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The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Microenvironment".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 90396

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Special Issue Editors

Dr. Maurizio Onisto

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Guest Editor

Department of Biomedical Sciences, University of Padova, 35100 Padua, Italy
Interests: extra-cellular matrix (ECM) turn-over and remodeling; matrix–metalloproteinases (MMPs) and TIMPs; heparanase; tumor invasiveness and metastasis; epithelial to mesenchymal transition (EMT); SPATA2 (spermatogenesis-associated protein 2)
Special Issues, Collections and Topics in MDPI journals

Dr. Valentina Masola

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Assistant Guest Editor

1. Department of Biomedical Sciences, University of Padova, 35100 Padua, Italy
2. Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Piazzale A. Stefani 1, 37126 Verona, Italy
Interests: heparanase; organ fibrosis; inflammation; renal physiology; renal pathology; acute and chronic renal injury; epithelial to mesenchymal transition (EMT); molecular mechanisms in cancer progression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Epithelial to Mesenchymal Transition (EMT) was originally described during embryonic development and later was observed in several pathological events, including tissue fibrosis, tumor invasiveness, and metastasis. During EMT, epithelial cells lose adhesion junctions and apical–basal polarity and acquire a mesenchymal phenotype with an enhanced motility. EMT can be considered as a continuum, whereby cells exhibit epithelial, intermediate, and mesenchymal phenotypes, thus contributing to cells’ heterogeneity. Various studies on fibrosis and tumor experimental models strongly support the notion that EMT is a key mechanism for these pathological events. However, the real impact of the EMT on the progression of these disorders is still far from fully understood. In this Special Issue, the focus will be the identification of signaling pathways leading to the activation of EMT programs during physiological and pathological processes in order to provide new knowledge on the plasticity of cellular phenotypes and possible therapeutic interventions.

Prof. Maurizio Onisto
Dr. Valentina Masola
Guest Editors

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Keywords

epithelial to mesenchymal transition (EMT)
tumor-associated EMT
mesenchymal to epithelial transition (MET)
cancer stem cells
tumor migration and metastasis
EMT and fibrosis
TGF-b and EMT induction
EMT and embryonic development
EMT and extracellular matrix (ECM) degradation
EMT and epigenetic control

Published Papers (13 papers)

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Research

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20 pages, 3262 KiB

Open AccessArticle

Lumican Inhibits In Vivo Melanoma Metastasis by Altering Matrix-Effectors and Invadopodia Markers

by Konstantina Karamanou, Marco Franchi, Isabelle Proult, Romain Rivet, Demitrios Vynios and Stéphane Brézillon

Cells 2021, 10(4), 841; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040841 - 08 Apr 2021

Cited by 11 | Viewed by 3200

Abstract

It was reported that lumican inhibits the activity of metalloproteinase MMP-14 and melanoma cell migration in vitro and in vivo. Moreover, Snail triggers epithelial-to-mesenchymal transition and the metastatic potential of cancer cells. Therefore, the aim of this study was to examine the effect of lumican on Mock and Snail overexpressing melanoma B16F1 cells in vivo. Lung metastasis was analyzed after intravenous injections of Mock-B16F1 and Snail-B16F1 cells in Lum^+/+ and Lum^−/− mice. At day 14, mice were sacrificed, and lungs were collected. The number of lung metastatic nodules was significantly higher in mice injected with Snail-B16F1 cells as compared to mice injected with Mock-B16F1 cells confirming the pro-metastatic effect of Snail. This effect was stronger in Lum^−/− mice as compared to Lum^+/+, suggesting that endogenous lumican of wild-type mice significantly inhibits metastasis to lungs. Scanning electron and confocal microscopy investigations demonstrated that lumican inhibits the development of elongated cancer cell phenotypes which are known to develop invadopodia releasing MMPs. Moreover, lumican was shown to affect the expression of cyclin D1, cortactin, vinculin, hyaluronan synthase 2, heparanase, MMP-14 and the phosphorylation of FAK, AKT, p130 Cas and GSK3α/β. Altogether, these data demonstrated that lumican significantly inhibits lung metastasis in vivo, as well as cell invasion in vitro, suggesting that a lumican-based strategy targeting Snail-induced metastasis could be useful for melanoma treatment. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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19 pages, 3737 KiB

Open AccessFeature PaperArticle

ΕGFR/ERβ-Mediated Cell Morphology and Invasion Capacity Are Associated with Matrix Culture Substrates in Breast Cancer

by Konstantina Kyriakopoulou, Eirini Riti, Zoi Piperigkou, Konstantina Koutroumanou Sarri, Heba Bassiony, Marco Franchi and Nikos K. Karamanos

Cells 2020, 9(10), 2256; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102256 - 08 Oct 2020

Cited by 8 | Viewed by 2844

Abstract

Breast cancer accounts for almost one in four cancer diagnoses in women. Studies in breast cancer patients have identified several molecular markers, indicators of aggressiveness, which help toward more individual therapeutic approaches. In triple-negative breast cancer (TNBC), epidermal growth factor receptor (EGFR) overexpression is associated with increased metastatic potential and worst survival rates. Specifically, abnormal EGFR activation leads to altered matrix metalloproteinases’ (MMPs) expression and, hence, extracellular matrix (ECM) degradation, resulting in induced migration and invasion. The use of matrix substrates for cell culture gives the opportunity to mimic the natural growth conditions of the cells and their microenvironment, as well as cell–cell and cell–matrix interactions. The aim of this study was to evaluate the impact of EGFR inhibition, estrogen receptor beta (ERβ) and different matrix substrates [type I collagen and fibronectin (FN)] on the functional properties, expression of MMPs and cell morphology of ERβ-positive TNBC cells and shERβ ones. Our results highlight EGFR as a crucial regulator of the expression and activity levels of MMPs, while ERβ emerges as a mediator of MMP7 and MT1-MMP expression. In addition, the EGFR/ERβ axis impacts the adhesion and invasion potential of breast cancer cells on collagen type I. Images obtained by scanning electron microscope (SEM) from cultures on the different matrix substrates revealed novel observations regarding various structures of breast cancer cells (filopodia, extravesicles, tunneling nanotubes, etc.). Moreover, the significant contribution of EGFR and ERβ in the morphological characteristics of these cells is also demonstrated, hence highlighting the possibility of dual pharmacological targeting. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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16 pages, 10149 KiB

Open AccessFeature PaperArticle

Extracellular Matrix-Mediated Breast Cancer Cells Morphological Alterations, Invasiveness, and Microvesicles/Exosomes Release

by Marco Franchi, Zoi Piperigkou, Konstantinos-Athanasios Karamanos, Leonardo Franchi and Valentina Masola

Cells 2020, 9(9), 2031; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092031 - 04 Sep 2020

Cited by 36 | Viewed by 6064

Abstract

Breast cancer is a leading disease in women. Several studies are focused to evaluate the critical role of extracellular matrix (ECM) in various biochemical and molecular aspects but also in terms of its effect on cancer cell morphology and therefore on cancer cell invasion and metastatic potential. ECM fibrillar components, such as collagen and fibronectin, affect cell behavior and properties of mammary cancer cells. The aim of this study was to investigate using the scanning electron microscopy (SEM) how the highly invasive MDA-MB-231 breast cancer cells, interplaying with ECM substrates during cell migration/invasion, modify their morphological characteristics and cytoplasmic processes in relation to their invasive potential. In particular we reproduced and analyzed how natural structural barriers to cancer cell invasion, such as the basement membrane (Matrigel) and fibrillar components of dermis (fibronectin as well as the different concentrations/array of type I collagen), could induce morphological changes in 3D cultures. Interestingly, we demonstrate that, even with different effects, all collagen concentrations/arrays lead to morphological alterations of breast cancer cells. Intriguingly, the elongated mesenchymal shaped cells were more prominent in 3D cultures with a dense and thick substrate (thick Matrigel, high concentrated collagen network, and densely packed collagen fibers), even though cells with different shape produced and released microvesicles and exosomes as well. It is therefore evident that the peri-tumoral collagen network may act not only as a barrier but also as a dynamic scaffold which stimulates the morphological changes of cancer cells, and modulates tumor development and metastatic potential in breast cancer. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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11 pages, 2248 KiB

Open AccessFeature PaperArticle

Glypican-1 Level Is Elevated in Extracellular Vesicles Released from MC38 Colon Adenocarcinoma Cells Overexpressing Snail

by Izabela Papiewska-Pająk, Damian Krzyżanowski, Maria Katela, Romain Rivet, Sylwia Michlewska, Patrycja Przygodzka, M. Anna Kowalska and Stéphane Brézillon

Cells 2020, 9(7), 1585; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9071585 - 30 Jun 2020

Cited by 9 | Viewed by 3720

Abstract

The transcription factor Snail triggers epithelial-to-mesenchymal transition (EMT), endowing cancer cells with invasive properties during tumor progression. Extracellular vesicles (EVs) released from cancer cells at various stages of cancer progression are known to influence the tumor pre-metastatic niche and metastatic potential. The aim of this study was to analyze the effect of Snail on murine colon adenocarcinoma cells (MC38 line) and on the characteristics of their EVs. Stable clones of Snail-overexpressing MC38 cells were investigated in vitro versus Mock cells. Increased expression of matrix metalloproteinase MMP-14 and augmented activity of MMP-9 and -14 were observed in Snail-MC38 cells. There was no change in the transcriptomic profile of proteoglycans in Snail-MC38 cells; however, the protein level of Glypican-1 (GPC1) was enhanced in EVs released from those cells. Our finding that GPC1 protein level was enhanced in EVs released from MC38 cells that overexpressed Snail and were in an early EMT stage might explain the specificity of the GPC1 biomarker in colon cancer diagnosis. Further, our data suggest that Snail, by changing the level of GPC1 on EVs released by colon cancer cells, may affect the generation of a distant premetastatic niche and metastatic organotropism in colon adenocarcinoma. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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15 pages, 3741 KiB

Open AccessArticle

BMP-2 Variants in Breast Epithelial to Mesenchymal Transition and Microcalcifications Origin

by Manuel Scimeca, Raffaella Giocondo, Manuela Montanaro, Annarita Granaglia, Rita Bonfiglio, Virginia Tancredi, Alessandro Mauriello, Nicoletta Urbano, Orazio Schillaci and Elena Bonanno

Cells 2020, 9(6), 1381; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9061381 - 02 Jun 2020

Cited by 20 | Viewed by 2482

Abstract

This study aims to investigate the possible different roles of the BMP-2 variants, cytoplasmic and nuclear variant, in both epithelial to mesenchymal transition and in microcalcifications origin in human breast cancers. To this end, the in situ expression of cytoplasmic and nuclear BMP-2 was associated with the expression of the main epithelial to mesenchymal transition biomarkers (e-cadherin and vimentin) and molecules involved in bone metabolisms (RUNX2, RANKL, SDF-1) by immunohistochemistry. In addition, the expression of cytoplasmic and nuclear BMP-2 was associated with the presence of microcalcifications. Our data showed a significant association among the number of cytoplasmic BMP-2-positive cells and the number of both vimentin (positive association) and e-cadherin (negative association) positive breast cells. Conversely, no associations were found concerning the nuclear BMP-2-positive breast cells. Surprisingly, the opposite result was obtained by analyzing the variants of BMP-2 and both the expression of RANKL and SDF-1 and the presence of microcalcifications. Specifically, the presence of microcalcifications was related to the expression of nuclear BMP-2 variant rather than the cytoplasmic one, as well as a strong association between the number of nuclear BMP-2 and the expression of the main breast osteoblast-like cells (BOLCs) biomarkers. To further corroborate these data, an in vitro experiment for demonstrating the co-expression of nBMP-2 and RANKL or vimentin or SDF-1 in breast cancer cells that acquire the capability to produce microcalcifications was developed. These investigations confirmed the association between the nBMP-2 expression and both RANKL and SDF-1. The data supports the idea that whilst cytoplasmic BMP-2 can be involved in epithelial to mesenchymal transition phenomenon, the nuclear variant is related to the essential mechanisms for the formation of breast microcalcifications. In conclusion, from these experimental and translational perspectives, the complexity of BMP-2 signaling will require a detailed understanding of the involvement of specific BMP-2 variants in breast cancers. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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17 pages, 3821 KiB

Open AccessArticle

Succinate Activates EMT in Intestinal Epithelial Cells through SUCNR1: A Novel Protagonist in Fistula Development

by Dolores Ortiz-Masiá, Laura Gisbert-Ferrándiz, Cristina Bauset, Sandra Coll, Céline Mamie, Michael Scharl, Juan V. Esplugues, Rafael Alós, Francisco Navarro, Jesús Cosín-Roger, María D. Barrachina and Sara Calatayud

Cells 2020, 9(5), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9051104 - 29 Apr 2020

Cited by 28 | Viewed by 4241

Abstract

The pathogenesis of Crohn’s disease-associated fibrostenosis and fistulas imply the epithelial-to-mesenchymal transition (EMT) process. As succinate and its receptor (SUCNR1) are involved in intestinal inflammation and fibrosis, we investigated their relevance in EMT and Crohn’s disease (CD) fistulas. Succinate levels and SUCNR1-expression were analyzed in intestinal resections from non-Inflammatory Bowel Disease (non-IBD) subjects and CD patients with stenosing-B2 or penetrating-B3 complications and in a murine heterotopic-transplant model of intestinal fibrosis. EMT, as increased expression of Snail1, Snail2 and vimentin and reduction in E-cadherin, was analyzed in tissues and succinate-treated HT29 cells. The role played by SUCNR1 was studied by silencing its gene. Succinate levels and SUCNR1 expression are increased in B3-CD patients and correlate with EMT markers. SUCNR1 is detected in transitional cells lining the fistula tract and in surrounding mesenchymal cells. Grafts from wild type (WT) mice present increased succinate levels, SUCNR1 up-regulation and EMT activation, effects not observed in SUCNR1^−/− tissues. SUCNR1 activation induces the expression of Wnt ligands, activates WNT signaling and induces a WNT-mediated EMT in HT29 cells. In conclusion, succinate and its receptor are up-regulated around CD-fistulas and activate Wnt signaling and EMT in intestinal epithelial cells. These results point to SUCNR1 as a novel pharmacological target for fistula prevention. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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19 pages, 4435 KiB

Open AccessArticle

Decreased Placental FPR2 in Early Pregnancies That Later Developed Small-For-Gestation Age: A Potential Role of FPR2 in the Regulation of Epithelial-Mesenchymal Transition

by Padma Murthi, Gayathri Rajaraman, Jan Jaap H.M. Erwich and Evdokia Dimitriadis

Cells 2020, 9(4), 921; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040921 - 10 Apr 2020

Cited by 7 | Viewed by 2694

Abstract

We reported earlier that an anti-inflammatory small peptide receptor-formyl peptide receptor-2 (FPR2) was significantly decreased in placentas from third trimester pregnancies complicated with fetal growth restriction (FGR), compared to placentas from uncomplicated control pregnancies, suggesting FPR2 may play a role in the development of FGR. The aim of this study is to investigate whether the actions of FPR2 alters placental growth process in humans. Accordingly, using small-for-gestation age (SGA) as a proxy for FGR, we hypothesize that FPR2 expression is decreased in first-trimester placentas of women who later manifest FGR, and contributes to aberrant trophoblast function and the development of FGR. Chorionic villus sampling (CVS) tissues were collected at 10–12 weeks gestation in 70 patients with singleton fetuses; surplus tissue was used. Real-time PCR and immunoassays were performed to quantitate FPR2 gene and protein expression. Silencing of FPR2 was performed in two independent, trophoblast-derived cell lines, HTR-8/SVneo and JEG-3 to investigate the functional consequences of FPR2 gene downregulation. FPR2 mRNA relative to 18S rRNA was significantly decreased in placentae from SGA-pregnancies (n = 28) compared with controls (n = 52) (p < 0.0001). Placental FPR2 protein was significantly decreased in SGA compared with control (n = 10 in each group, p < 0.05). Proliferative, migratory and invasive potential of the human placental-derived cell lines, HTR-8/SVneo and JEG-3 were significantly reduced in siFPR2 treated cells compared with siCONT control groups. Down-stream signaling molecules, STAT5B and SOCS3 were identified as target genes of FPR2 action in the trophoblast-derived cell lines and in SGA and control chorionic villous tissues. FPR2 is a novel regulator of key molecular pathways and functions in placental development, and its decreased expression in women destined to develop FGR reinforces a placental origin of SGA/FGR, and that it contributes to causing the development of SGA/FGR. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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22 pages, 4203 KiB

Open AccessArticle

CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma

by Shin Pai, Oluwaseun Adebayo Bamodu, Yen-Kuang Lin, Chun-Shu Lin, Pei-Yi Chu, Ming-Hsien Chien, Liang-Shun Wang, Michael Hsiao, Chi-Tai Yeh and Jo-Ting Tsai

Cells 2019, 8(12), 1658; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8121658 - 17 Dec 2019

Cited by 46 | Viewed by 5679

Abstract

Background: Oral squamous cell carcinoma (OSCC), with high mortality rates, is one of the most diagnosed head and neck cancers. Epithelial-to-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two keys for therapy-resistance, relapse, and distant metastasis. Accumulating evidence indicates that aberrantly expressed cluster of differentiation (CD)47 is associated with cell-death evasion and metastasis; however, the role of CD47 in the generation of CSCs in OSCC is not clear. Methods: We investigated the functional roles of CD47 in OSCC cell lines SAS, TW2.6, HSC-3, and FaDu using the bioinformatics approach, immunoblotting, immunofluorescence staining, and assays for cellular migration, invasion, colony, and orosphere formation, as well as radiosensitivity. Results: We demonstrated increased expression of CD47 in OSCC patients was associated with an estimated poorly survival disadvantage (p = 0.0391) and positively correlated with the expression of pluripotency factors. Silencing CD47 significantly suppressed cell viability and orosphere formation, accompanied by a downregulated expression of CD133, SRY-Box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and c-Myc. In addition, CD47-silenced OSCC cells showed reduced EMT, migration, and clonogenicity reflected by increased E-cadherin and decreased vimentin, Slug, Snail, and N-cadherin expression. Conclusion: Of therapeutic relevance, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Collectively, we showed an increased CD47 expression promoted the generation of CSCs and malignant OSCC phenotypes. Silencing CD47, in combination with radiation, could provide an alternative and improved therapeutic efficacy for OSCC patients. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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20 pages, 5982 KiB

Open AccessArticle

Leptin Promotes Expression of EMT-Related Transcription Factors and Invasion in a Src and FAK-Dependent Pathway in MCF10A Mammary Epithelial Cells

by Monserrat Olea-Flores, Miriam Zuñiga-Eulogio, Arvey Tacuba-Saavedra, Magdalena Bueno-Salgado, Andrea Sánchez-Carvajal, Yovani Vargas-Santiago, Miguel A. Mendoza-Catalán, Eduardo Pérez Salazar, Alejandra García-Hernández, Teresita Padilla-Benavides and Napoleón Navarro-Tito

Cells 2019, 8(10), 1133; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101133 - 24 Sep 2019

Cited by 35 | Viewed by 5572

Abstract

Leptin is one of the main adipokines secreted in breast tissue. Leptin promotes epithelial–mesenchymal transition (EMT), cell migration and invasion in epithelial breast cells, leading to tumor progression. Although, the molecular mechanisms that underlie these events are not fully understood, the activation of different signaling pathways appears to be essential. In this sense, the effects of leptin on the activation of kinases like Src and FAK, which regulate signaling pathways that activate the EMT program, are not completely described. Therefore, we investigated the involvement of these kinases using an in vitro model for leptin-induced EMT process in the non-tumorigenic MCF10A cell line. To this end, MCF10A cells were stimulated with leptin, and Src and FAK activation was assessed. Specific events occurring during EMT were also evaluated in the presence or absence of the kinases’ chemical inhibitors PP2 and PF-573228. For instance, we tested the expression and subcellular localization of the EMT-related transcription factors Twist and β-catenin, by western blot and immunofluorescence. We also evaluated the secretion and activation of matrix metalloproteases (MMP-2 and MMP-9) by gelatin zymography. Invasiveness properties of leptin-stimulated cells were determined by invadopodia formation assays, and by the Transwell chamber method. Our results showed that leptin promotes EMT through Src and FAK activation, which leads to the secretion and activation of MMP-2 and MMP-9, invadopodia formation and cell invasion in MCF10A cells. In conclusion, our data suggest that leptin promotes an increase in the expression levels of Twist and β-catenin, the secretion of MMP-2, MMP-9, the invadopodia formation and invasion in MCF10A cells in a Src and FAK-dependent manner. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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Review

Jump to: Research

20 pages, 1902 KiB

Open AccessFeature PaperReview

E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT

by Michele Sommariva and Nicoletta Gagliano

Cells 2020, 9(4), 1040; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9041040 - 22 Apr 2020

Cited by 53 | Viewed by 6807

Abstract

Epithelial-to-mesenchymal transition (EMT) is a step-wise process observed in normal and tumor cells leading to a switch from epithelial to mesenchymal phenotype. In tumors, EMT provides cancer cells with a metastatic phenotype characterized by E-cadherin down-regulation, cytoskeleton reorganization, motile and invasive potential. E-cadherin down-regulation is known as a key event during EMT. However, E-cadherin expression can be influenced by the different experimental settings and environmental stimuli so that the paradigm of EMT based on the loss of E-cadherin determining tumor cell behavior and fate often becomes an open question. In this review, we aimed at focusing on some critical points in order to improve the knowledge of the dynamic role of epithelial cells plasticity in EMT and, specifically, address the role of E-cadherin as a marker for the EMT axis. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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21 pages, 1297 KiB

Open AccessReview

The Emerging Roles of Exosomes as EMT Regulators in Cancer

by Hyunwoo Kim, Sungmin Lee, Eunguk Shin, Ki Moon Seong, Young Woo Jin, HyeSook Youn and BuHyun Youn

Cells 2020, 9(4), 861; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040861 - 02 Apr 2020

Cited by 82 | Viewed by 7051

Abstract

Epithelial–mesenchymal transition (EMT) causes epithelial cells to lose their polarity and adhesion property, and endows them with migratory and invasive properties to enable them to become mesenchymal stem cells. EMT occurs throughout embryonic development, during wound healing, and in various pathological processes, including tumor progression. Considerable research in the last few decades has revealed that EMT is invariably related to tumor aggressiveness and metastasis. Apart from the interactions between numerous intracellular signaling pathways known to regulate EMT, extracellular modulators in the tumor microenvironment also influence tumor cells to undergo EMT, with extracellular vesicles (EVs) receiving increasing attention as EMT inducers. EVs comprise exosomes and microvesicles that carry proteins, nucleic acids, lipids, and other small molecules to stimulate EMT in cells. Among EVs, exosomes have been investigated in many studies, and their role has been found to be significant with respect to regulating intercellular communications. In this review, we summarize recent studies on exosomes and their cargoes that induce cancer-associated EMT. Furthermore, we describe the possible applications of exosomes as promising therapeutic strategies. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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13 pages, 1139 KiB

Open AccessReview

Hybrid Epithelial/Mesenchymal State in Cancer Metastasis: Clinical Significance and Regulatory Mechanisms

by Tsai-Tsen Liao and Muh-Hwa Yang

Cells 2020, 9(3), 623; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9030623 - 04 Mar 2020

Cited by 59 | Viewed by 6022

Abstract

Epithelial-mesenchymal transition (EMT) has been well recognized for its essential role in cancer progression as well as normal tissue development. In cancer cells, activation of EMT permits the cells to acquire migratory and invasive abilities and stem-like properties. However, simple categorization of cancer cells into epithelial and mesenchymal phenotypes misleads the understanding of the complicated metastatic process, and contradictory results from different studies also indicate the limitation of application of EMT theory in cancer metastasis. Nowadays, growing evidence suggests the existence of an intermediate status between epithelial and mesenchymal phenotypes, i.e., the “hybrid epithelial-mesenchymal (hybrid E/M)” state, provides a possible explanation for those conflicting results. Appearance of hybrid E/M phenotype offers a more plastic status for cancer cells to adapt the stressful environment for proceeding metastasis. In this article, we review the biological importance of the dynamic changes between the epithelial and the mesenchymal states. The regulatory mechanisms encompassing the translational, post-translational, and epigenetic control for this complex and plastic status are also discussed. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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33 pages, 2337 KiB

Open AccessEditor’s ChoiceReview

The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges

by Chin-Yap Loh, Jian Yi Chai, Ting Fang Tang, Won Fen Wong, Gautam Sethi, Muthu Kumaraswamy Shanmugam, Pei Pei Chong and Chung Yeng Looi

Cells 2019, 8(10), 1118; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8101118 - 20 Sep 2019

Cited by 689 | Viewed by 32892

Abstract

Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside. Full article

(This article belongs to the Special Issue The Multifaceted Nature of Epithelial to Mesenchymal Transition (EMT): From Embryonic Development to Cellular Plasticity in Normal Tissue and Tumors)

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