Abstract
Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein, which is frequently and highly expressed on carcinomas, tumor-initiating cells, selected tissue progenitors, and embryonic and adult stem cells. During liver development, EpCAM demonstrates a dynamic expression, since it can be detected in fetal liver, including cells of the parenchyma, whereas mature hepatocytes are devoid of EpCAM. Liver regeneration is associated with a population of EpCAM-positive cells within ductular reactions, which gradually lose the expression of EpCAM along with maturation into hepatocytes. EpCAM can be switched on and off through a wide panel of strategies to fine-tune EpCAM-dependent functional and differentiative traits. EpCAM-associated functions relate to cell–cell adhesion, proliferation, maintenance of a pluripotent state, regulation of differentiation, migration, and invasion. These functions can be conferred by the full-length protein and/or EpCAM-derived fragments, which are generated upon regulated intramembrane proteolysis. Control by EpCAM therefore not only depends on the presence of full-length EpCAM at cellular membranes but also on varying rates of the formation of EpCAM-derived fragments that have their own regulatory properties and on changes in the association of EpCAM with interaction partners. Thus spatiotemporal localization of EpCAM in immature liver progenitors, transit-amplifying cells, and mature liver cells will decisively impact the regulation of EpCAM functions and might be one of the triggers that contributes to the adaptive processes in stem/progenitor cell lineages. This review will summarize EpCAM-related molecular events and how they relate to hepatobiliary differentiation and regeneration.
Highlights
Based on the strong expression in hepatic stem/progenitor cells (HSPCs) and the dynamic expression pattern of epithelial cell adhesion molecule (EpCAM) during liver cell differentiation, this molecule might represent a central target in the field of hepatocellular differentiation and liver regeneration
The investigators found a high presence of EpCAMMF in noncancerous tissues, whereas in pancreatic cancer, EpCAMMT was highly increased and associated with a more aggressive phenotype [34, 35]. These results suggest the presence of two distinct EpCAM variants that may occur during carcinogenesis and that loss of membranous EpICD expression is a frequent event in human cancer
Critical appraisal on its biology has illustrated different aspects of EpCAM, and compelling data indicate that different mechanisms exist to switch on/off EpCAM expression or function
Summary
Retention of EpCAM on the cell surface of differentiated cells might allow for a rapid, EpCAMdependent response when necessary Another conceivable scenario for the function of EpCAM in liver repair is that HSPCs may require the (re-)expression of EpCAM at their membrane to mature successfully and restrictively toward the hepatocytic lineage in response to the niche cell signals [8, 81]. Mesenchymal stromal and cellular partners are the chief orchestrators for these cell-fate decisions [8], EpCAM might confer the ability to translate the signal that progenitors sense from their neighborhood by regulating the bioavailability of receptors (i.e., sequestration of corepressor), as was shown for Lrp by Lu et al [81] In such a scenario, the presence of EpCAM on the plasma membrane in developing hepatocytes would foster Wnt signaling to differentiate further toward hepatocytes instead of biliary tract cells (Fig. 6). With their potential to generate pancreatic endocrine cells [12, 13, 16, 144], the EpCAMϩ cells offer hope for saving diabetic patients [61]
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