Epithelial cell adhesion molecule

EpCAM was first found to play a role in homotypic cell adhesion.[5] This means that EpCAM on the surface of one cell binds to the EpCAM on a neighboring cell thereby holding the cells together. The adhesions mediated by EpCAM are relatively weak, as compared to some other adhesion molecules, such as classic cadherins.

EpICD is required for EpCAM to mediate intercellular adhesion; EpCAM mediates intercellular adhesion and associates with the actin cytoskeleton via EpICD.[16]

EpCAM has a negative impact on cadherin-mediated adhesions. Overexpression of EpCAM does not alter the expression level of cadherin but rather decreases the association of the cadherin/ catenin complex in the cytoskeleton. As EpCAM expression increases, the total amount of α-catenin decreases, whereas cellular β-catenin levels remain constant.[17]

The homotypic adhesive activity has been questioned, as a variety of in vivo and in vitro biochemical experiments have failed to detect trans-interactions.[18] EpCAM pro-adhesive activity could be explained by alternative models,[19] based on its ability to regulate PKC signalling and myosin activity.[20]

Active proliferation in a number of epithelial tissues is associated with increased or de novo EpCAM expression. This is especially evident in tissues that normally reveal no or low levels of EpCAM expression, such as squamous epithelium. The level of EpCAM expression correlates with the proliferative activity of intestinal cells, and inversely correlates with their differentiation.[8]

EpCAM can be cleaved which lends the molecule oncogenic potential. Upon cleavage, the extracellular domain (EpEX) is released into the area surrounding the cell, and the intracellular domain (EpICD) is released into the cytoplasm of the cell. EpICD forms a complex with the proteins FHL2, β-catenin, and Lef inside the nucleus. This complex then binds to DNA and promotes the transcription of various genes. Targets of upregulation include c-myc, e-fabp, and cyclins A & E.[6] This has the effect of promoting tumor growth. Additionally, EpEX that has been cleaved can stimulate the cleavage of additional EpCAM molecules resulting in a positive feedback loop.[14] The amount of β-catenin in the nucleus can modulate the expression level of EpCAM.[21]

EpCAM may also play a role in epithelial mesenchymal transition (EMT) in tumors, although its exact effects are poorly understood. Its ability to suppress E-cadherin suggests that EpCAM would promote EMT and tumor metastasis, but its homotypic cell adhesion properties can counteract its ability to suppress E-cadherin.[22] Results from different studies are often conflicting. In one study, for example, silencing of EpCAM with short interfering RNA (siRNA) led to a reduction of proliferation, migration, and invasion of breast cancer cells in vitro[7] supporting the role of EpCAM in promoting EMT. In another study, cells undergoing EMT were found to downregulate EpCAM.[23] In one study, epithelial tumors were often strongly positive for EpCAM, but mesenchymal tumors showed only occasional and weak positivity.[15] It has been suggested that EpCAM expression is downregulated during EMT but then upregulated once the metastasis reaches its future tumor site.[24]

It has been speculated that since EpCAM in normal epithelia is expressed mostly on the basolateral membrane, it would be much less accessible to antibodies than EpCAM in cancer tissue, where it is homogeneously distributed on the cancer cell surface. In addition to being overexpressed in many carcinomas, EpCAM is expressed in cancer stem cells, making EpCAM an attractive target for immunotherapy. However, the heterogeneous expression of EpCAM in carcinomas and the fact that EpCAM is not tumor-specific (i.e., it is found in normal epithelium) raise concerns that immunotherapy directed towards EpCAM could have severe side effects.[13] As the role of EpCAM in cancer cell signaling is better understood, EpCAM signaling rather than EpCAM itself may be a target for therapeutic intervention.[14]

Edrecolomab, catumaxomab and other monoclonal antibodies are designed to bind to it.[10][25] also nofetumomab.

Comparison H&E stain (left) with BerEP4 immunohistochemistry staining (right) on a pathological section having basal cell carcinoma (BCC) with squamous cell metaplasia. Only BCC cells are stained with BerEP4 in this image.[26]

EpCAM is often overexpressed in certain carcinomas, including in breast cancer, colon cancer and basal cell carcinoma of the skin.[27] The diagnosis of such conditions can therefore be assisted by immunohistochemistry using BerEp4, which is an antibody to EpCAM.[27]

A problem in EpCAM can indirectly cause Lynch syndrome,[28] a genetic disorder that leads to increased risk of cancer. Deletion of a portion of the 3' end of the EpCAM gene causes epigenetic inactivation of the MSH2 gene by hypermethylating the promoter region of the MSH2 gene.

Mutations in EpCAM have also been associated with congenital tufting enteropathy[29] which causes intractable diarrhea in newborn children.