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Biomarkers for epithelial-mesenchymal transitions
Open accessAbstract
Somatic cells that change from one mature phenotype to another exhibit the property of plasticity. It is increasingly clear that epithelial and endothelial cells enjoy some of this plasticity, which is easily demonstrated by studying the process of epithelial-mesenchymal transition (EMT). Published reports from the literature typically rely on ad hoc criteria for determining EMT events; consequently, there is some uncertainty as to whether the same process occurs under different experimental conditions. As we discuss in this Personal Perspective, we believe that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon - namely, the transition of epithelial and endothelial cells to a motile phenotype.
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“Moreover, proteins in the most significantly up-regulated network module (Extended Data Fig. 10d, 10f) included collagens (COL1A1 and COL3A1) and extracellular matrix glycoproteins (FN1, BGN, FBN1, and FBN2) that also are markers of EMT34, 35.”
From Proteogenomic characterization of human colon and rectal cancer (2014) · cites this paper as [35]
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“An EMT event is involved in the formation of motile cells from parent epithelial cells that are not themselves motile [21].”
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“However, what is occurring in podocytes in vitro or in vivo is not classic EMT, as recently defined by Zeisberg and Neilson (32) and Wang et al. (33).”
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“In the present study we developed a new methodology using the ARIOL system, in order to evaluate the protein expression pattern of a putative stemness (ALDH1) and an EMT (TWIST) marker on CTCs of early and metastatic breast cancer patients.”
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“Rather, it has now been proposed that analyzing changes in expression of a number of different markers, including cytoskelatal proteins, transcription factors, matrix proteins, cell surface receptors, and miRNAs, are required to identify cells undergoing EMT.(50) So far, we have been unable to demonstrate expression o…”
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“This is valid for EMT, but also to the apparent reverse process known as Mesenchymal to Epithelial Transition (MET), that occurs during embryonic development, tissue regeneration, wound-healing and thought to occur in cancer initiation/ progression [18,19,20].”
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“Those markers are well known as EMT-associated markers [17].”
BackgroundProspects for new lung cancer treatments that target EMT signaling
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Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway
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Thymic fatness and approaches to enhance thymopoietic fitness in aging
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“Recent data suggest that CR efficiently blocks EMT and age-related increase in pro-adipogenic machinery in thymus (26).”
BackgroundInfluentialLin, D. C.-C., Kuang, G., Wan, J., Zhang, X., Li, H., Gong, X., & Li, H. (2016) · Oncology Reports · doi:10.3892/or.2016.5311 · Cited by 113
“From a molecular viewpoint, EMT is characterized by downregulation of epithelial cell markers such as E-cadherin and claudin, and upregulation of mesenchymal molecules such as vimentin and N-cadherin (5,6).”
BackgroundInfluentialEllagic acid inhibits human pancreatic cancer growth in Balb c nude mice
Zhao, M., Tang, S., Marsh, J. L., Shankar, S., & Srivastava, R. K. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.05.009 · Cited by 111
“Tumor cells undergoing EMT are also known to increase the secretion of specific factors, including cytokines, chemokines and growth factors, which could play an important role in tumor progression [78–81].”
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“EMT entails the downregulation of E-cadherin and the upregulation of its suppressor, Snail and Twist, in carcinoma cells [5,6,10].”
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PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer
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Role of metastasis-induced protein S100A4 in human non-tumor pathophysiologies
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“Type III EMT is part of the metastatic process in which epithelial carcinoma cells in their primary nodule forms migrate to a distant site via blood circulation to reform as a secondary tumor nodule [34].”
BackgroundTRPV 4 regulates matrix stiffness and TGF β1‐induced epithelial‐mesenchymal transition
Sharma, S., Goswami, R., Zhang, D. X., & Rahaman, S. O. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13972 · Cited by 108
“The increased expression of YAP and TAZ proteins may modulate nuclear availability of these proteins under multiple pathophysiological conditions.(52-60) Here, we found that TRPV4 deletion blocked both matrix stiffness‐induced and TGFβ1‐induced expression of YAP and TAZ proteins in NMEKs, suggesting an additional mech…”
BackgroundInfluentialSeidlitz, T., Chen, Y., Uhlemann, H., Schölch, S., Kochall, S., Merker, S. R., Klimová, A., Hennig, A., Schweitzer, C., Pape, K., et al. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.09.026 · Cited by 110
hnRNP A2/B1 Modulates Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines
Tauler, J., Zudaire, E., Liu, H., Shih, J. H., & Mulshine, J. L. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0860 · Cited by 110
Jakobsen, K. R., Demuth, C., Sørensen, B. S., & Nielsen, A. L. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.04.07 · Cited by 112
E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT
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New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer
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Fibrosis in the lens. Sprouty regulation of TGFβ-signaling prevents lens EMT leading to cataract
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“…such as cytokeratin and ZO-1, loss of E-cadherin and expression of transcription factors including Snail (Snai1), Slug (Snai2) and Twist (Figure 2; Zeisberg and Neilson, 2009). αSMA is a common marker of active fibroblasts, but it is not specific for fibroblasts (Zeisberg and Neilson, 2009).”
BackgroundRole of microRNA/Epithelial-to-Mesenchymal Transition Axis in the Metastasis of Bladder Cancer
Ashrafizadeh, M., Hushmandi, K., Hashemi, M., Akbari, M. E., Kubatka, P., Raei, M., Koklesová, L., Shahinozzaman, M., Mohammadinejad, R., Najafi, M., et al. (2020) · Biomolecules · doi:10.3390/biom10081159 · Cited by 108
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“Epithelial to mesenchymal transition (EMT) occurs during embryonic development and during cancer tumorigenesis and metastasis [ 16 ].”
BackgroundTumor-promoting functions of transforming growth factor-β in progression of cancer
Miyazono, K., Ehata, S., & Koinuma, D. (2011) · Upsala Journal of Medical Sciences · doi:10.3109/03009734.2011.638729 · Cited by 106
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MYC as a Multifaceted Regulator of Tumor Microenvironment Leading to Metastasis
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Epithelial-mesenchymal transitions and hepatocarcinogenesis
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“EMT is observed in subsets of carcinoma cells undergoing phenotypic conversion for invasion and metastasis and is characterized by the loss of epithelial cell junction proteins, such as E-cadherin, and the gain of mesenchymal markers, such as vimentin and N-cadherin (36).”
BackgroundThe Cancer Stem Cell Hypothesis: A Guide to Potential Molecular Targets
Allegra, A., Alonci, A., Penna, G., Innao, V., Gerace, D. G., Rotondo, F., & Musolino, C. (2014) · Cancer Investigation · doi:10.3109/07357907.2014.958231 · Cited by 107
“enchymal (N-cadherin expression, mesenchymal morphology, enhanced migration abilities) (111,112).”
BackgroundLee, H. H., Jung, J., Moon, A., Kang, H., & Cho, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133143 · Cited by 101
“Cancer cells undergoing the EMT process exhibit upregulated expression of N-cadherin, vimentin, fibronectin, and snail and downregulated expression of E-cadherin [60].”
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“Type 3 EMT also occurs in adult tissues and involves the mesenchymal transition of epithelial carcinoma cells, leading to generation of metastatic tumor cells [38].”
BackgroundOkon, I. S., Coughlan, K. A., Zhang, M., Wang, Q., & Zou, M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.631580 · Cited by 102
“Consistent with EMT, the formation of motile cells from parental cells that lack such motility have been shown to be a hallmark of invasive and metastatic phenotypes displayed by tumors (12, 16, 17).”
BackgroundDu, X., Shimizu, A., Masuda, Y., Kuwahara, N., Arai, T., Kataoka, M., Uchiyama, M., Kaneko, T., Akimoto, T., Iino, Y., et al. (2012) · Laboratory Investigation · doi:10.1038/labinvest.2012.68 · Cited by 102
Endothelial Induced EMT in Breast Epithelial Cells with Stem Cell Properties
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“creased mobility and an invasive phenotype [3,4,5].”
Karagiannis, G. S., Petraki, C. D., Prassas, I., Saraon, P., Musrap, N., Dimitromanolakis, A., & Diamandis, E. P. (2012) · Oncotarget · doi:10.18632/oncotarget.451 · Cited by 103
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Evidence for and against epithelial-to-mesenchymal transition in the liver
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“EMT has been categorized into three different subtypes based on the biological context in which it occurs: development and organogenesis (type 1); wound healing, tissue, regeneration and organ fibrosis (type 2); and carcinogenesis (type 3) (28, 29, 94).”
BackgroundInfluentialKurahara, H., Takao, S., Maemura, K., Mataki, Y., Kuwahata, T., Maeda, K., Ding, Q., Sakoda, M., Iino, S., Ishigami, S., et al. (2011) · Journal of Surgical Oncology · doi:10.1002/jso.23020 · Cited by 101
“Activation of the EMT program, in which cancer cells acquire a mesenchymal phenotype, has been proposed as the critical mechanism for the progression of epithelial cancer cells [3,4].”
BackgroundInflammation Fuels Tumor Progress and Metastasis
Liu, J., Lin, P. C., & Zhou, B. P. (2015) · Current Pharmaceutical Design · doi:10.2174/1381612821666150514105741 · Cited by 103
Tiberti, S., Catozzi, C., Croci, O., Ballerini, M., Cagnina, D., Soriani, C., Scirgolea, C., Gong, Z., He, J.-T., Macandog, A. D. G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34467-3 · Cited by 103
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Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis
Hultgren, N. W., Fang, J. S., Ziegler, M. E., Ramírez, R. N., Phan, D. T. T., Hatch, M. M. S., Welch, K. M., Paniagua, A. E., Kim, L. S., Shon, N. N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18633-z · Cited by 104
Epithelial-to-mesenchymal transition and stem cells in endometrial cancer
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“This EMT promotes the interaction of tumor cells with the stroma, thus facilitating invasion and metastasis [17,18].”
BackgroundCancer of the Pancreas: Molecular Pathways and Current Advancement in Treatment
Polireddy, K., & Chen, Q. (2016) · Journal of Cancer · doi:10.7150/jca.14922 · Cited by 103
“During type 3 EMT, some cells retain epithelial traits while acquiring mesenchymal features and other cells shed most epithelial features and become fully mesenchymal (45, 46).”
BackgroundHypoxia Stimulates the EMT of Gastric Cancer Cells through Autocrine TGFβ Signaling
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“In epithelial cancers, EMT is recognized as one of the mechanisms responsible for initiating the invasive and metastatic behaviors [3–5].”
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“This was described as one of the three EMT subtypes that occurs, and is also suggested to be an underlying mechanism for derivation of hESC-MSCs (Zeisberg and Neilson, 2009; Ullmann et al., 2007).”
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MiR-30a-5p Suppresses Tumor Metastasis of Human Colorectal Cancer by Targeting ITGB3
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“Reduced expression of the epithelial-specific marker E-cadherin, accompanied by increased expression of the mesenchymal-specific marker vimentin, is indicative of EMT (Zeisberg and Neilson, 2009).”
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“is typically characterized by decrease in expression of epithelial markers such as E-cadherin, and increase in expression of mesenchymal markers such as vimentin [18].”
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“Cells undergoing EMT, in addition to losing inter-cellular junctions, lose epithelial cell polarity, gain a fibroblast-like shape, down-regulate epithelial markers such as E-cadherin, claudins, occludins and cytokeratins, and up-regulate mesenchymal markers such as S100A4 (also called FSP1(Fibroblast-Specific Protein…”
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Sarcomatoid renal cell carcinoma is an example of epithelial–mesenchymal transition
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“We further examined the status of actin in the cells by TRITC-conjugated phalloidin staining, since actin reorganization occurs during the EMT process.(17) In contrast to untreated cells (Fig.”
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Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs
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“During the EMT process, epithelial cells lose their phenotypes, with a downregulation of E-cadherin and α-catenin and acquire mesenchymal markers (N-cadherin, vimentin, fibronectin) leading to cell mobility and invasiveness (Zeisberg and Neilson, 2009).”
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“Besides, during EMT, epithelial marker Ecadherin is downregulated, and mesenchymal markers vimentin and N-cadherin are upregulated through regulating different EMT-related signaling pathways [7].”
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Molecular Signaling in Tumorigenesis of Gastric Cancer
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“Changes in gene expression associated with EMT include down-regulation of epithelial markers including E-cadherin and upregulation of mesenchymal markers including vimentin, α-smooth muscle actin, N-cadherin, and fibronectin [ 31 ].”
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Metadata
- Authors
- Zeisberg, M., & Neilson, E. G.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Vanderbilt University (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2009-06-01
- Volume
- 119
- Issue
- 6
- Pages
- 1429-1437
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2689132
- OpenAlex
- W1996118868
- Cited by
- 2,299
- References
- 124
- Citations by year
- 2026: 50 · 2025: 79 · 2024: 127 · 2023: 113 · 2022: 146 · 2021: 148 · 2020: 180 · 2019: 163 · 2018: 170 · 2017: 189 · 2016: 153 · 2015: 162 · 2014: 162 · 2013: 149 · 2012: 109
- FWCI
- 8.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R03DK081687, R01DK046282, DK46282, K08DK074558, DK-081687, DK074558)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- epithelial-mesenchymal transition, cellular plasticity, epithelial cells, endothelial cells, cell motility
- MeSH terms
- Animals, Cell Differentiation, Epithelial Cells, Fibroblasts, Humans, Neoplasms, Biomarkers, Mesenchymal Stem Cells
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