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EMT and Cancer

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 46641

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Prof. Dr. Alan Prem Kumar

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Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
Interests: breast cancer; cancer therapeutics; Wnt signaling; PI3K/Akt signaling; hippo pathway; drug development; biomarker identification; transcription factors; sumoylation
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Dear Colleagues,

Epithelial-to-mesenchymal transition (EMT) is one of the most crucial mechanisms, its role has been explored and defined in both normal and pathological conditions. The EMT is tightly regulated by a variety of molecular pathways whereby epithelial cells obtain more motility by losing their apical–basal polarity and acquire a front–rear polarity that is the characteristic feature of mesenchymal cells. In spite of being vital for some normal cellular processes, cancer cells use the EMT mechanism to enhance their progression and malignancy. However, more knowledge about the role of the EMT in metastasis, its control, and its reversion is needed. To address current and future perspectives on the role of the EMT in cancer, we invite authors to submit research or review articles describing recent findings in their pathology, EMT inducers and their corresponding pathways, EMT involvement in metastasis and drug resistance, chromatin remodeling, mitochondrial remodeling, senescence, and therapeutic perspectives. Cutting-edge studies in therapeutics development and preventive strategies against EMT are highly welcome.

Potential topics in this Special Issue include but are not limited to the following:

Tumor progression with metastatic expansion;
Generation of tumor cells with stem cell properties;
Disruption of cell–cell adhesion and cellular polarity;
Remodeling of the cytoskeleton;
Changes in cell–matrix adhesion;
Tumor microenvironment;
Non-coding RNAs;
Chromatin remodeling and epigenetic modifications;
Regulatory networks involving transcriptional control;

Prof. Dr. Alan Prem Kumar
Guest Editor

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Keywords

EMT and MET
cancer progression
tumor microenvironment
tumor metastasis
cytoskeletal changes
transcription factors
mitochondrial remodeling
senescence

Related Special Issue

EMT and Cancer II in Biomolecules (6 articles)

Published Papers (11 papers)

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Research

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18 pages, 5995 KiB

Open AccessArticle

SCRIB Is Involved in the Progression of Ovarian Carcinomas in Association with the Factors Linked to Epithelial-to-Mesenchymal Transition and Predicts Shorter Survival of Diagnosed Patients

by Usama Khamis Hussein, Asmaa Gamal Ahmed, Won Ku Choi, Kyoung Min Kim, See-Hyoung Park, Ho Sung Park, Sang Jae Noh, Ho Lee, Myoung Ja Chung, Woo Sung Moon, Myoung Jae Kang, Dong Hyu Cho and Kyu Yun Jang

Biomolecules 2021, 11(3), 405; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11030405 - 09 Mar 2021

Cited by 7 | Viewed by 2531

Abstract

SCRIB is a polarity protein important in maintaining cell junctions. However, recent reports have raised the possibility that SCRIB might have a role in human cancers. Thus, this study evaluated the roles of SCRIB in ovarian cancers. In 102 human ovarian carcinomas, nuclear expression of SCRIB predicted shorter survival of ovarian carcinoma patients, especially in the patients who received post-operative chemotherapy. In SKOV3 and SNU119 ovarian cancer cells, overexpression of SCRIB stimulated the proliferation and invasion of cells. Knockout of SCRIB inhibited in vivo tumor growth of SKOV3 cells and overexpression of SCRIB promoted tumor growth. Overexpression of SCRIB stimulated epithelial-to-mesenchymal transition by increasing the expression of N-cadherin, snail, TGF-β1, and smad2/3, and decreasing the expression of E-cadherin; the converse was observed with inhibition of SCRIB. In conclusion, this study presents the nuclear expression of SCRIB as a prognostic marker of ovarian carcinomas and suggests that SCRIB is involved in the progression of ovarian carcinomas by stimulating proliferation and epithelial-to-mesenchymal transition-related invasiveness. Full article

(This article belongs to the Special Issue EMT and Cancer)

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12 pages, 5804 KiB

Open AccessFeature PaperArticle

Corilagin Represses Epithelial to Mesenchymal Transition Process Through Modulating Wnt/β-Catenin Signaling Cascade

by Sun Tae Hwang, Min Hee Yang, Alan Prem Kumar, Gautam Sethi and Kwang Seok Ahn

Biomolecules 2020, 10(10), 1406; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10101406 - 05 Oct 2020

Cited by 40 | Viewed by 2664

Abstract

Corilagin (CLG), a major component of several medicinal plants, can exhibit diverse pharmacological properties including those of anti-cancer, anti-inflammatory, and hepatoprotective qualities. However, there are no prior studies on its potential impact on the epithelial-to-mesenchymal transition (EMT) process. EMT can lead to dissemination of tumor cells into other organs and promote cancer progression. Hence, we aimed to investigate the effect of CLG on EMT and its mechanism(s) of action in tumor cells. We noted that CLG reduced the expression of various epithelial markers and up-regulated the expression of Occludin and E-cadherin in both basal and TGFβ-stimulated tumor cells. CLG treatment also abrogated cellular invasion and migration in colon and prostate carcinoma cells. In addition, CLG effectively attenuated the Wnt/β-catenin signaling cascade in TGFβ-stimulated cells. Overall, our study suggests that CLG may function as and effective modulator of EMT and metastasis in neoplastic cells. Full article

(This article belongs to the Special Issue EMT and Cancer)

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Review

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15 pages, 797 KiB

Open AccessReview

The Underappreciated Role of Epithelial Mesenchymal Transition in Chronic Obstructive Pulmonary Disease and Its Strong Link to Lung Cancer

by Malik Quasir Mahmood, Shakti D. Shukla, Chris Ward and Eugene Haydn Walters

Biomolecules 2021, 11(9), 1394; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11091394 - 21 Sep 2021

Cited by 19 | Viewed by 3427

Abstract

The World Health Organisation reported COPD to be the third leading cause of death globally in 2019, and in 2020, the most common cause of cancer death was lung cancer; when these linked conditions are added together they come near the top of the leading causes of mortality. The cell-biological program termed epithelial-to-mesenchymal transition (EMT) plays an important role in organ development, fibrosis and cancer progression. Over the past decade there has emerged a substantial literature that also links EMT specifically to the pathophysiology of chronic obstructive pulmonary disease (COPD) as primarily an airway fibrosis disease; COPD is a recognised strong independent risk factor for the development of lung cancer, over and above the risks associated with smoking. In this review, our primary focus is to highlight these linkages and alert both the COPD and lung cancer fields to these complex interactions. We emphasise the need for inter-disciplinary attention and research focused on the likely crucial roles of EMT (and potential for its inhibition) with recognition of its strategic place mechanistically in both COPD and lung cancer. As part of this we discuss the future potential directions for novel therapeutic opportunities, including evidence-based strategic repurposing of currently used familiar/approved medications. Full article

(This article belongs to the Special Issue EMT and Cancer)

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22 pages, 2152 KiB

Open AccessEditor’s ChoiceReview

Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition

by Taylor C. Brown, Narendra V. Sankpal and William E. Gillanders

Biomolecules 2021, 11(7), 956; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11070956 - 29 Jun 2021

Cited by 36 | Viewed by 4765

Abstract

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities. Full article

(This article belongs to the Special Issue EMT and Cancer)

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23 pages, 1795 KiB

Open AccessEditor’s ChoiceReview

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

by Jingjing Sha, Yunpeng Bai, Huy Xuan Ngo, Tatsuo Okui and Takahiro Kanno

Biomolecules 2021, 11(6), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060893 - 16 Jun 2021

Cited by 28 | Viewed by 3753

Abstract

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy drug resistance. EMT-activating transcription factors (EMT-ATFs), such as Snail, TWIST, and ZEB, can activate several different molecular pathways, e.g., PI3K/AKT, NF-κB, and TGF-β. In contrast, the activated oncological signal pathways provide reciprocal feedback that affects the expression of EMT-ATFs, resulting in a peritumoral extracellular environment conducive to cancer cell survival and evasion of the immune system, leading to resistance to multiple chemotherapeutic agents. We present an overview of evidence-based chemotherapy for OC treatment based on the National Comprehensive Cancer Network (NCCN) Chemotherapy Order Templates. We focus on the molecular pathways involved in drug resistance related to the EMT and highlight the signal pathways and transcription factors that may be important for EMT-regulated drug resistance. Rapid progress in antitumor regimens, together with the application of powerful techniques such as high-throughput screening and microRNA technology, will facilitate the development of therapeutic strategies to augment chemotherapy. Full article

(This article belongs to the Special Issue EMT and Cancer)

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18 pages, 2151 KiB

Open AccessReview

Epithelial to Mesenchymal Transition History: From Embryonic Development to Cancers

by Camille Lachat, Paul Peixoto and Eric Hervouet

Biomolecules 2021, 11(6), 782; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11060782 - 22 May 2021

Cited by 21 | Viewed by 3117

Abstract

Epithelial to mesenchymal transition (EMT) is a process that allows epithelial cells to progressively acquire a reversible mesenchymal phenotype. Here, we recount the main events in the history of EMT. EMT was first studied during embryonic development. Nowadays, it is an important field in cancer research, studied all around the world by more and more scientists, because it was shown that EMT is involved in cancer aggressiveness in many different ways. The main features of EMT’s involvement in embryonic development, fibrosis and cancers are briefly reviewed here. Full article

(This article belongs to the Special Issue EMT and Cancer)

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17 pages, 1023 KiB

Open AccessReview

Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

by Akshita B. Bhatt, Saloni Patel, Margarite D. Matossian, Deniz A. Ucar, Lucio Miele, Matthew E. Burow, Patrick T. Flaherty and Jane E. Cavanaugh

Biomolecules 2021, 11(2), 183; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11020183 - 29 Jan 2021

Cited by 12 | Viewed by 5314

Abstract

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed. Full article

(This article belongs to the Special Issue EMT and Cancer)

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19 pages, 2329 KiB

Open AccessReview

Deciphering the Importance of Glycosphingolipids on Cellular and Molecular Mechanisms Associated with Epithelial-to-Mesenchymal Transition in Cancer

by Cécile Cumin, Yen-Lin Huang, Arun Everest-Dass and Francis Jacob

Biomolecules 2021, 11(1), 62; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11010062 - 06 Jan 2021

Cited by 25 | Viewed by 4583

Abstract

Every living cell is covered with a dense and complex layer of glycans on the cell surface, which have important functions in the interaction between cells and their environment. Glycosphingolipids (GSLs) are glycans linked to lipid molecules that together with sphingolipids, sterols, and proteins form plasma membrane lipid rafts that contribute to membrane integrity and provide specific recognition sites. GSLs are subdivided into three major series (globo-, ganglio-, and neolacto-series) and are synthesized in a non-template driven process by enzymes localized in the ER and Golgi apparatus. Altered glycosylation of lipids are known to be involved in tumor development and metastasis. Metastasis is frequently linked with reversible epithelial-to-mesenchymal transition (EMT), a process involved in tumor progression, and the formation of new distant metastatic sites (mesenchymal-to-epithelial transition or MET). On a single cell basis, cancer cells lose their epithelial features to gain mesenchymal characteristics via mechanisms influenced by the composition of the GSLs on the cell surface. Here, we summarize the literature on GSLs in the context of reversible and cancer-associated EMT and discuss how the modification of GSLs at the cell surface may promote this process. Full article

(This article belongs to the Special Issue EMT and Cancer)

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22 pages, 1487 KiB

Open AccessReview

Emerging Concepts of Hybrid Epithelial-to-Mesenchymal Transition in Cancer Progression

by Dona Sinha, Priyanka Saha, Anurima Samanta and Anupam Bishayee

Biomolecules 2020, 10(11), 1561; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10111561 - 16 Nov 2020

Cited by 53 | Viewed by 4359

Abstract

Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon. Full article

(This article belongs to the Special Issue EMT and Cancer)

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26 pages, 1448 KiB

Open AccessReview

Role of microRNA/Epithelial-to-Mesenchymal Transition Axis in the Metastasis of Bladder Cancer

by Milad Ashrafizadeh, Kiavash Hushmandi, Mehrdad Hashemi, Mohammad Esmaeil Akbari, Peter Kubatka, Mehdi Raei, Lenka Koklesova, Md Shahinozzaman, Reza Mohammadinejad, Masoud Najafi, Gautam Sethi, Alan Prem Kumar and Ali Zarrabi

Biomolecules 2020, 10(8), 1159; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10081159 - 07 Aug 2020

Cited by 91 | Viewed by 4994

Abstract

Bladder cancer (BC) is the 11th most common diagnosed cancer, and a number of factors including environmental and genetic ones participate in BC development. Metastasis of BC cells into neighboring and distant tissues significantly reduces overall survival of patients with this life-threatening disorder. Recently, studies have focused on revealing molecular pathways involved in metastasis of BC cells, and in this review, we focus on microRNAs (miRNAs) and their regulatory effect on epithelial-to-mesenchymal transition (EMT) mechanisms that can regulate metastasis. EMT is a vital process for migration of BC cells, and inhibition of this mechanism restricts invasion of BC cells. MiRNAs are endogenous non-coding RNAs with 19–24 nucleotides capable of regulating different cellular events, and EMT is one of them. In BC cells, miRNAs are able to both induce and/or inhibit EMT. For regulation of EMT, miRNAs affect different molecular pathways such as transforming growth factor-beta (TGF-β), Snail, Slug, ZEB1/2, CD44, NSBP1, which are, discussed in detail this review. Besides, miRNA/EMT axis can also be regulated by upstream mediators such as lncRNAs, circRNAs and targeted by diverse anti-tumor agents. These topics are also discussed here to reveal diverse molecular pathways involved in migration of BC cells and strategies to target them to develop effective therapeutics. Full article

(This article belongs to the Special Issue EMT and Cancer)

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45 pages, 5387 KiB

Open AccessFeature PaperReview

MicroRNAs and Their Influence on the ZEB Family: Mechanistic Aspects and Therapeutic Applications in Cancer Therapy

by Milad Ashrafizadeh, Hui Li Ang, Ebrahim Rahmani Moghadam, Shima Mohammadi, Vahideh Zarrin, Kiavash Hushmandi, Saeed Samarghandian, Ali Zarrabi, Masoud Najafi, Reza Mohammadinejad and Alan Prem Kumar

Biomolecules 2020, 10(7), 1040; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10071040 - 12 Jul 2020

Cited by 55 | Viewed by 5548

Abstract

Molecular signaling pathways involved in cancer have been intensively studied due to their crucial role in cancer cell growth and dissemination. Among them, zinc finger E-box binding homeobox-1 (ZEB1) and -2 (ZEB2) are molecules that play vital roles in signaling pathways to ensure the survival of tumor cells, particularly through enhancing cell proliferation, promoting cell migration and invasion, and triggering drug resistance. Importantly, ZEB proteins are regulated by microRNAs (miRs). In this review, we demonstrate the impact that miRs have on cancer therapy, through their targeting of ZEB proteins. MiRs are able to act as onco-suppressor factors and inhibit the malignancy of tumor cells through ZEB1/2 down-regulation. This can lead to an inhibition of epithelial-mesenchymal transition (EMT) mechanism, therefore reducing metastasis. Additionally, miRs are able to inhibit ZEB1/2-mediated drug resistance and immunosuppression. Additionally, we explore the upstream modulators of miRs such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), as these regulators can influence the inhibitory effect of miRs on ZEB proteins and cancer progression. Full article

(This article belongs to the Special Issue EMT and Cancer)

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