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Cells
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Epithelial–Mesenchymal Transition and Hallmarks of Cancer
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Epithelial–Mesenchymal Transition and Hallmarks of Cancer

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (1 July 2019) | Viewed by 34784

Special Issue Editors

Dr. Eugene Tulchinsky

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Guest Editor
Department of Genetics and Genome Biology, University of Leicester, RKCSB, LRI, Leicester LE2 7LX, UK
Interests: epithelial–mesenchymal transition; hallmarks of cancer; cell stemness; cell cycle regulation; apoptosis; DNA repair; genetic instability; mesenchymal–epithelial transition
Special Issues, Collections and Topics in MDPI journals
Dr. A. Emre Sayan

E-Mail Website
Guest Editor
Faculty of Medicine and CRUK Center, University of Southampton, Southampton SO16 6YD, UK
Interests: epithelial–mesenchymal transition; DNA repair; tumour microenvironment; therapy resistance; biomarker discovery; drug discovery
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epithelial–mesenchymal transition (EMT) is a reversible embryonic genetic program that is often reactivated in cancer. During EMT, cells lose their epithelial appearance, and dissolute intercellular adhesion complexes, which are the determinants of apico-basal polarity. These changes are associated with the global cytoskeletal reorganisation; cells adopt mesenchymal back-front polarity and the ability to migrate individually. During the reverse program, mesenchymal–epithelial transition (MET), cells restore epithelial morphology; this is a process that is important for the establishment of epithelial tissues in embryos. In cancer, reversible EMT/MET programs represent the basis of tumour cell plasticity. The ability to transit between epithelial and mesenchymal states is a prerequisite for the successful completion of a metastatic process. It is accepted that in the mesenchymal state, cells withstand oncogenic insults and avoid cellular failsafe programs. More motile and invasive mesenchymal cells are capable of intravasation; they form pools of circulating tumour cells, which survive in the circulation for long periods of time. Cells of growing carcinomas maintain epithelial characteristics in most cases; extravasated cells restore epithelial morphology and form metastases in target organs. Tumour cell plasticity affects most if not all hallmarks of cancer. EMT/MET programs alter cell cycle progression, apoptotic response, and cell stemness escape from host-immune surveillance; they influence DNA repair mechanisms and chromosomal instability and regulate metabolic pathways. Epithelial–mesenchymal plasticity is an important factor affecting tumour responses to conventional and targeted therapies.

In this Special Issue of Cells, we collect original reports and review articles, which highlight the interrelationship between tumour cell plasticity and hallmarks of cancer. This knowledge is important for the development of new approaches in cancer treatment.

Dr. Eugene Tulchinsky
Dr. A. Emre Sayan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • epithelial–mesenchymal transition
  • hallmarks of cancer
  • cell stemness
  • cell cycle regulation
  • apoptosis
  • DNA repair
  • genetic instability
  • mesenchymal–epithelial transition

Published Papers (7 papers)

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Research

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18 pages, 2919 KiB  
Article
Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells
by Bálint Szeder, Júlia Tárnoki-Zách, Dóra Lakatos, Virág Vas, Gyöngyi Kudlik, Balázs Merő, Kitti Koprivanacz, László Bányai, Lilla Hámori, Gergely Róna, András Czirók, András Füredi and László Buday
Cells 2019, 8(11), 1343; https://doi.org/10.3390/cells8111343 - 29 Oct 2019
Cited by 9 | Viewed by 3651
Abstract
Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this [...] Read more.
Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this study, the function of Tks4 was investigated in HCT116 colon cancer cells by knocking the protein out using the CRISPR/Cas9 system. Surprisingly, the absence of Tks4 induced significant changes in cell morphology, motility, adhesion and expression, and localization of E-cadherin, which are all considered as hallmarks of EMT. In agreement with these findings, the marked appearance of fibronectin, a marker of the mesenchymal phenotype, was also observed in Tks4-KO cells. Analysis of the expression of well-known EMT transcription factors revealed that Snail2 was strongly overexpressed in cells lacking Tks4. Tks4-KO cells showed increased motility and decreased cell–cell attachment. Collagen matrix invasion assays demonstrated the abundance of invasive solitary cells. Finally, the reintroduction of Tks4 protein in the Tks4-KO cells restored the expression levels of relevant key transcription factors, suggesting that the Tks4 scaffold protein has a specific and novel role in EMT regulation and cancer progression. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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18 pages, 2404 KiB  
Article
The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition
by Burcu Sengez, Ilkin Aygün, Huma Shehwana, Neslihan Toyran, Sanem Tercan Avci, Ozlen Konu, Marc P. Stemmler and Hani Alotaibi
Cells 2019, 8(8), 858; https://doi.org/10.3390/cells8080858 - 09 Aug 2019
Cited by 23 | Viewed by 5869
Abstract
The epithelial to mesenchymal transition (EMT) and the mesenchymal to epithelial transition (MET) are two critical biological processes that are involved in both physiological events such as embryogenesis and development and also pathological events such as tumorigenesis. They present with dramatic changes in [...] Read more.
The epithelial to mesenchymal transition (EMT) and the mesenchymal to epithelial transition (MET) are two critical biological processes that are involved in both physiological events such as embryogenesis and development and also pathological events such as tumorigenesis. They present with dramatic changes in cellular morphology and gene expression exhibiting acute changes in E-cadherin expression. Despite the comprehensive understanding of EMT, the regulation of MET is far from being understood. To find novel regulators of MET, we hypothesized that such factors would correlate with Cdh1 expression. Bioinformatics examination of several expression profiles suggested Elf3 as a strong candidate. Depletion of Elf3 at the onset of MET severely impaired the progression to the epithelial state. This MET defect was explained, in part, by the absence of E-cadherin at the plasma membrane. Moreover, during MET, ELF3 interacts with the Grhl3 promoter and activates its expression. Our findings present novel insights into the regulation of MET and reveal ELF3 as an indispensable guardian of the epithelial state. A better understanding of MET will, eventually, lead to better management of metastatic cancers. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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17 pages, 3552 KiB  
Article
Gas6 Prevents Epithelial-Mesenchymal Transition in Alveolar Epithelial Cells via Production of PGE2, PGD2 and Their Receptors
by Jihye Jung, Ye-Ji Lee, Youn-Hee Choi, Eun-Mi Park, Hee-Sun Kim and Jihee L. Kang
Cells 2019, 8(7), 643; https://doi.org/10.3390/cells8070643 - 26 Jun 2019
Cited by 14 | Viewed by 3611
Abstract
The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-β1-induced EMT [...] Read more.
The epithelial-mesenchymal transition (EMT) is important in organ fibrosis. We hypothesized that growth arrest-specific protein 6 (Gas6) and its underlying mechanisms play roles in the prevention of EMT in alveolar epithelial cells (ECs). In this study, to determine whether Gas6 prevents TGF-β1-induced EMT in LA-4 and primary alveolar type II ECs, real-time PCR and immunoblotting in cell lysates and ELISA in culture supernatants were performed. Migration and invasion assays were performed using Transwell chambers. Pretreatment of ECs with Gas6 inhibited TGF-β1-induced EMT based on cell morphology, changes in EMT marker expression, and induction of EMT-activating transcription factors. Gas6 enhanced the levels of cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) and PGD2 as well as of their receptors. COX-2 inhibitors and antagonists of PGE2 and PGD2 receptors reversed the inhibition of TGF-β1-induced EMT, migration, and invasion by Gas6. Moreover, knockdown of Axl or Mer reversed the enhancement of PGE2 and PGD2 and suppression of EMT, migration and invasion by Gas6. Our data suggest Gas6-Axl or -Mer signalling events may reprogram ECs to resist EMT via the production of PGE2, PGD2, and their receptors. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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18 pages, 3552 KiB  
Article
ROR1 Expression and Its Functional Significance in Hepatocellular Carcinoma Cells
by Metin Cetin, Gorkem Odabas, Leon R. Douglas, Patrick J. Duriez, Pelin Balcik-Ercin, Irem Yalim-Camci, Abdulkadir Emre Sayan and Tamer Yagci
Cells 2019, 8(3), 210; https://doi.org/10.3390/cells8030210 - 02 Mar 2019
Cited by 12 | Viewed by 5474
Abstract
Background: Hepatocellular carcinoma (HCC) is a common and deadly cancer; however, very little improvement has been made towards its diagnosis and prognosis. The expression and functional contribution of the receptor tyrosine kinase ROR1 have not been investigated in HCC before. Hence, we investigated [...] Read more.
Background: Hepatocellular carcinoma (HCC) is a common and deadly cancer; however, very little improvement has been made towards its diagnosis and prognosis. The expression and functional contribution of the receptor tyrosine kinase ROR1 have not been investigated in HCC before. Hence, we investigated the expression of ROR1 in HCC cells and assessed its involvement in hepatocarcinogenesis. Methods: Recombinant bacterial ROR1 protein was used as an immunogen to generate ROR1 monoclonal antibodies. ROR1 transcript levels were detected by RT-qPCR and the protein expression of ROR1 in HCC was assessed by Western blotting by using homemade anti-ROR1 monoclonal antibodies. Apoptosis, cell cycle, trans-well migration, and drug efflux assays were performed in shRNA-ROR1 HCC cell clones to uncover the functional contribution of ROR1 to hepatocarcinogenesis. Results: New ROR1 antibodies specifically detected endogenous ROR1 protein in human and mouse HCC cell lines. ROR1-knockdown resulted in decreased proliferation and migration but enhanced resistance to apoptosis and anoikis. The observed chemotherapy-resistant phenotype of ROR1-knockdown cells was due to enhanced drug efflux and increased expression of multi-drug resistance genes. Conclusions: ROR1 is expressed in HCC and contributes to disease development by interfering with multiple pathways. Acquired ROR1 expression may have diagnostic and prognostic value in HCC. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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18 pages, 3467 KiB  
Article
Cathepsin B Is Upregulated and Mediates ECM Degradation in Colon Adenocarcinoma HT29 Cells Overexpressing Snail
by Jakub Kryczka, Izabela Papiewska-Pajak, M. Anna Kowalska and Joanna Boncela
Cells 2019, 8(3), 203; https://doi.org/10.3390/cells8030203 - 27 Feb 2019
Cited by 31 | Viewed by 5094
Abstract
During tumor development and ongoing metastasis the acquisition of mesenchymal cell traits by epithelial carcinoma cells is achieved through a programmed phenotypic shift called the epithelial-to-mesenchymal transition, EMT. EMT contributes to increased cancer cell motility and invasiveness mainly through invadosomes, the adhesion structures [...] Read more.
During tumor development and ongoing metastasis the acquisition of mesenchymal cell traits by epithelial carcinoma cells is achieved through a programmed phenotypic shift called the epithelial-to-mesenchymal transition, EMT. EMT contributes to increased cancer cell motility and invasiveness mainly through invadosomes, the adhesion structures that accompany the mesenchymal migration. The invadosomes and their associated proteases restrict protease activity to areas of the cell in direct contact with the ECM, thus precisely controlling cell invasion. Our data prove that Snail-overexpressing HT-29 cells that imitate the phenotype of colon cancer cells in the early stage of the EMT showed an increase in the expression and pericellular activity of cathepsin B. It appears that the pericellular localization of cathepsin B, also observed in colon and rectum adenocarcinoma tissue samples, plays a key role in its function. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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22 pages, 3298 KiB  
Article
Activation of Polyamine Catabolism by N1,N11-Diethylnorspermine in Hepatic HepaRG Cells Induces Dedifferentiation and Mesenchymal-Like Phenotype
by Olga N. Ivanova, Anastasiya V. Snezhkina, George S. Krasnov, Vladimir T. Valuev-Elliston, Olga A. Khomich, Alexey R. Khomutov, Tuomo A. Keinanen, Leena Alhonen, Birke Bartosch, Anna V. Kudryavtseva, Sergey N. Kochetkov and Alexander V. Ivanov
Cells 2018, 7(12), 275; https://doi.org/10.3390/cells7120275 - 18 Dec 2018
Cited by 13 | Viewed by 5254
Abstract
Tumorigenesis is accompanied by the metabolic adaptation of cells to support enhanced proliferation rates and to optimize tumor persistence and amplification within the local microenvironment. In particular, cancer cells exhibit elevated levels of biogenic polyamines. Inhibitors of polyamine biosynthesis and inducers of their [...] Read more.
Tumorigenesis is accompanied by the metabolic adaptation of cells to support enhanced proliferation rates and to optimize tumor persistence and amplification within the local microenvironment. In particular, cancer cells exhibit elevated levels of biogenic polyamines. Inhibitors of polyamine biosynthesis and inducers of their catabolism have been evaluated as antitumor drugs, however, their efficacy and safety remain controversial. Our goal was to investigate if drug-induced modulation of polyamine metabolism plays a role in dedifferentiation using differentiated human hepatocyte-like HepaRG cell cultures. N1,N11-diethylnorspermine (DENSpm), a potent inducer of polyamine catabolism, triggered an epithelial-mesenchymal transition (EMT)-like dedifferentiation in HepaRG cultures, as shown by down-regulation of mature hepatocytes markers and upregulation of classical EMT markers. Albeit the fact that polyamine catabolism produces H2O2, DENSpm-induced de-differentiation was not affected by antioxidants. Use of a metabolically stable spermidine analogue showed furthermore, that spermidine is a key regulator of hepatocyte differentiation. Comparative transcriptome analyses revealed, that the DENSpm-triggered dedifferentiation of HepaRG cells was accompanied by dramatic metabolic adaptations, exemplified by down-regulation of the genes of various metabolic pathways and up-regulation of the genes involved in signal transduction pathways. These results demonstrate that polyamine metabolism is tightly linked to EMT and differentiation of liver epithelial cells. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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Review

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16 pages, 636 KiB  
Review
Role of ACTN4 in Tumorigenesis, Metastasis, and EMT
by Dmitri Tentler, Ekaterina Lomert, Ksenia Novitskaya and Nikolai A. Barlev
Cells 2019, 8(11), 1427; https://doi.org/10.3390/cells8111427 - 13 Nov 2019
Cited by 38 | Viewed by 5174
Abstract
The actin-binding protein ACTN4 belongs to a family of actin-binding proteins and is a non-muscle alpha-actinin that has long been associated with cancer development. Numerous clinical studies showed that changes in ACTN4 gene expression are correlated with aggressiveness, invasion, and metastasis in certain [...] Read more.
The actin-binding protein ACTN4 belongs to a family of actin-binding proteins and is a non-muscle alpha-actinin that has long been associated with cancer development. Numerous clinical studies showed that changes in ACTN4 gene expression are correlated with aggressiveness, invasion, and metastasis in certain tumors. Amplification of the 19q chromosomal region where the gene is located has also been reported. Experimental manipulations with ACTN4 expression further confirmed its involvement in cell proliferation, motility, and epithelial-mesenchymal transition (EMT). However, both clinical and experimental data suggest that the effects of ACTN4 up- or down-regulation may vary a lot between different types of tumors. Functional studies demonstrated its engagement in a number of cytoplasmic and nuclear processes, ranging from cytoskeleton reorganization to regulation of different signaling pathways. Such a variety of functions may be the reason behind cell type and cell line specific responses. Herein, we will review research progress and controversies regarding the prognostic and functional significance of ACTN4 for tumorigenesis. Full article
(This article belongs to the Special Issue Epithelial–Mesenchymal Transition and Hallmarks of Cancer)
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