Epithelial Cell Adhesion Molecule and Cancers: From Molecular Mechanisms to Therapeutic Opportunities

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

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 38083

Special Issue Editor


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Guest Editor
Department of Otorhinolaryngology, Grosshadern Medical Center, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377 Munich, Germany
Interests: regulation of tumor cell and embryonic stem cell differentiation; epithelial cell adhesion molecule (EpCAM); epithelial–mesenchymal transition (EMT)

Special Issue Information

Dear Colleagues,

Epithelial cell adhesion molecule (EpCAM) is a membrane-tethered glycoprotein, which was first discovered 40 years ago, as a humoral antigen expressed in colon cancer. Owing to its frequent and strong expression in the majority of carcinomas, EpCAM serves as a target for therapeutic monoclonal antibodies and as an anchor molecule to isolate circulating tumor cells in peripheral blood in clinical practice. At the molecular level, EpCAM was initially described as a cell adhesion protein and, more recently, as a signalling-active membrane protein involved in the regulation of proliferation, metabolism, morphogenic processes, stemness, and cell differentiation, amongst others. Beyond carcinoma cells, EpCAM is highly expressed in embryonic stem cells and various progenitor cells, in which it also displays a plethora of functions.

This Special Issue of Cells is centered around all the various aspects of EpCAM biology and aims at compiling a collection of original and review articles addressing this central topic in molecular oncology and cell differentiation. Suggested potential topics may include: EpCAM expression patterns and regulation, cellular functions, EpCAM in tumor and metastases formation, (functional) interactions with other molecules, regulation of normal and pathogenic differentiation, including EMT, and clinical and therapeutic applications.

This Special Issue is processed according to the International Ethical COPE guidelines. Any irregularities which may happen during the process of this special issue are mistakes and not part of the contradictory policy.

Prof. Dr. Olivier Gires
Guest Editor

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Keywords

  • EpCAM
  • carcinogenesis
  • normal and malignant cell differentiation
  • systemic tumor cells
  • metastatic cascade
  • cell signaling

Published Papers (8 papers)

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Research

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18 pages, 3560 KiB  
Article
Amelioration of Congenital Tufting Enteropathy in EpCAM (TROP1)-Deficient Mice via Heterotopic Expression of TROP2 in Intestinal Epithelial Cells
by Gaku Nakato, Sohshi Morimura, Michael Lu, Xu Feng, Chuanjin Wu and Mark C. Udey
Cells 2020, 9(8), 1847; https://doi.org/10.3390/cells9081847 - 6 Aug 2020
Cited by 7 | Viewed by 3707
Abstract
TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. [...] Read more.
TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. Adult intestinal epithelial cells (IEC) express high levels of EpCAM, while TROP2 is not expressed. EpCAM deficiency causes congenital tufting enteropathy (CTE) in humans and a corresponding lethal condition in mice. We expressed TROP2 and EpCAM in the IEC of EpCAM-deficient mice utilizing a villin promoter to assess EpCAM and TROP2 function. Expression of EpCAM or TROP2 in the IEC of EpCAM knockout mice prevented CTE. TROP2 rescue (T2R) mice were smaller than controls, while EpCAM rescue (EpR) mice were not. Abnormalities were observed in the diameters and histology of T2R small intestine, and Paneth and stem cell markers were decreased. T2R mice also exhibited enlarged mesenteric lymph nodes, enhanced permeability to 4 kDa FITC-dextran and increased sensitivity to detergent-induced colitis, consistent with compromised barrier function. Studies of IEC organoids and spheroids revealed that stem cell function was also compromised in T2R mice. We conclude that EpCAM and TROP2 exhibit functional redundancy, but they are not equivalent. Full article
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17 pages, 1987 KiB  
Article
In Vitro Modeling of Reoxygenation Effects on mRNA and Protein Levels in Hypoxic Tumor Cells upon Entry into the Bloodstream
by Kai Bartkowiak, Claudia Koch, Sebastian Gärtner, Antje Andreas, Tobias M Gorges and Klaus Pantel
Cells 2020, 9(5), 1316; https://doi.org/10.3390/cells9051316 - 25 May 2020
Cited by 14 | Viewed by 3080
Abstract
Background: Solid epithelial tumors like breast cancer are the most frequent malignancy in women. Circulating tumor cells (CTCs) are frequently released from hypoxic areas into the blood, where CTCs face elevated oxygen concentrations. This reoxygenation might challenge the use of CTCs for liquid [...] Read more.
Background: Solid epithelial tumors like breast cancer are the most frequent malignancy in women. Circulating tumor cells (CTCs) are frequently released from hypoxic areas into the blood, where CTCs face elevated oxygen concentrations. This reoxygenation might challenge the use of CTCs for liquid biopsy. Methods: We modeled this situation in vitro using the breast cancer cell lines—MCF-7, MDA-MB-468, MDA-MB-231—and the cell line BC-M1 established from DTCs in the bone marrow. Cells were cultured under hypoxia, followed by a reoxygenation pulse for 4 h, reflecting the circulation time of CTCs. Analyzed were gene products like EGFR, ErbB-2, EpCAM, PD-L1 on mRNA and protein level. Results: mRNAs of erbb2 or pdl1 and protein levels of PD-L1 displayed significant changes, whereas ErbB-2 protein levels remained constant. The strongest discrepancy between protein and mRNA levels under hypoxia was observed for EGFR, supporting the idea of cap-independent translation of egfr mRNA. Analyses of the phosphorylation of AKT, Erk 1/2, and Stat3 revealed strong alterations after reoxygenation. Conclusions: CTCs reaching secondary sites faster than reoxygenation could alter the mRNA and protein levels in the cells. CTC and DTC with high PD-L1 levels might become quiescent under hypoxia but were easily reactivated by reoxygenation. Full article
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12 pages, 2161 KiB  
Article
Matriptase Cleaves EpCAM and TROP2 in Keratinocytes, Destabilizing Both Proteins and Associated Claudins
by Chuan-Jin Wu, Michael Lu, Xu Feng, Gaku Nakato and Mark C. Udey
Cells 2020, 9(4), 1027; https://doi.org/10.3390/cells9041027 - 21 Apr 2020
Cited by 20 | Viewed by 4086
Abstract
The homologs EpCAM and TROP2, which both interact with claudin-1 and claudin-7, are frequently coexpressed in epithelia including skin. Intestine uniquely expresses high levels of EpCAM but not TROP2. We previously identified EpCAM as a substrate of the membrane-anchored protease matriptase and linked [...] Read more.
The homologs EpCAM and TROP2, which both interact with claudin-1 and claudin-7, are frequently coexpressed in epithelia including skin. Intestine uniquely expresses high levels of EpCAM but not TROP2. We previously identified EpCAM as a substrate of the membrane-anchored protease matriptase and linked HAI-2, matriptase, EpCAM and claudin-7 in a pathway that is pivotal for intestinal epithelial cells (IEC) homeostasis. Herein, we reveal that TROP2 is also a matriptase substrate. Matriptase cleaved TROP2 when purified recombinant proteins were mixed in vitro. TROP2, like EpCAM, was also cleaved after co-transfection of matriptase in 293T cells. Neither EpCAM nor TROP2 cleavage was promoted by protease-disabled matriptase or matriptase that harbored the ichthyosis-associated G827R mutation. We confirmed that EpCAM and TROP2 are both expressed in skin and detected cleavage of these proteins in human keratinocytes (HaCaT cells) after the physiologic inhibition of matriptase by HAI proteins was relieved by siRNA knockdown. Knockdown of EpCAM or TROP2 individually had only small effects on claudin-1 and claudin-7 levels, whereas elimination of both markedly diminished claudin levels. HAI-1 knockdown promoted EpCAM and TROP2 cleavage accompanied by reductions in claudins, whereas HAI-2 knockdown had little impact. Double knockdown of HAI-1 and HAI-2 induced nearly complete cleavage of EpCAM and TROP2 and drastic reductions of claudins. These effects were eliminated by concurrent matriptase knockdown. Decreases in claudin levels were also diminished by the lysosomal inhibitor chloroquine and cleaved EpCAM/TROP2 fragments accumulated preferentially. We demonstrate that TROP2 and EpCAM exhibit redundancies with regard to regulation of claudin metabolism and that an HAI, matriptase, EpCAM and claudin pathway analogous to what we described in IECs exists in keratinocytes. This study may offer insights into the mechanistic basis for matriptase dysregulation-induced ichthyosis. Full article
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16 pages, 2713 KiB  
Article
Congenital Tufting Enteropathy-Associated Mutant of Epithelial Cell Adhesion Molecule Activates the Unfolded Protein Response in a Murine Model of the Disease
by Barun Das, Kevin Okamoto, John Rabalais, Ronald R. Marchelletta, Kim E. Barrett, Soumita Das, Maho Niwa and Mamata Sivagnanam
Cells 2020, 9(4), 946; https://doi.org/10.3390/cells9040946 - 11 Apr 2020
Cited by 7 | Viewed by 3769
Abstract
Congenital tufting enteropathy (CTE) is a rare chronic diarrheal disease of infancy caused by mutations in epithelial cell adhesion molecule (EpCAM). Previously, a murine CTE model showed mis-localization of EpCAM away from the basolateral cell surface in the intestine. Here we demonstrate that [...] Read more.
Congenital tufting enteropathy (CTE) is a rare chronic diarrheal disease of infancy caused by mutations in epithelial cell adhesion molecule (EpCAM). Previously, a murine CTE model showed mis-localization of EpCAM away from the basolateral cell surface in the intestine. Here we demonstrate that mutant EpCAM accumulated in the endoplasmic reticulum (ER) where it co-localized with ER chaperone, GRP78/BiP, revealing potential involvement of ER stress-induced unfolded protein response (UPR) pathway in CTE. To investigate the significance of ER-localized mutant EpCAM in CTE, activation of the three UPR signaling branches initiated by the ER transmembrane protein components IRE1, PERK, and ATF6 was tested. A significant reduction in BLOS1 and SCARA3 mRNA levels in EpCAM mutant intestinal cells demonstrated that regulated IRE1-dependent decay (RIDD) was activated. However, IRE1 dependent XBP1 mRNA splicing was not induced. Furthermore, an increase in nuclear-localized ATF6 in mutant intestinal tissues revealed activation of the ATF6-signaling arm. Finally, an increase in both the phosphorylated form of the translation initiation factor, eIF2α, and ATF4 expression in the mutant intestine provided support for activation of the PERK-mediated pathway. Our results are consistent with a significant role for UPR in gastrointestinal homeostasis and provide a working model for CTE pathophysiology. Full article
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Review

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15 pages, 1138 KiB  
Review
EpCAM as Modulator of Tissue Plasticity
by François Fagotto
Cells 2020, 9(9), 2128; https://doi.org/10.3390/cells9092128 - 19 Sep 2020
Cited by 7 | Viewed by 3357
Abstract
The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While its name relates to its proposed function as a cell adhesion molecule, EpCAM has been shown to have [...] Read more.
The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While its name relates to its proposed function as a cell adhesion molecule, EpCAM has been shown to have various signalling functions. In particular, it has been identified as an important positive regulator of cell adhesion and migration, playing an essential role in embryonic morphogenesis as well as intestinal homeostasis. This activity is not due to its putative adhesive function, but rather to its ability to repress myosin contractility by impinging on a PKC signalling cascade. This mechanism confers EpCAM the unique property of favouring tissue plasticity. I review here the currently available data, comment on possible connections with other properties of EpCAM, and discuss the potential significance in the context of cancer invasion. Full article
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17 pages, 1342 KiB  
Review
Epithelial Cell Adhesion Molecule: An Anchor to Isolate Clinically Relevant Circulating Tumor Cells
by Zahra Eslami-S, Luis Enrique Cortés-Hernández and Catherine Alix-Panabières
Cells 2020, 9(8), 1836; https://doi.org/10.3390/cells9081836 - 5 Aug 2020
Cited by 62 | Viewed by 8329
Abstract
In the last few decades, the epithelial cell adhesion molecule (EpCAM) has received increased attention as the main membrane marker used in many enrichment technologies to isolate circulating tumor cells (CTCs). Although there has been a great deal of progress in the implementation [...] Read more.
In the last few decades, the epithelial cell adhesion molecule (EpCAM) has received increased attention as the main membrane marker used in many enrichment technologies to isolate circulating tumor cells (CTCs). Although there has been a great deal of progress in the implementation of EpCAM-based CTC detection technologies in medical settings, several issues continue to limit their clinical utility. The biology of EpCAM and its role are not completely understood but evidence suggests that the expression of this epithelial cell-surface protein is crucial for metastasis-competent CTCs and may not be lost completely during the epithelial-to-mesenchymal transition. In this review, we summarize the most significant advantages and disadvantages of using EpCAM as a marker for CTC enrichment and its potential biological role in the metastatic cascade. Full article
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22 pages, 1980 KiB  
Review
Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis
by Peter Ping Lin
Cells 2020, 9(6), 1539; https://doi.org/10.3390/cells9061539 - 24 Jun 2020
Cited by 39 | Viewed by 6399
Abstract
Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived [...] Read more.
Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy. Full article
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18 pages, 4207 KiB  
Review
Current View on EpCAM Structural Biology
by Aljaž Gaber, Brigita Lenarčič and Miha Pavšič
Cells 2020, 9(6), 1361; https://doi.org/10.3390/cells9061361 - 31 May 2020
Cited by 15 | Viewed by 4780
Abstract
EpCAM, a carcinoma cell-surface marker protein and a therapeutic target, has been primarily addressed as a cell adhesion molecule. With regard to recent discoveries of its role in signaling with implications in cell proliferation and differentiation, and findings contradicting a direct role in [...] Read more.
EpCAM, a carcinoma cell-surface marker protein and a therapeutic target, has been primarily addressed as a cell adhesion molecule. With regard to recent discoveries of its role in signaling with implications in cell proliferation and differentiation, and findings contradicting a direct role in mediating adhesion contacts, we provide a comprehensive and updated overview on the available structural data on EpCAM and interpret it in the light of recent reports on its function. First, we describe the structure of extracellular part of EpCAM, both as a subunit and part of a cis-dimer which, according to several experimental observations, represents a biologically relevant oligomeric state. Next, we provide a thorough evaluation of reports on EpCAM as a homophilic cell adhesion molecule with a structure-based explanation why direct EpCAM participation in cell–cell contacts is highly unlikely. Finally, we review the signaling aspect of EpCAM with focus on accessibility of signaling-associated cleavage sites. Full article
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