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

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          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.

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          Most cited references231

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          Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.

          S Fulda, K-M Debatin (2006)
          Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death mostly by apoptosis is crucially involved in the regulation of tumor formation and also critically determines treatment response. Killing of tumor cells by most anticancer strategies currently used in clinical oncology, for example, chemotherapy, gamma-irradiation, suicide gene therapy or immunotherapy, has been linked to activation of apoptosis signal transduction pathways in cancer cells such as the intrinsic and/or extrinsic pathway. Thus, failure to undergo apoptosis may result in treatment resistance. Understanding the molecular events that regulate apoptosis in response to anticancer chemotherapy, and how cancer cells evade apoptotic death, provides novel opportunities for a more rational approach to develop molecular-targeted therapies for combating cancer.
          Article 0 comments Cited 615 times – based on 0 reviews     Review now
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            High absorption but very low bioavailability of oral resveratrol in humans.

            Thomas Walle, Faye Hsieh, Mark Delegge … (2004)
            The dietary polyphenol resveratrol has been shown to have chemopreventive activity against cardiovascular disease and a variety of cancers in model systems, but it is not clear whether the drug reaches the proposed sites of action in vivo after oral ingestion, especially in humans. In this study, we examined the absorption, bioavailability, and metabolism of 14C-resveratrol after oral and i.v. doses in six human volunteers. The absorption of a dietary relevant 25-mg oral dose was at least 70%, with peak plasma levels of resveratrol and metabolites of 491 +/- 90 ng/ml (about 2 microM) and a plasma half-life of 9.2 +/- 0.6 h. However, only trace amounts of unchanged resveratrol (<5 ng/ml) could be detected in plasma. Most of the oral dose was recovered in urine, and liquid chromatography/mass spectrometry analysis identified three metabolic pathways, i.e., sulfate and glucuronic acid conjugation of the phenolic groups and, interestingly, hydrogenation of the aliphatic double bond, the latter likely produced by the intestinal microflora. Extremely rapid sulfate conjugation by the intestine/liver appears to be the rate-limiting step in resveratrol's bioavailability. Although the systemic bioavailability of resveratrol is very low, accumulation of resveratrol in epithelial cells along the aerodigestive tract and potentially active resveratrol metabolites may still produce cancer-preventive and other effects.
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              The cell-cell adhesion molecule E-cadherin.

              F Van Roy, G. Berx (2008)
              This review is dedicated to E-cadherin, a calcium-dependent cell-cell adhesion molecule with pivotal roles in epithelial cell behavior, tissue formation, and suppression of cancer. As founder member of the cadherin superfamily, it has been extensively investigated. We summarize the structure and regulation of the E-cadherin gene and transcript. Models for E-cadherin-catenin complexes and cell junctions are presented. The structure of the E-cadherin protein is discussed in view of the diverse functions of this remarkable protein. Homophilic and heterophilic adhesion are compared, including the role of E-cadherin as a receptor for pathogens. The complex post-translational processing of E-cadherin is reviewed, as well as the many signaling activities. The role of E-cadherin in embryonic development and morphogenesis is discussed for several animal models. Finally, we review the multiple mechanisms that disrupt E-cadherin function in cancer: inactivating somatic and germline mutations, epigenetic silencing by DNA methylation and epithelial to mesenchymal transition-inducing transcription factors, and dysregulated protein processing.
              Article 0 comments Cited 401 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 20 September 2019
                Publication date Collection: October 2019
                Volume: 8
                Issue: 10
                Electronic Location Identifier: 1118
                Affiliations
                [1 ]School of Biosciences, Faculty of Health and Medical Sciences, Taylor’s University, Subang Jaya 47500, Malaysia; cyloh5@ 123456gmail.com (C.-Y.L.); benjaminchaijy@ 123456gmail.com (J.Y.C.); peipei.chong@ 123456taylors.edu.my (P.P.C.)
                [2 ]Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; tiffanytftang@ 123456gmail.com
                [3 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
                Author notes
                [* ]Correspondence: wonfen@ 123456um.edu.my (W.F.W.); phcgs@ 123456nus.edu.sg (G.S.); phcsmk@ 123456nus.edu.sg (M.K.S.); chungyeng.looi@ 123456taylors.edu.my (C.Y.L.); Tel.: +603-7967-6672 (W.F.W.); +65-6516-3267 (G.S. & M.K.S.); +603-5629-5099 (C.Y.L.); Fax: +603-7967-6678 (W.F.W.); +65-6873-7690 (G.S. & M.K.S.); +603-5629-5455 (C.Y.L.)
                Author information
                https://orcid.org/0000-0003-1082-1956
                https://orcid.org/0000-0002-8229-3593
                Article
                Publisher ID: cells-08-01118
                DOI: 10.3390/cells8101118
                PMC ID: 6830116
                PubMed ID: 31547193
                SO-VID: 696b4222-f911-4bc6-8564-c709531dac7c
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 07 August 2019
                Date accepted : 19 September 2019
                Categories
                Subject: Review

                Keywords: e-cadherin,n-cadherin,epithelial-to-mesenchymal transition,signaling pathways,natural compounds
                Data availability:
                Keywords: e-cadherin, n-cadherin, epithelial-to-mesenchymal transition, signaling pathways, natural compounds

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