • embryogenesis
  • fibrosis
  • cancer

Published Papers (26 papers)

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Research

Jump to: Review

Open AccessArticle
Tacrolimus Modulates TGF-β Signaling to Induce Epithelial-Mesenchymal Transition in Human Renal Proximal Tubule Epithelial Cells
J. Clin. Med. 2016, 5(5), 50; https://doi.org/10.3390/jcm5050050
Received: 21 November 2015 / Revised: 16 April 2016 / Accepted: 19 April 2016 / Published: 26 April 2016
Cited by 4 | PDF Full-text (3796 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial-mesenchymal transition (EMT), a process which describes the trans-differentiation of epithelial cells into motile mesenchymal cells, is pivotal in stem cell behavior, development and wound healing, as well as contributing to disease processes including fibrosis and cancer progression. Maintenance immunosuppression with calcineurin inhibitors [...] Read more.
Epithelial-mesenchymal transition (EMT), a process which describes the trans-differentiation of epithelial cells into motile mesenchymal cells, is pivotal in stem cell behavior, development and wound healing, as well as contributing to disease processes including fibrosis and cancer progression. Maintenance immunosuppression with calcineurin inhibitors (CNIs) has become routine management for renal transplant patient, but unfortunately the nephrotoxicity of these drugs has been well documented. HK-2 cells were exposed to Tacrolimus (FK506) and EMT markers were assessed by RT PCR and western blot. FK506 effects on TGF-β mRNA were assessed by RT PCR and TGF-β secretion was measured by ELISA. The impact of increased TGF-β secretion on Smad signaling pathways was investigated. The impact of inhibition of TGF-β signaling on EMT processes was assessed by scratch-wound assay. The results presented in this study suggest that FK506 initiates EMT processes in the HK-2 cell line, with altered expression of epithelial and myofibroblast markers evident. Additionally, the study demonstrates that FK506 activation of the TGF-β/ SMAD pathways is an essential step in the EMT process. Overall the results demonstrate that EMT is heavily involved in renal fibrosis associated with CNI nephrotoxicity. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessArticle
Role of the Slug Transcription Factor in Chemically-Induced Skin Cancer
J. Clin. Med. 2016, 5(2), 21; https://doi.org/10.3390/jcm5020021
Received: 12 November 2015 / Revised: 15 January 2016 / Accepted: 25 January 2016 / Published: 3 February 2016
PDF Full-text (1684 KB) | HTML Full-text | XML Full-text
Abstract
The Slug transcription factor plays an important role in ultraviolet radiation (UVR)-induced skin carcinogenesis, particularly in the epithelial-mesenchymal transition (EMT) occurring during tumor progression. In the present studies, we investigated the role of Slug in two-stage chemical skin carcinogenesis. Slug and the related [...] Read more.
The Slug transcription factor plays an important role in ultraviolet radiation (UVR)-induced skin carcinogenesis, particularly in the epithelial-mesenchymal transition (EMT) occurring during tumor progression. In the present studies, we investigated the role of Slug in two-stage chemical skin carcinogenesis. Slug and the related transcription factor Snail were expressed at high levels in skin tumors induced by 7,12-dimethylbenz[α]anthracene application followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. TPA-induced transient elevation of Slug and Snail proteins in normal mouse epidermis and studies in Slug transgenic mice indicated that Slug modulates TPA-induced epidermal hyperplasia and cutaneous inflammation. Although Snail family factors have been linked to inflammation via interactions with the cyclooxygenase-2 (COX-2) pathway, a pathway that also plays an important role in skin carcinogenesis, transient TPA induction of Slug and Snail appeared unrelated to COX-2 expression. In cultured human keratinocytes, TPA induced Snail mRNA expression while suppressing Slug expression, and this differential regulation was due specifically to activation of the TPA receptor. These studies show that Slug and Snail exhibit similar patterns of expression during both UVR and chemical skin carcinogenesis, that Slug and Snail can be differentially regulated under some conditions and that in vitro findings may not recapitulate in vivo results. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Review

Jump to: Research

Open AccessReview
Epithelial Mesenchymal Transition in Embryonic Development, Tissue Repair and Cancer: A Comprehensive Overview
J. Clin. Med. 2018, 7(1), 1; https://doi.org/10.3390/jcm7010001
Received: 4 October 2017 / Revised: 30 November 2017 / Accepted: 11 December 2017 / Published: 22 December 2017
Cited by 16 | PDF Full-text (285 KB) | HTML Full-text | XML Full-text
Abstract
The epithelial mesenchymal transition (EMT) plays a central role in both normal physiological events (e.g., embryonic development) and abnormal pathological events (e.g., tumor formation and metastasis). The processes that occur in embryonic development are often reactivated under pathological conditions such as oncogenesis. Therefore, [...] Read more.
The epithelial mesenchymal transition (EMT) plays a central role in both normal physiological events (e.g., embryonic development) and abnormal pathological events (e.g., tumor formation and metastasis). The processes that occur in embryonic development are often reactivated under pathological conditions such as oncogenesis. Therefore, defining the regulatory networks (both gene and protein levels) involved in the EMT during embryonic development will be fundamental in understanding the regulatory networks involved in tumor development, as well as metastasis. There are many molecules, factors, mediators and signaling pathways that are involved in the EMT process. Although the EMT is a very old topic with numerous publications, recent new technologies and discoveries give this research area some new perspective and direction. It is now clear that these important processes are controlled by a network of transcriptional and translational regulators in addition to post-transcriptional and post-translational modifications that amplify the initial signals. In this review article, we will discuss some key concepts, historical findings, as well as some recent progresses in the EMT research field. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
Open AccessReview
EMT in Breast Carcinoma—A Review
J. Clin. Med. 2016, 5(7), 65; https://doi.org/10.3390/jcm5070065
Received: 21 November 2015 / Revised: 1 July 2016 / Accepted: 6 July 2016 / Published: 14 July 2016
Cited by 41 | PDF Full-text (926 KB) | HTML Full-text | XML Full-text
Abstract
The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in embryonic development; wound healing, but also in tumorigenesis. Breast carcinoma (BC) is the most common cancer in women worldwide, and the majority of deaths (90%) are caused by invasion [...] Read more.
The epithelial to mesenchymal transition (EMT) is a cellular program that is involved in embryonic development; wound healing, but also in tumorigenesis. Breast carcinoma (BC) is the most common cancer in women worldwide, and the majority of deaths (90%) are caused by invasion and metastasis. The EMT plays an important role in invasion and subsequent metastasis. Several distinct biological events integrate a cascade that leads not only to a change from an epithelial to mesenchymal phenotype, but allows for detachment, migration, invasion and ultimately, colonization of a second site. Understanding the biological intricacies of the EMT may provide important insights that lead to the development of therapeutic targets in pre-invasive and invasive breast cancer, and could be used as biomarkers identifying tumor subsets with greater chances of recurrence, metastasis and therapeutic resistance leading to death. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Tumor Budding: The Name is EMT. Partial EMT.
J. Clin. Med. 2016, 5(5), 51; https://doi.org/10.3390/jcm5050051
Received: 24 February 2016 / Revised: 14 April 2016 / Accepted: 22 April 2016 / Published: 29 April 2016
Cited by 85 | PDF Full-text (732 KB) | HTML Full-text | XML Full-text
Abstract
Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma. Postulated to be mirror epithelial-mesenchymal transition, tumor budding has been associated with poor cancer outcomes. However, the [...] Read more.
Tumor budding is a histological phenomenon encountered in various cancers, whereby individual malignant cells and/or small clusters of malignant cells are seen in the tumor stroma. Postulated to be mirror epithelial-mesenchymal transition, tumor budding has been associated with poor cancer outcomes. However, the vast heterogeneity in its exact definition, methodology of assessment, and patient stratification need to be resolved before it can be routinely used as a standardized prognostic feature. Here, we discuss the heterogeneity in defining and assessing tumor budding, its clinical significance across multiple cancer types, and its prospective implementation in clinical practice. Next, we review the emerging evidence about partial, rather than complete, epithelial-mesenchymal phenotype at the tumor bud level, and its connection with tumor proliferation, quiescence, and stemness. Finally, based on recent literature, indicating a co-expression of epithelial and mesenchymal markers in many tumor buds, we posit tumor budding to be a manifestation of this hybrid epithelial/mesenchymal phenotype displaying collective cell migration. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Endothelial to Mesenchymal Transition (EndoMT) in the Pathogenesis of Human Fibrotic Diseases
J. Clin. Med. 2016, 5(4), 45; https://doi.org/10.3390/jcm5040045
Received: 21 January 2016 / Revised: 18 March 2016 / Accepted: 6 April 2016 / Published: 11 April 2016
Cited by 68 | PDF Full-text (1288 KB) | HTML Full-text | XML Full-text
Abstract
Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft versus host disease, nephrogenic systemic fibrosis, and IgG4-associated sclerosing disease, as well as numerous organ-specific disorders including radiation-induced fibrosis, and cardiac, pulmonary, [...] Read more.
Fibrotic diseases encompass a wide spectrum of clinical entities including systemic fibrotic diseases such as systemic sclerosis, sclerodermatous graft versus host disease, nephrogenic systemic fibrosis, and IgG4-associated sclerosing disease, as well as numerous organ-specific disorders including radiation-induced fibrosis, and cardiac, pulmonary, liver, and kidney fibrosis. Although their causative mechanisms are quite diverse, these diseases share the common feature of an uncontrolled and progressive accumulation of fibrous tissue macromolecules in affected organs leading to their dysfunction and ultimate failure. The pathogenesis of fibrotic diseases is complex and despite extensive investigation has remained elusive. Numerous studies have identified myofibroblasts as the cells responsible for the establishment and progression of the fibrotic process. Tissue myofibroblasts in fibrotic diseases originate from several sources including quiescent tissue fibroblasts, circulating CD34+ fibrocytes, and the phenotypic conversion of various cell types including epithelial and endothelial cells into activated myofibroblasts. However, the role of the phenotypic transition of endothelial cells into mesenchymal cells (Endothelial to Mesenchymal Transition or EndoMT) in the pathogenesis of fibrotic disorders has not been fully elucidated. Here, we review the evidence supporting EndoMT’s contribution to human fibrotic disease pathogenesis. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Effect of Cigarette Smoking on Epithelial to Mesenchymal Transition (EMT) in Lung Cancer
J. Clin. Med. 2016, 5(4), 44; https://doi.org/10.3390/jcm5040044
Received: 4 January 2016 / Revised: 4 April 2016 / Accepted: 6 April 2016 / Published: 11 April 2016
Cited by 20 | PDF Full-text (955 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial to mesenchymal transition (EMT) is a process that allows an epithelial cell to acquire a mesenchymal phenotype through multiple biochemical changes resulting in an increased migratory capacity. During cancer progression, EMT is found to be associated with an invasive or metastatic phenotype. [...] Read more.
Epithelial to mesenchymal transition (EMT) is a process that allows an epithelial cell to acquire a mesenchymal phenotype through multiple biochemical changes resulting in an increased migratory capacity. During cancer progression, EMT is found to be associated with an invasive or metastatic phenotype. In this review, we focus on the discussion of recent studies about the regulation of EMT by cigarette smoking. Various groups of active compounds found in cigarette smoke such as polycyclic aromatic hydrocarbons (PAH), nicotine-derived nitrosamine ketone (NNK), and reactive oxygen specicies (ROS) can induce EMT through different signaling pathways. The links between EMT and biological responses to cigarette smoke, such as hypoxia, inflammation, and oxidative damages, are also discussed. The effect of cigarette smoke on EMT is not only limited to cancer types directly related to smoking, such as lung cancer, but has also been found in other types of cancer. Altogether, this review emphasizes the importance of understanding molecular mechanisms of the induction of EMT by cigarette smoking and will help in identifying novel small molecules for targeting EMT induced by smoking. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
EMT Involved in Migration of Stem/Progenitor Cells for Pituitary Development and Regeneration
J. Clin. Med. 2016, 5(4), 43; https://doi.org/10.3390/jcm5040043
Received: 4 December 2015 / Revised: 24 March 2016 / Accepted: 29 March 2016 / Published: 6 April 2016
Cited by 7 | PDF Full-text (1845 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial–mesenchymal transition (EMT) and cell migration are important processes in embryonic development of many tissues as well as oncogenesis. The pituitary gland is a master endocrine tissue and recent studies indicate that Sox2-expressing stem/progenitor cells actively migrate and develop this tissue during [...] Read more.
Epithelial–mesenchymal transition (EMT) and cell migration are important processes in embryonic development of many tissues as well as oncogenesis. The pituitary gland is a master endocrine tissue and recent studies indicate that Sox2-expressing stem/progenitor cells actively migrate and develop this tissue during embryogenesis. Notably, although migration activity of stem/progenitor cells in the postnatal period seems to be reduced compared to that in the embryonic period, it is hypothesized that stem/progenitor cells in the adult pituitary re-migrate from their microenvironment niche to contribute to the regeneration system. Therefore, elucidation of EMT in the pituitary stem/progenitor cells will promote understanding of pituitary development and regeneration, as well as diseases such as pituitary adenoma. In this review, so as to gain more insights into the mechanisms of pituitary development and regeneration, we summarize the EMT in the pituitary by focusing on the migration of pituitary stem/progenitor cells during both embryonic and postnatal organogenesis. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks
J. Clin. Med. 2016, 5(4), 41; https://doi.org/10.3390/jcm5040041
Received: 20 November 2015 / Revised: 31 January 2016 / Accepted: 21 March 2016 / Published: 28 March 2016
Cited by 91 | PDF Full-text (1662 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key [...] Read more.
Epithelial-to-mesenchymal transition (EMT) is a key step in development, wound healing, and cancer development. It involves cooperation of signaling pathways, such as transformation growth factor-β (TGF-β), Sonic Hedgehog (SHH), and WNT pathways. These signaling pathways crosstalk to each other and converge to key transcription factors (e.g., SNAIL1) to initialize and maintain the process of EMT. The functional roles of multi-signaling pathway crosstalks in EMT are sophisticated and, thus, remain to be explored. In this review, we focused on three major signal transduction pathways that promote or regulate EMT in carcinoma. We discussed the network structures, and provided a brief overview of the current therapy strategies and drug development targeted to these three signal transduction pathways. Finally, we highlighted systems biology approaches that can accelerate the process of deconstructing complex networks and drug discovery. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Osteopontin—A Master Regulator of Epithelial-Mesenchymal Transition
J. Clin. Med. 2016, 5(4), 39; https://doi.org/10.3390/jcm5040039
Received: 21 December 2015 / Revised: 8 February 2016 / Accepted: 14 March 2016 / Published: 23 March 2016
Cited by 20 | PDF Full-text (1311 KB) | HTML Full-text | XML Full-text
Abstract
Osteopontin (OPN) plays an important functional role in both physiologic and pathologic states. OPN is implicated in the progression of fibrosis, cancer, and metastatic disease in several organ systems. The epithelial-mesenchymal transition (EMT), first described in embryology, is increasingly being recognized as a [...] Read more.
Osteopontin (OPN) plays an important functional role in both physiologic and pathologic states. OPN is implicated in the progression of fibrosis, cancer, and metastatic disease in several organ systems. The epithelial-mesenchymal transition (EMT), first described in embryology, is increasingly being recognized as a significant contributor to fibrotic phenotypes and tumor progression. Several well-established transcription factors regulate EMT and are conserved across tissue types and organ systems, including TWIST, zinc finger E-box-binding homeobox (ZEB), and SNAIL-family members. Recent literature points to an important relationship between OPN and EMT, implicating OPN as a key regulatory component of EMT programs. In this review, OPN’s interplay with traditional EMT activators, both directly and indirectly, will be discussed. Also, OPN’s ability to restructure the tissue and tumor microenvironment to indirectly modify EMT will be reviewed. Together, these diverse pathways demonstrate that OPN is able to modulate EMT and provide new targets for directing therapeutics. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessFeature PaperReview
New Insights into the Crossroads between EMT and Stemness in the Context of Cancer
J. Clin. Med. 2016, 5(3), 37; https://doi.org/10.3390/jcm5030037
Received: 15 December 2015 / Revised: 1 March 2016 / Accepted: 4 March 2016 / Published: 12 March 2016
Cited by 55 | PDF Full-text (1102 KB) | HTML Full-text | XML Full-text
Abstract
The epithelial-mesenchymal transition (EMT) is an example of cellular plasticity, where an epithelial cell acquires a mesenchymal-like phenotype that increases its migratory and invasive properties. Stemness is the ability of stem cells to proliferate in an asymmetric way that allows them to maintain [...] Read more.
The epithelial-mesenchymal transition (EMT) is an example of cellular plasticity, where an epithelial cell acquires a mesenchymal-like phenotype that increases its migratory and invasive properties. Stemness is the ability of stem cells to proliferate in an asymmetric way that allows them to maintain the reservoir of undifferentiated cells with stem cell identity, but also to produce new differentiated cells. Initial works revealed that activation of the EMT program in epithelial cells induces the acquisition of stem cell properties, which in the context of cancer may contribute to the appearance of tumor initiating cells (TIC). However, a number of groups have recently reported that mesenchymal-epithelial transition (MET) is required for efficient metastatic colonization and that EMT may be not necessarily associated with stemness. In this review, we summarize recent findings that extend our knowledge about the crossroads between EMT and stemness and their relevance under physiological or pathological conditions. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Epicardial Epithelial-to-Mesenchymal Transition in Heart Development and Disease
J. Clin. Med. 2016, 5(2), 27; https://doi.org/10.3390/jcm5020027
Received: 21 November 2015 / Revised: 22 January 2016 / Accepted: 3 February 2016 / Published: 19 February 2016
Cited by 12 | PDF Full-text (510 KB) | HTML Full-text | XML Full-text
Abstract
The epicardium is an epithelial monolayer that plays a central role in heart development and the myocardial response to injury. Recent developments in our understanding of epicardial cell biology have revealed this layer to be a dynamic participant in fundamental processes underlying the [...] Read more.
The epicardium is an epithelial monolayer that plays a central role in heart development and the myocardial response to injury. Recent developments in our understanding of epicardial cell biology have revealed this layer to be a dynamic participant in fundamental processes underlying the development of the embryonic ventricles, the coronary vasculature, and the cardiac valves. Likewise, recent data have identified the epicardium as an important contributor to reparative and regenerative processes in the injured myocardium. These essential functions of the epicardium rely on both non-cell autonomous and cell-autonomous mechanisms, with the latter featuring the process of epicardial Epithelial-to-Mesenchymal Transition (EMT). This review will focus on the induction and regulation of epicardial EMT, as it pertains to both cardiogenesis and the response of the myocardium to injury. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Homeostatic Signaling by Cell–Cell Junctions and Its Dysregulation during Cancer Progression
J. Clin. Med. 2016, 5(2), 26; https://doi.org/10.3390/jcm5020026
Received: 18 December 2015 / Revised: 5 February 2016 / Accepted: 5 February 2016 / Published: 18 February 2016
Cited by 19 | PDF Full-text (966 KB) | HTML Full-text | XML Full-text
Abstract
The transition of sessile epithelial cells to a migratory, mesenchymal phenotype is essential for metazoan development and tissue repair, but this program is exploited by tumor cells in order to escape the confines of the primary organ site, evade immunosurveillance, and resist chemo-radiation. [...] Read more.
The transition of sessile epithelial cells to a migratory, mesenchymal phenotype is essential for metazoan development and tissue repair, but this program is exploited by tumor cells in order to escape the confines of the primary organ site, evade immunosurveillance, and resist chemo-radiation. In addition, epithelial-to-mesenchymal transition (EMT) confers stem-like properties that increase efficiency of colonization of distant organs. This review evaluates the role of cell–cell junctions in suppressing EMT and maintaining a quiescent epithelium. We discuss the conflicting data on junctional signaling in cancer and recent developments that resolve some of these conflicts. We focus on evidence from breast cancer, but include other organ sites where appropriate. Current and potential strategies for inhibition of EMT are discussed. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessFeature PaperReview
Hypoxia, Epithelial-Mesenchymal Transition, and TET-Mediated Epigenetic Changes
J. Clin. Med. 2016, 5(2), 24; https://doi.org/10.3390/jcm5020024
Received: 29 November 2015 / Revised: 15 January 2016 / Accepted: 26 January 2016 / Published: 4 February 2016
Cited by 22 | PDF Full-text (797 KB) | HTML Full-text | XML Full-text
Abstract
Tumor hypoxia is a pathophysiologic outcome of disrupted microcirculation with inadequate supply of oxygen, leading to enhanced proliferation, epithelial-mesenchymal transition (EMT), metastasis, and chemo-resistance. Epigenetic changes induced by hypoxia are well documented, and they lead to tumor progression. Recent advances show that DNA [...] Read more.
Tumor hypoxia is a pathophysiologic outcome of disrupted microcirculation with inadequate supply of oxygen, leading to enhanced proliferation, epithelial-mesenchymal transition (EMT), metastasis, and chemo-resistance. Epigenetic changes induced by hypoxia are well documented, and they lead to tumor progression. Recent advances show that DNA demethylation mediated by the Ten-eleven translocation (TET) proteins induces major epigenetic changes and controls key steps of cancer development. TET enzymes serve as 5mC (5-methylcytosine)-specific dioxygenases and cause DNA demethylation. Hypoxia activates the expression of TET1, which also serves as a co-activator of HIF-1α transcriptional regulation to modulate HIF-1α downstream target genes and promote epithelial-mesenchymal transition. As HIF is a negative prognostic factor for tumor progression, hypoxia-activated prodrugs (HAPs) may provide a favorable therapeutic approach to lessen hypoxia-induced malignancy. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Protein Kinase D Enzymes as Regulators of EMT and Cancer Cell Invasion
J. Clin. Med. 2016, 5(2), 20; https://doi.org/10.3390/jcm5020020
Received: 1 September 2015 / Revised: 15 December 2015 / Accepted: 18 January 2016 / Published: 3 February 2016
Cited by 17 | PDF Full-text (1239 KB) | HTML Full-text | XML Full-text
Abstract
The Protein Kinase D (PKD) isoforms PKD1, PKD2, and PKD3 are effectors of the novel Protein Kinase Cs (nPKCs) and diacylglycerol (DAG). PKDs impact diverse biological processes like protein transport, cell migration, proliferation, epithelial to mesenchymal transition (EMT) and apoptosis. PKDs however, have [...] Read more.
The Protein Kinase D (PKD) isoforms PKD1, PKD2, and PKD3 are effectors of the novel Protein Kinase Cs (nPKCs) and diacylglycerol (DAG). PKDs impact diverse biological processes like protein transport, cell migration, proliferation, epithelial to mesenchymal transition (EMT) and apoptosis. PKDs however, have distinct effects on these functions. While PKD1 blocks EMT and cell migration, PKD2 and PKD3 tend to drive both processes. Given the importance of EMT and cell migration to the initiation and progression of various malignancies, abnormal expression of PKDs has been reported in multiple types of cancers, including breast, pancreatic and prostate cancer. In this review, we discuss how EMT and cell migration are regulated by PKD isoforms and the significance of this regulation in the context of cancer development. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Role of EMT in Metastasis and Therapy Resistance
J. Clin. Med. 2016, 5(2), 17; https://doi.org/10.3390/jcm5020017
Received: 20 October 2015 / Revised: 22 December 2015 / Accepted: 23 December 2015 / Published: 27 January 2016
Cited by 147 | PDF Full-text (1040 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial–mesenchymal transition (EMT) is a complex molecular program that regulates changes in cell morphology and function during embryogenesis and tissue development. EMT also contributes to tumor progression and metastasis. Cells undergoing EMT expand out of and degrade the surrounding microenvironment to subsequently migrate [...] Read more.
Epithelial–mesenchymal transition (EMT) is a complex molecular program that regulates changes in cell morphology and function during embryogenesis and tissue development. EMT also contributes to tumor progression and metastasis. Cells undergoing EMT expand out of and degrade the surrounding microenvironment to subsequently migrate from the primary site. The mesenchymal phenotype observed in fibroblasts is specifically important based on the expression of smooth muscle actin (α-SMA), fibroblast growth factor (FGF), fibroblast-specific protein-1 (FSP1), and collagen to enhance EMT. Although EMT is not completely dependent on EMT regulators such as Snail, Twist, and Zeb-1/-2, analysis of upstream signaling (i.e., TGF-β, EGF, Wnt) is necessary to understand tumor EMT more comprehensively. Tumor epithelial–fibroblast interactions that regulate tumor progression have been identified during prostate cancer. The cellular crosstalk is significant because these events influence therapy response and patient outcome. This review addresses how canonical EMT signals originating from prostate cancer fibroblasts contribute to tumor metastasis and recurrence after therapy. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessFeature PaperReview
Epithelial-Mesenchymal Transition and Breast Cancer
J. Clin. Med. 2016, 5(2), 13; https://doi.org/10.3390/jcm5020013
Received: 1 December 2015 / Revised: 11 January 2016 / Accepted: 19 January 2016 / Published: 26 January 2016
Cited by 61 | PDF Full-text (826 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer is the most common cancer in women and distant site metastasis is the main cause of death in breast cancer patients. There is increasing evidence supporting the role of epithelial-mesenchymal transition (EMT) in tumor cell progression, invasion, and metastasis. During the [...] Read more.
Breast cancer is the most common cancer in women and distant site metastasis is the main cause of death in breast cancer patients. There is increasing evidence supporting the role of epithelial-mesenchymal transition (EMT) in tumor cell progression, invasion, and metastasis. During the process of EMT, epithelial cancer cells acquire molecular alternations that facilitate the loss of epithelial features and gain of mesenchymal phenotype. Such transformation promotes cancer cell migration and invasion. Moreover, emerging evidence suggests that EMT is associated with the increased enrichment of cancer stem-like cells (CSCs) and these CSCs display mesenchymal characteristics that are resistant to chemotherapy and target therapy. However, the clinical relevance of EMT in human cancer is still under debate. This review will provide an overview of current evidence of EMT from studies using clinical human breast cancer tissues and its associated challenges. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Epithelial-Mesenchymal Transition (EMT) and Regulation of EMT Factors by Steroid Nuclear Receptors in Breast Cancer: A Review and in Silico Investigation
J. Clin. Med. 2016, 5(1), 11; https://doi.org/10.3390/jcm5010011
Received: 8 December 2015 / Revised: 23 December 2015 / Accepted: 30 December 2015 / Published: 19 January 2016
Cited by 29 | PDF Full-text (1419 KB) | HTML Full-text | XML Full-text
Abstract
Steroid Nuclear Receptors (SNRs) are transcription factors of the nuclear receptor super-family. Estrogen Receptor (ERα) is the best-studied and has a seminal role in the clinic both as a prognostic marker but also as a predictor of response to anti-estrogenic therapies. Progesterone Receptor [...] Read more.
Steroid Nuclear Receptors (SNRs) are transcription factors of the nuclear receptor super-family. Estrogen Receptor (ERα) is the best-studied and has a seminal role in the clinic both as a prognostic marker but also as a predictor of response to anti-estrogenic therapies. Progesterone Receptor (PR) is also used in the clinic but with a more debatable prognostic role and the role of the four other SNRs, ERβ, Androgen Receptor (AR), Glucocorticoid Receptor (GR) and Mineralocorticoid Receptor (MR), is starting only to be appreciated. ERα, but also to a certain degree the other SNRs, have been reported to be involved in virtually every cancer-enabling process, both promoting and impeding carcinogenesis. Epithelial-Mesenchymal Transition (EMT) and the reverse Mesenchymal Epithelial Transition (MET) are such carcinogenesis-enabling processes with important roles in invasion and metastasis initiation but also establishment of tumor in the metastatic site. EMT is governed by several signal transduction pathways culminating in core transcription factors of the process, such as Snail, Slug, ZEB1 and ZEB2, and Twist, among others. This paper will discuss direct regulation of these core transcription factors by SNRs in breast cancer. Interrogation of publicly available databases for binding sites of SNRs on promoters of core EMT factors will also be included in an attempt to fill gaps where other experimental data are not available. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessFeature PaperReview
Controversies over the Epithelial-to-Mesenchymal Transition in Liver Fibrosis
J. Clin. Med. 2016, 5(1), 9; https://doi.org/10.3390/jcm5010009
Received: 18 December 2015 / Revised: 3 January 2016 / Accepted: 11 January 2016 / Published: 14 January 2016
Cited by 15 | PDF Full-text (195 KB) | HTML Full-text | XML Full-text
Abstract
Liver fibrosis is a universal consequence of chronic liver diseases. It is accompanied by activation of collagen-producing myofibroblasts, resulting in excessive deposition of extracellular matrix. The origin of myofibroblasts in the fibrotic liver has not been completely resolved and remains a matter of [...] Read more.
Liver fibrosis is a universal consequence of chronic liver diseases. It is accompanied by activation of collagen-producing myofibroblasts, resulting in excessive deposition of extracellular matrix. The origin of myofibroblasts in the fibrotic liver has not been completely resolved and remains a matter of debate. Recently, the epithelial-to-mesenchymal transition (EMT) was proposed as one of the mechanisms that give rise to collagen-producing myofibroblasts in liver fibrosis. However, subsequent studies contradicted this hypothesis, and the EMT theory has become one of the most controversial and debatable issues in the field of liver fibrosis research. This review will summarize the existing literature on EMT in liver fibrosis and will analyze the causes for the contradictory results to draw a reasonable conclusion based on current knowledge in the field. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
Open AccessFeature PaperReview
MicroRNA Regulation of Epithelial to Mesenchymal Transition
J. Clin. Med. 2016, 5(1), 8; https://doi.org/10.3390/jcm5010008
Received: 23 November 2015 / Revised: 18 December 2015 / Accepted: 5 January 2016 / Published: 14 January 2016
Cited by 34 | PDF Full-text (777 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, [...] Read more.
Epithelial to mesenchymal transition (EMT) is a central regulatory program that is similar in many aspects to several steps of embryonic morphogenesis. In addition to its physiological role in tissue repair and wound healing, EMT contributes to chemo resistance, metastatic dissemination and fibrosis, amongst others. Classically, the morphological change from epithelial to mesenchymal phenotype is characterized by the appearance or loss of a group of proteins which have come to be recognized as markers of the EMT process. As with all proteins, these molecules are controlled at the transcriptional and translational level by transcription factors and microRNAs, respectively. A group of developmental transcription factors form the backbone of the EMT cascade and a large body of evidence shows that microRNAs are heavily involved in the successful coordination of mesenchymal transformation and vice versa, either by suppressing the expression of different groups of transcription factors, or otherwise acting as their functional mediators in orchestrating EMT. This article dissects the contribution of microRNAs to EMT and analyzes the molecular basis for their roles in this cellular process. Here, we emphasize their interaction with core transcription factors like the zinc finger enhancer (E)-box binding homeobox (ZEB), Snail and Twist families as well as some pluripotency transcription factors. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Reversible Human TGF-β Signal Shifting between Tumor Suppression and Fibro-Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions
J. Clin. Med. 2016, 5(1), 7; https://doi.org/10.3390/jcm5010007
Received: 18 November 2015 / Revised: 16 December 2015 / Accepted: 4 January 2016 / Published: 12 January 2016
Cited by 15 | PDF Full-text (1553 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate [...] Read more.
Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-β and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-β signal transduction pathway. As the TGF-β receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally-phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-β upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-β and pro-inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-β and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser-245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho-Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor-suppression in a process of MET after therapy. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Emerging Transcriptional Mechanisms in the Regulation of Epithelial to Mesenchymal Transition and Cellular Plasticity in the Kidney
J. Clin. Med. 2016, 5(1), 6; https://doi.org/10.3390/jcm5010006
Received: 20 November 2015 / Revised: 18 December 2015 / Accepted: 4 January 2016 / Published: 12 January 2016
Cited by 9 | PDF Full-text (777 KB) | HTML Full-text | XML Full-text
Abstract
Notwithstanding controversies over the role of epithelial to mesenchymal transition in the pathogenesis of renal disease, the last decade has witnessed a revolution in our understanding of the regulation of renal cell plasticity. Significant parallels undoubtedly exist between ontogenic processes and the initiation [...] Read more.
Notwithstanding controversies over the role of epithelial to mesenchymal transition in the pathogenesis of renal disease, the last decade has witnessed a revolution in our understanding of the regulation of renal cell plasticity. Significant parallels undoubtedly exist between ontogenic processes and the initiation and propagation of damage in the diseased kidney as evidenced by the reactivation of developmental programmes of gene expression, in particular with respect to TGFβ superfamily signaling. Indeed, multiple signaling pathways converge on a complex transcriptional regulatory nexus that additionally involves epigenetic activator and repressor mechanisms and microRNA regulatory networks that control renal cell plasticity. It is becoming increasingly apparent that differentiated cells can acquire an undifferentiated state akin to “stemness” which is leading us towards new models of complex cell behaviors and interactions. Here we discuss the latest findings that delineate new and novel interactions between this transcriptional regulatory network and highlight a hitherto poorly recognized role for the Polycomb Repressive Complex (PRC2) in the regulation of renal cell plasticity. A comprehensive understanding of how external stimuli interact with the epigenetic control of gene expression, in normal and diseased contexts, establishes a new therapeutic paradigm to promote the resolution of renal injury and regression of fibrosis. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Pathogenesis of Type 2 Epithelial to Mesenchymal Transition (EMT) in Renal and Hepatic Fibrosis
J. Clin. Med. 2016, 5(1), 4; https://doi.org/10.3390/jcm5010004
Received: 30 November 2015 / Revised: 22 December 2015 / Accepted: 24 December 2015 / Published: 30 December 2015
Cited by 11 | PDF Full-text (994 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also [...] Read more.
Epithelial to mesenchymal transition (EMT), particularly, type 2 EMT, is important in progressive renal and hepatic fibrosis. In this process, incompletely regenerated renal epithelia lose their epithelial characteristics and gain migratory mesenchymal qualities as myofibroblasts. In hepatic fibrosis (importantly, cirrhosis), the process also occurs in injured hepatocytes and hepatic progenitor cells (HPCs), as well as ductular reaction-related bile epithelia. Interestingly, the ductular reaction contributes partly to hepatocarcinogenesis of HPCs, and further, regenerating cholangiocytes after injury may be derived from hepatic stellate cells via mesenchymal to epithelia transition, a reverse phenomenon of type 2 EMT. Possible pathogenesis of type 2 EMT and its differences between renal and hepatic fibrosis are reviewed based on our experimental data. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Epithelial–Mesenchymal Transitions during Neural Crest and Somite Development
J. Clin. Med. 2016, 5(1), 1; https://doi.org/10.3390/jcm5010001
Received: 24 November 2015 / Revised: 9 December 2015 / Accepted: 14 December 2015 / Published: 25 December 2015
Cited by 11 | PDF Full-text (1786 KB) | HTML Full-text | XML Full-text
Abstract
Epithelial-to-mesenchymal transition (EMT) is a central process during embryonic development that affects selected progenitor cells of all three germ layers. In addition to driving the onset of cellular migrations and subsequent tissue morphogenesis, the dynamic conversions of epithelium into mesenchyme and vice-versa are [...] Read more.
Epithelial-to-mesenchymal transition (EMT) is a central process during embryonic development that affects selected progenitor cells of all three germ layers. In addition to driving the onset of cellular migrations and subsequent tissue morphogenesis, the dynamic conversions of epithelium into mesenchyme and vice-versa are intimately associated with the segregation of homogeneous precursors into distinct fates. The neural crest and somites, progenitors of the peripheral nervous system and of skeletal tissues, respectively, beautifully illustrate the significance of EMT to the above processes. Ongoing studies progressively elucidate the gene networks underlying EMT in each system, highlighting the similarities and differences between them. Knowledge of the mechanistic logic of this normal ontogenetic process should provide important insights to the understanding of pathological conditions such as cancer metastasis, which shares some common molecular themes. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessFeature PaperReview
Epithelial-to-Mesenchymal Transition and Cancer Invasiveness: What Can We Learn from Cholangiocarcinoma?
J. Clin. Med. 2015, 4(12), 2028-2041; https://doi.org/10.3390/jcm4121958
Received: 19 November 2015 / Revised: 4 December 2015 / Accepted: 14 December 2015 / Published: 19 December 2015
Cited by 21 | PDF Full-text (493 KB) | HTML Full-text | XML Full-text
Abstract
In addition to its well-established role in embryo development, epithelial-to-mesenchymal transition (EMT) has been proposed as a general mechanism favoring tumor metastatization in several epithelial malignancies. Herein, we review the topic of EMT in cholangiocarcinoma (CCA), a primary liver cancer arising from the [...] Read more.
In addition to its well-established role in embryo development, epithelial-to-mesenchymal transition (EMT) has been proposed as a general mechanism favoring tumor metastatization in several epithelial malignancies. Herein, we review the topic of EMT in cholangiocarcinoma (CCA), a primary liver cancer arising from the epithelial cells lining the bile ducts (cholangiocytes) and characterized by an abundant stromal reaction. CCA carries a dismal prognosis, owing to a pronounced invasiveness and scarce therapeutic opportunities. In CCA, several reports indicate that cancer cells acquire a number of EMT biomarkers and functions. These phenotypic changes are likely induced by both autocrine and paracrine signals released in the tumor microenvironment (cytokines, growth factors, morphogens) and intracellular stimuli (microRNAs, oncogenes, tumor suppressor genes) variably associated with specific disease mechanisms, including chronic inflammation and hypoxia. Nevertheless, evidence supporting a complete EMT of neoplastic cholangiocytes into stromal cells is lacking, and the gain of EMT-like changes by CCA cells rather reflects a shift towards an enhanced pro-invasive phenotype, likely induced by the tumor stroma. This concept may help to identify new biomarkers of early metastatic behavior along with potential therapeutic targets. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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Open AccessReview
Claudin 1 in Breast Cancer: New Insights
J. Clin. Med. 2015, 4(12), 1960-1976; https://doi.org/10.3390/jcm4121952
Received: 1 October 2015 / Revised: 9 November 2015 / Accepted: 14 November 2015 / Published: 27 November 2015
Cited by 14 | PDF Full-text (785 KB) | HTML Full-text | XML Full-text
Abstract
Claudin 1 is a small transmembrane protein responsible for maintaining the barrier function that exists between epithelial cells. A tight junction protein that regulates the paracellular transport of small ions across adjacent cells, claudin 1 maintains cellular polarity and plays a major role [...] Read more.
Claudin 1 is a small transmembrane protein responsible for maintaining the barrier function that exists between epithelial cells. A tight junction protein that regulates the paracellular transport of small ions across adjacent cells, claudin 1 maintains cellular polarity and plays a major role in cell-cell communication and epithelial cell homeostasis. Long considered to be a putative tumor suppressor in human breast cancer, new studies suggest a role much more complex. While most invasive breast cancers exhibit a down regulation or absence of claudin 1, some aggressive subtypes that exhibit high claudin 1 levels have now been described. Furthermore, a causal role for claudin 1 in breast cancer progression has recently been demonstrated in some breast cancer cell lines. In this review we highlight new insights into the role of claudin 1 in breast cancer, including its involvement in collective migration and epithelial mesenchymal transition (EMT). Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition)
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