The epithelial cell adhesion molecule (EpCAM, CD326) is a glycoprotein of ∼40 kd that was originally identified as a marker for carcinoma, attributable to its high expression on rapidly proliferating tumors of epithelial origin. Normal epithelia express EpCAM at a variable but generally lower level than carcinoma cells. In early studies, EpCAM was proposed to be a cell-cell adhesion molecule. However, recent insights revealed a more versatile role for EpCAM that is not limited only to cell adhesion but includes diverse processes such as signaling, cell migration, proliferation, and differentiation. Cell surface expression of EpCAM may actually prevent cell-cell adhesion. Here, we provide a comprehensive review of the current knowledge on EpCAM biology in relation to other cell adhesion molecules. We discuss the implications of the newly identified functions of EpCAM in view of its prognostic relevance in carcinoma, inflammatory pathophysiology, and tissue development and regeneration as well as its role in normal epithelial homeostasis.

Epithelial cell adhesion molecule: more than a carcinoma marker and adhesion molecule.

The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7

The aberrant expression of the transmembrane protein EpCAM is associated with tumor progression, affecting different cellular processes such as cell–cell adhesion, migration, proliferation, differentiation, signaling, and invasion. However, the in vivo function of EpCAM still remains elusive due to the lack of genetic loss-of-function studies. Here, we describe epcam (tacstd) null mutants in zebrafish. Maternal-zygotic mutants display compromised basal protrusive activity and epithelial morphogenesis in cells of the enveloping layer (EVL) during epiboly. In partial redundancy with E-cadherin (Ecad), EpCAM made by EVL cells is further required for cell–cell adhesion within the EVL and, possibly, for proper attachment of underlying deep cells to the inner surface of the EVL, thereby also affecting deep cell epiboly movements. During later development, EpCAM per se becomes indispensable for epithelial integrity within the periderm of the skin, secondarily leading to disrupted morphology of the underlying basal epidermis and moderate hyper-proliferation of skin cells. On the molecular level, EVL cells of epcam mutant embryos display reduced levels of membranous Ecad, accompanied by an enrichment of tight junction proteins and a basal extension of apical junction complexes (AJCs). Our data suggest that EpCAM acts as a partner of E-cadherin to control adhesiveness and integrity as well as plasticity and morphogenesis within simple epithelia. In addition, EpCAM is required for the interaction of the epithelia with underlying cell layers.

The Epithelial Cell Adhesion Molecule EpCAM Is Required for Epithelial Morphogenesis and Integrity during Zebrafish Epiboly and Skin Development

EpCAM has been described as a therapeutically relevant tumor marker. We noted an interaction between EpCAM and the tight junction protein claudin-7 and here explored the nature of this interaction and its effect on EpCAM-mediated functions. The interaction between EpCAM and claudin-7 was defined in HEK293 cells transfected with rat claudin-7 and EpCAM cDNA. Deletions of the epidermal growth factor-like and the thyroglobin repeat domains of EpCAM or the cytoplasmic domain of EpCAM or claudin-7 did not prevent the EpCAM-claudin-7 association. A chimeric EpCAM molecule with an exchange of the cytoplasmic and transmembrane domains and an EpCAM molecule with point mutations in an AxxxG motif in the transmembrane region do not associate with claudin-7. HEK cells and the rat pancreatic tumor line BSp73AS, transfected with (mutated) EpCAM and claudin-7 cDNA, revealed that the association of both molecules severely alters the functional activity of EpCAM. Claudin-7-associated EpCAM is recruited into tetraspanin-enriched membrane microdomains (TEM). The TEM-located claudin-7-EpCAM complex supports proliferation accompanied by sustained extracellular signal-regulated kinase-1/2 phosphorylation, up-regulation of antiapoptotic proteins, and drug resistance, but not EpCAM-mediated cell-cell adhesion. Enhanced motility may be supported by colocalization of claudin-7 with actin bundles, which is only seen in EpCAM-claudin-7-expressing cells. The EpCAM-claudin-7 complex strongly promotes tumorigenicity, accelerates tumor growth, and supports ascites production and thymic metastasis formation. High expression of the tumor marker EpCAM is frequently associated with poor prognosis, which could well rely on the EpCAM-claudin-7 association that prohibits EpCAM-mediated cell-cell adhesion but promotes migration, proliferation, apoptosis resistance, and tumorigenicity.

https://mcr.aacrjournals.org/content/molcanres/7/3/285.full.pdf

Claudin-7 regulates EpCAM-mediated functions in tumor progression.

Definedbymonoclonal antibodyGA733,theGA733-2antigen is acell surface 40-kDaglycoprotein associ-ated with human carcinomas of various origins. MolecularclonesfortheGA733-2antigenwereisolatedfromacolorectalcarcinomacelllinecDNAlibraryusingthehigh-efficiencyCOScell expression system. A 1.4-kilobase cDNAspecies was en-riched by immunoselection with monoclonal antibody. The authenticity ofindividual clones wasestablished byimmuno-logic andsequencecriteria. Atthe aminoacid sequencelevel,GA733-2 was found to be >99% identical to the previouslydescribed KSA antigen defined by monoclonal antibodyKS1/4.TheaminoacidsequencederivedfromthepreviouslydescribedGA733-relatedgene,GA733-1,wasfoundtobe49%identical to GA733-2. Thepositions of 12 cysteine residues inthe extracellular domains of the two GA733 antigens areconserved, as is the overall distribution of hydrophobic andhydrophilic residues. A 1.45-kilobase transcript of theGA733-2/KSA gene was found to be expressed in cell lines derived fromcolorectal

Molecular cloning ofcDNAforthecarcinoma-associated antigen GA733-2

Screening for surface molecules expressed by metastasizing rat tumors had revealed evidence for metastasis-association of a molecule also expressed on epithelial cells. The similarity to the expression profile of the panepithelial glycoprotein EGP314 prompted us to isolate and sequence the gene and to explore functional features of the molecule in transfected tumor lines. The molecule D5.7A, named according to the antibody, D5.7, used for selection, indeed, is the ortholog of EGP314 with 92% and 80% identity to the murine and the human molecules. Like EGP314, D5.7A has a particular cleavage site, a small cleavage product being resolved under reducing conditions from the membrane anchored part of the molecule. Transfection of a low metastasizing fibrosarcoma, pheochromoblastoma and adenocarcinoma revealed that expression of D5.7A facilitates tumor progression. Depending on the origin of the tumor, D5.7A transfectants either metastasized via the lymphatic system (pheochromoblastoma, adenocarcinoma) or hematogeneously (fibrosarcoma). Particularly after proteolytic cleavage, D5.7A facilitated cell – cell adhesion and provided a proliferative signal upon crosslinking. Thus, the rat ortholog of EGP314 is involved in metastasis formation. Importantly, its functional activities apparently rely on proteolytic cleavage. These findings provide a first evidence on how a panepithelial marker can be involved in tumor progression.

Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314.

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Metastasis-association of the rat ortholog of the human epithelial glycoprotein antigen EGP314.