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

Abstract

The epithelial cell adhesion molecule (EpCAM, CD326) is a glycoprotein of approximately 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.

Figure 1

EpCAM expression pattern in murine EBs. A: EpCAM expression along the cell membrane (arrow) and intracellular expression (inset, arrow). B: EpCAM expression on these parts of the cell membrane, in contact with a neighboring cell (arrow). Staining intensity indicates that EpCAM expression level in EB differs between cells.

Figure 2

Schematic representation of ligands identified for EpCAM and possible functions related to them. (1) The extracellular domain of EpCAM interacts with a second EpCAM molecule resulting in homotypic cell-cell adhesion, hence, the name epithelial cell adhesion molecule. (2) EpCAM directly interacts with claudin-7, a protein required for the formation of tight junctions, again implying a role of EpCAM in cellular adherence. (3) EpCAM directly interacts with CD44v4-v7 (carcinoma-associated variants of CD44). The exact consequence of this interaction remains to be elucidated. (4) EpCAM indirectly associates with E-cadherin. The adaptor proteins that facilitate this complex formation have yet to be identified. (5) EpCAM forms a primary complex with CD9 in the tetraspanin web. (6) Direct interactions of α-actinin with the intracellular domain of EpCAM links this molecule to the cytoskeletal organization. (7) EpCAM modulates the expression of NF-κB, c-myc, and E-FABP. The molecular pathway of this modulation has not yet been found. We propose that a proteolytic cleavage in the extracellular domain may initiate a signaling cascade that results in the augmented expression of NF-κB, c-myc, and E-FABP. The interplay of EpCAM with E-cadherin (4) and CD9 (5), as well as the influence of EpCAM on NF-κB, c-myc, and E-FABP (7) provides a link for its involvement in cell migration, metastasis, and cell signaling. ECM, extracellular matrix; E-FABP, epidermal fatty acid-binding protein.