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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.

Backgound Alveolar type 2 (AT2) cells play important roles in maintaining adult lung homeostasis. AT2 cells isolated from the lung have revealed the cell-specific functions of AT2 cells. Comprehensive molecular and transcriptional profiling of purified AT2 cells would be helpful for elucidating the underlying mechanisms of their cell-specific functions. To enable the further purification of AT2 cells, we aimed to discriminate AT2 cells from non-AT2 lung epithelial cells based on surface antigen expression via fluorescence activated cell sorting (FACS). Methods Single-cell suspensions obtained from enzymatically digested murine lungs were labeled for surface antigens (CD45/CD31/epithelial cell adhesion molecule (EpCAM)/ major histocompatibility complex class II (MHCII)) and for pro-surfactant protein C (proSP-C), followed by FACS analysis for surface antigen expression on AT2 cells. AT2 cells were sorted, and purity was evaluated by immunofluorescence and FACS. This newly developed strategy for AT2 cell isolation was validated in different strains and ages of mice, as well as in a lung injury model. Results FACS analysis revealed that EpCAM + epithelial cells existed in 3 subpopulations based on EpCAM and MHCII expression: EpCAM med MHCII + cells (Population1:P1), EpCAM hi MHCII − cells (P2), and EpCAM low MHCII − cells (P3). proSP-C + cells were enriched in P1 cells, and the purity values of the sorted AT2 cells in P1 were 99.0% by immunofluorescence analysis and 98.0% by FACS analysis. P2 cells were mainly composed of ciliated cells and P3 cells were composed of AT1 cells, respectively, based on the gene expression analysis and immunofluorescence. EpCAM and MHCII expression levels were not significantly altered in different strains or ages of mice or following lipopolysaccharide (LPS)-induced lung injury. Conclusions We successfully classified murine distal lung epithelial cells based on EpCAM and MHCII expression. The discrimination of AT2 cells from non-AT2 epithelial cells resulted in the isolation of pure AT2 cells. Highly pure AT2 cells will provide accurate and deeper insights into the cell-specific mechanisms of alveolar homeostasis.

Cell-surface tumor marker EpCAM plays a key role in proliferation, differentiation and adhesion processes in stem and epithelial cells. It is established as a cell-cell adhesion molecule, forming intercellular interactions through homophilic association. However, the mechanism by which such interactions arise has not yet been fully elucidated. Here, we first show that EpCAM monomers do not associate into oligomers that would resemble an inter-cellular homo-oligomer, capable of mediating cell-cell adhesion, by using SAXS, XL-MS and bead aggregation assays. Second, we also show that EpCAM forms stable dimers on the surface of a cell with pre-formed cell-cell contacts using FLIM-FRET; however, no inter-cellular homo-oligomers were detectable. Thus, our study provides clear evidence that EpCAM indeed does not function as a homophilic cell adhesion molecule and therefore calls for a significant revision of its role in both normal and cancerous tissues. In the light of this, we strongly support the previously suggested name Epithelial Cell Activating Molecule instead of the Epithelial Cell Adhesion Molecule.

Epithelial–mesenchymal transition (EMT) is an important biological process that has been implicated in cancer metastasis. Epithelial cell adhesion molecule (EpCAM) is expressed at the basolateral membrane of most normal epithelial cells but is overexpressed in many epithelial cancers. In our studies on the role of EpCAM in cancer biology, we observed that EpCAM expression is decreased in mesenchymal-like primary cancer specimens in vivo and following induction of EMT in cancer cell lines in vitro . Extracellular signal-related kinase (ERK) is a key regulator of EMT. We observed that EpCAM expression is decreased with activation of the ERK pathway in primary cancer specimens in vivo and in cancer cell lines in vitro . In experimental models, growth factor stimulation and/or oncogene-induced ERK2 activation suppressed EpCAM expression, whereas genetic or pharmacological inhibition of the ERK pathway restored EpCAM expression. In detailed studies of the EpCAM promoter region, we observed that ERK2 suppresses EpCAM transcription directly by binding to a consensus ERK2-binding site in the EpCAM promoter and indirectly through activation of EMT-associated transcription factors SNAI1, SNAI2, TWIST1 and ZEB1, which bind to E-box sites in the EpCAM promoter. Surprisingly, EpCAM appears to modulate ERK activity. Using multiple cell lines, we demonstrated that specific ablation of EpCAM resulted in increased ERK pathway activity and SNAI2 expression, migration and invasion, whereas forced expression of EpCAM resulted in decreased ERK pathway activity and SNAI2 expression, migration and invasion. These observations provide important insights into the regulation of EpCAM expression during EMT, demonstrate an unexpected role for EpCAM in the regulation of ERK and define a novel double-negative feedback loop between EpCAM and ERK that contributes to the regulation of EMT. These studies have important translational implications as both EpCAM and ERK are currently being targeted in human clinical trials.

Background The low survival rate of hepatocellular carcinoma (HCC) is partly attributable to its resistance to existing chemotherapeutic agents. Until now, there have been limited chemotherapeutic agents for liver cancer. Epithelial cell adhesion molecule (EpCAM) has been found to be over-expressed during stages of carcinogenesis and has been associated with poor overall survival in many cancers. The aim of this study was to evaluate EpCAM expression in HCC and evaluate the effects of EpCAM to established chemotherapy. Methods Three human hepatocellular carcinoma cell lines—HepG2, Hep3B and HuH-7—were pre- and post-treated with doxorubicin, 5-fluorouracil (5-FU) and cisplatin. Cell viability and EpCAM protein expression were measured by MTT assay and Western Blotting respectively. EpCAM positive cells were analyzed by flow cytometry. To evaluate the effects of doxorubicin efficacy on EpCAM positive cells, a small interfering RNA (siRNA) specific to EpCAM was transfected into the cells and treated with doxorubicin. Results: EpCAM was significantly down-regulated by doxorubicin treatment in all three HCC cell lines ( P <0.05 or 0.01). EpCAM expression was down-regulated by the 5-FU and cisplatin in HepG2 cells, however the EpCAM expression was up-regulated by 5-FU and cisplatin in Hep3B cell line. EpCAM expression was down-regulated by 5-FU, and up-regulated by cisplatin in Huh-7 cell line. Flow cytometry assay showed doxorubicin exposure decreased EpCAM positive cell quantities in three HCC cell lines. EpCAM siRNA knock-down attenuated cell mortality after doxorubicin exposure. Conclusion All of these findings demonstrate that EpCAM is one of targets of chemoresistence.

MAGE-A9, a well-characterized cancer testis antigen (CTA), belongs to a member of melanoma antigen gene (MAGE) family. In human malignancies, aberrant expression of MAGE genes correlated with poor clinical prognosis, increased tumor growth, metastases, and enrichment in stem cell populations of certain cancers. Cancer stem cells (CSCs) have been proposed to contribute to the major malignant phenotypes of liver cancer, including recurrence, metastasis and chemoresistance. However, expression and potential role of MAGE-A9 in liver cancer stem cells (LCSCs) still remain unclear. In the present study, we first analyzed the expression profiling of MAGE family genes in EpCAM+ and EpCAM− human hepatocellular carcinoma (HCC), based on public Gene Expression Omnibus (GEO) database. Among these examined MAGE members, MAGE-A9 is the only one with significantly higher expression in EpCAM+ HCC specimens as compared with EpCAM− HCC. Quantitative PCR analysis further confirmed that MAGE-A9 expression significantly elevated in a subtype of HCC patients that had features of hepatic stem/progenitor cells with high-level expression of EpCAM and α-fetoprotein (AFP). Moreover, MAGE-A9 displayed remarkably enriched expression in EpCAM+ HCC cells that were sorted by fluorescence-activated cell sorting and cultured HCC cell spheroids with characteristics of stem/progenitor cells. Functional experiments further revealed that MAGE-A9 overexpression promoted cell proliferation, colony formation, migration, chemoresistance, and tumorigenicity in the context of EpCAM+ HCC cells, whereas MAGE-A9 knockdown significantly inhibited anchorage-dependent and spheroid colony formation and in vivo tumorigenicity. Collectively, these data demonstrate that MAGE-A9 functions as an important regulator of LCSCs, and MAGE-A9 may serve as a potential therapeutic target against HCC stem/progenitor cells.

The epithelial cell adhesion molecule (EpCAM) is closely correlated with the occurrence and development of various cancers of epithelial origin. This study tested, for the first time, the ability of EpCAM aptamer SYL3C to detect EpCAM expression in 170 cases of esophageal cancer (EC) and precancerous lesions, as well as 20 cases of EC series samples, using immunofluorescence imaging analysis. Corresponding antibodies were used as control. EpCAM overexpression was 98% in both esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EACA) and 100% in metastasis, but no EpCAM overexpression was detected in undifferentiated EC (UEC). Significant differences were noted among various stages of differentiation (p < 0.05) with the degree of differentiation inversely correlated with the expression of EpCAM. Overexpressed EpCAM was detected in severe dysplasia, but negative in mild to moderate dysplasia and benign esophageal lesions. In a competitive binding experiment, EpCAM aptamer generated a staining pattern similar to that of antibody, but the binding sites with EpCAM were different. Based on these results, it can be concluded that EpCAM is suitable for use as an EC biomarker, therapeutic target and effective parameter for tumor transfer and prognosis evaluation by aptamer SYL3C staining.

Background Epithelial cell adhesion molecule (EpCAM) expression has been reported in many types of cancer, including prostate cancer (PCa). However, the role of EpCAM expression remains inconsistent. We conducted a meta-analysis to assess the clinicopathological and prognostic significance of EpCAM expression in PCa. Methods Publications were searched online using electronic databases. The available data were obtained from The Cancer Genome Atlas (TCGA). The odds ratios (ORs) or hazard ratios (HRs) with their 95% confidence intervals (CIs) were calculated. Results We identified seven studies in which immunohistochemistry was used and that included 871 prostatic tissue samples. EpCAM expression was significantly higher in PCa samples than in benign and normal tissue samples (OR = 77.93, P  = 0.002; OR = 161.61, P  <  0.001; respectively). No correlation of EpCAM overexpression with pT stage and lymph node metastasis was observed; however, EpCAM overexpression showed a significant correlation with Gleason score (OR = 0.48, P  = 0.012) and bone metastasis (OR = 145.80, P  <  0.001). Furthermore, TCGA data showed that EpCAM overexpression was not closely correlated with age, pT stage, lymph node metastasis, number of lymph node, prostate-specific antigen level, Gleason score, biochemical recurrence, and overall survival. Based on multivariate Cox proportional-hazards regression analysis, a significant correlation was observed between EpCAM overexpression and 5-year worse biochemical recurrence free-survival. Conclusions EpCAM overexpression may be correlated with the development of bone metastasis and worse biochemical recurrence free-survival of PCa. Further studies are needed to verify these findings.

In this retrospective pilot study, the feasibility of the epithelial cell adhesion molecule (EpCAM) as an imaging target for lymph node (LN) metastatic disease of urothelial cell carcinoma (UCC) of the bladder was investigated. LN metastases and LNs without metastases of patients who underwent pelvic lymph node dissection because of muscle invasive bladder cancer (MIBC) were used. Primary tumors of the same patients were used from cystectomy specimen, transurethral resections, and biopsies. A pathologist, blinded to clinical data, scored EpCAM immunoreactivity. This method determines a total immunostaining score, which is the product of a proportion score and an intensity score. EpCAM expression was observed in 19/20 (95%) LNs with UCC metastases and in 11/12 (92%) of the primary tumors. EpCAM expression was absent in 14/14 (100%) LNs without metastases. Median EpCAM expression (TIS) in LN metastases was 5 (IQR 2.0–8.0) and in the primary tumors 6 (IQR 2.3–11.0). Based on the absence of staining in LNs without metastases, EpCAM show high tumor distinctiveness. EpCAM seems to be a feasible imaging target in LN metastases of UCC of the bladder. Pre- and perioperative visualization of these metastases will improve disease staging and improve the complete resection of LN metastases in MIBC.