Expression and function of epithelial cell adhesion molecule EpCAM: where are we after 40 years?

Abstract

EpCAM (epithelial cell adhesion molecule) was discovered four decades ago as a tumor antigen on colorectal carcinomas. Owing to its frequent and high expression on carcinomas and their metastases, EpCAM serves as a prognostic marker, a therapeutic target, and an anchor molecule on circulating and disseminated tumor cells (CTCs/DTCs), which are considered the major source for metastatic cancer cells. Today, EpCAM is reckoned as a multi-functional transmembrane protein involved in the regulation of cell adhesion, proliferation, migration, stemness, and epithelial-to-mesenchymal transition (EMT) of carcinoma cells. To fulfill these functions, EpCAM is instrumental in intra- and intercellular signaling as a full-length molecule and following regulated intramembrane proteolysis, generating functionally active extra- and intracellular fragments. Intact EpCAM and its proteolytic fragments interact with claudins, CD44, E-cadherin, epidermal growth factor receptor (EGFR), and intracellular signaling components of the WNT and Ras/Raf pathways, respectively. This plethora of functions contributes to shaping intratumor heterogeneity and partial EMT, which are major determinants of the clinical outcome of carcinoma patients. EpCAM represents a marker for the epithelial status of primary and systemic tumor cells and emerges as a measure for the metastatic capacity of CTCs. Consequentially, EpCAM has reclaimed potential as a prognostic marker and target on primary and systemic tumor cells.

Keywords: Carcinoma; EpCAM; Epithelial-to-mesenchymal transition; Liquid biopsy; Metastasis; Regulated intramembrane proteolysis.

Fig. 1

Publication numbers retrieved from PubMed using “EpCAM” as a search term. Two time points of increase in publication numbers are marked by dashed lines. The first wave of increased publications maps to the cloning of the EpCAM cDNA in 1989. The second wave coincides with the description of EpCAM function in proliferation and migration in 2004

Fig. 2

Milestones of EpCAM discoveries in basic research (in blue) and in clinical application (in green). ESC: embryonic stem cells, CTE: congenic tufting enteropathy, iPS: induced pluripotent stem cells, MBC: metastatic breast cancer, CTCs: circulating tumor cells

Fig. 3

Schematic representation of the EpCAM protein. EpCAM is composed of a signal peptide (SP) that is removed from the mature protein. Mature EpCAM comprises an extracellular domain (EpEX), a single transmembrane domain (TMD), and a short intracellular domain (EpICD). N-Terminal (N-domain), thyroglobulin (TY-domain), and C-terminal domains (C-domain) within EpEX, as defined by Pavsic et al. [3], are marked. N- and TY-domains are cysteine-rich protein stretches that have initially been defined as EGF-like domains. Disulfide bonds involving cysteines, N-glycosylation at asparagines, ubiquitylation at lysines, and cleavage sites related to regulated intramembrane proteolysis of EpCAM (α-, β-, γ-, and ε-sites) [33, 34] are annotated. The approximated additional cleavage site reported by Schnell et al. [35] is indicated. Sizes are not at scale

Fig. 4

EpCAM expression in normal mucosa, primary head and neck squamous cell carcinoma, and lymph node metastasis. Shown are immunohistochemistry staining of EpCAM in normal mucosa, primary tumor, and lymph node metastases of head and neck squamous cell carcinomas (HNSCC)

Fig. 5

Schematic representation of the signaling mechanisms associated with EpCAM. Signaling by EpCAM and degradation of EpCAM via regulated intramembrane proteolysis (RIP) is depicted in the left part of the scheme. Membrane-associated signaling, trafficking, and intracellular RIP in endocytic vesicles are depicted on the right part. Effects of distinct pathways and the associated molecules are color-coded and implemented in the schematic representation of the cell nucleus