Biology and clinical relevance of EpCAM

Abstract

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein primarily known to mediate homotypic cell contacts in epithelia tissues. Because EpCAM expression is limited to normal and malignant epithelia, it has been used as diagnostic marker for the detection of carcinoma cells in mesenchymal organs such as blood, bone marrow or lymph nodes. In particular, the detection and molecular characterization of EpCAM-positive circulating tumor cells (CTCs) in the blood of carcinoma patients has gained considerable interest over the past ten years. EpCAM is primarily considered as an adhesion molecule, but recent studies have shown diverse biological functions including regulation of cell proliferation and cancer stemness. In this review, we summarize the current knowledge on the biological properties of EpCAM with emphasis on mechanisms involved in cancer progression and discuss the clinical implications of these findings for the clinical use of EpCAM as a diagnostic marker.

Keywords: EMT; EpCAM; Tumor biomarker; circulating tumor cells; liquid biopsy; tumor cell dissemination.

Figure 1. FIGURE 1: Schematic diagram of the domain structure of full length EpCAM protein and crystal structure of an extracellular EpCAM cis-homodimer according to Pavsic et al.

Full length EpCAM consists of a N-terminal signal peptide (SP) followed by three compactly folded extracellular domains (N-Domain (ND), Thyroglobulin type 1A domain (TY) C-Domain CD), a single spanning transmembrane domain (TM) and a c-terminal intracellular domain (EpIC). Two EpCAM subunits form a heart-shaped dimer on the cell surface [11]. Protein Data Base entry 4MZV.

Figure 2. FIGURE 2: EpCAM cleavage and downstream signalization.

Cellular contacts, binding of EpEX or another unknown lig- and, lead to the activation of EpCAM cleavage by disintegrin and metalloprotease (ADAM17), and the subsequent release of the soluble EpEx domain in the intercellular space. In a second step, sheddases are acting at several sites in the transmembrane domain and generate Aβ-like fragments and an intracellular domain EpIC. If EpIC has been shown as a signalisation molecule, the functions of Aβ-like fragments are still unknown.

Figure 3. FIGURE 3: Targeted expression analysis of normalized gene expression values of EPCAM in groups of Scarff Bloom & Richardson grade status (SBR) and Nottingham Prognostic Index status (NPI) using the Breast Cancer Gene-Expression Miner v4.1 (bc-GenExMiner v4.1).

Figure 4. FIGURE 4: Reduced schematic of EpCAM regulation in the context of EMT.

Stimulation of tyrosine kinase receptors via TGF-β1 or EGF is leading to ERK2 activation and suppresses EPCAM mRNA expression indirectly through activation of EMT-associated transcription factors (TF) like SNAI1, SNAI2, TWIST1 and ZEB1. The EpCAM protein on the other hand could also contribute to the regulation of EMT by suppressing ERK2 activity. The soluble EpEX-fragment is acting as an EGF competitor for EGFR, counteracted EMT via inhibiting of the EMTTF (Snail, ZEB1, and Slug) which leads to activation of EPCAM expression. For detailed review, see references [42, 91, 92].