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.

Epithelial Cell Adhesion Molecule: An Anchor to Isolate Clinically Relevant Circulating Tumor Cells

“…EpCAM is involved in the regulation of cancer cell adhesion, proliferation, migration, invasion, stemness, and epithelial-to-mesenchymal transition (EMT) during cancer progression [ 35 , 36 ]. EpCAM expression was correlated with abnormal cell proliferation in cervical squamous epithelium for the first time in 1996 [ 37 ].…”

EpCAM as Modulator of Tissue Plasticity

“…The first clear evidence of a function of EpCAM independent of adhesion was the discovery of a signalling function of the short cytoplasmic domain [ 28 ]. This topic has been recently reviewed [ 29 ], and will be here only briefly summarized. The signalling cascade uncovered by Gires and colleagues starts with the shedding of the extracellular domain of EpCAM, which in turn triggers regulated intracellular proteolysis (RIP), resulting in the release of the cytoplasmic peptide.…”

“…The position of the inhibitory pseudosubstrate sequence, adjacent to the lipid bilayer, appears optimal for the efficient inhibition of membrane-bound PKC [ 44 ]. Thus, the release of the EpCAM in the cytoplasm by RIP [ 28 , 29 , 30 , 31 ] would be predicted to abolish EpCAM inhibitory function. Another potential protease-dependent regulatory mechanism involves cleavage of the extracellular domain by an extracellular protease called matriptase [ 52 , 59 ].…”

EpCAM-Mediated Cellular Plasticity Promotes Radiation Resistance and Metastasis in Breast Cancer

“…EpCAM is reported to be involved in BC metastasis ( Osta et al, 2004 ; Gao et al, 2015 ; Hiraga et al, 2016 ). EpCAM is also used as a marker for the detection of circulating tumor cells (CTCs) ( Gires et al, 2020 ). It has been observed that EpCAM high CTCs in metastatic BC are associated with poor overall survival ( de Wit et al, 2018 ).…”