Epithelial cell adhesion molecule

First discovered in 1979, EpCAM was initially described as a dominant surface antigen on human colon carcinoma. Because of its prevalence on many carcinomas, it has been "discovered" many different times. EpCAM therefore has many aliases the most notable of which include TACSTD1 (tumor-associated calcium signal transducer 1), CD326 (cluster of differentiation 326), and the 17-1A antigen. EpCAM expression is not limited to human colon carcinomas; in fact, EpCAM is expressed in a variety of human epithelial tissues, carcinomas, and progenitor and stem cells. However, EpCAM is not found in non-epithelial cells or cancers of non-epithelial origin. EpCAM is expressed on the basolateral membrane of all simple (especially glandular), pseudo-stratified, and transitional epithelia. In contrast, normal squamous stratified epithelia are negative for EpCAM. The level of expression may differ significantly between the individual tissue types. In the gastrointestinal tract, the gastric epithelium expresses very low levels of EpCAM. Expression levels are substantially higher in small intestine, and in colon EpCAM is probably expressed at the highest levels among all epithelial cell types. However, EpCAM expression in carcinomas is often heterogeneous; some cells in a tumor have more EpCAM than other cells in the same tumor. Squamous carcinomas often express EpCAM whereas normal squamous cells do not express EpCAM. EpCAM expression differs between different types of renal cell carcinomas, and EpCAM expression increases during development of androgen resistance in prostate cancer. All of this points towards the utility of EpCAM as a diagnostic tool for various cancers. == Structure ==

Although it is identified as a cell adhesion molecule, EpCAM does not structurally resemble any of the four major families of cell adhesion molecules, namely cadherins, integrins, selectins, and members of the immunoglobulin super-family. EpCAM is a glycosylated, 30- to 40-kDa type I membrane protein. The sequence of the EpCAM molecule predicts the presence of three potential N-linked glycosylation sites. It is composed of 314 amino acids. EpCAM consists of an extracellular domain (242 amino acids) with epidermal growth factor (EGF)- and thyroglobulin repeat-like domains, a single transmembrane domain (23 amino acids), and a short intracellular domain (26 amino acids). The extracellular domain is sometimes referred to as EpEX, and the intracellular domain is sometimes referred to as EpICD. == Function ==

The exact function of EpCAM is currently being elucidated, but EpCAM appears to play many different roles. Cell adhesion EpCAM was first found to play a role in homotypic cell adhesion. EpCAM has a negative impact on cadherin-mediated adhesions. Overexpression of EpCAM does not alter overall total cellular level of cadherins 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. The homotypic adhesive activity has been questioned, as a variety of in vivo and in vitro biochemical experiments have failed to detect trans-interactions. EpCAM pro-adhesive activity could be explained by alternative models, based on its ability to regulate PKC signalling and myosin activity. Recently, it has been discovered that EpCAM contributes to the maintenance of tight junctions. 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. 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. 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 In one study, epithelial tumors were often strongly positive for EpCAM, but mesenchymal tumors showed only occasional and weak positivity. ==Clinical significance==

Target for immunotherapy 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. Histopathology (BCC) with squamous cell metaplasia. Only BCC cells are stained with BerEP4 in this image. EpCAM is often overexpressed in certain carcinomas, including in breast cancer, colon cancer and basal cell carcinoma of the skin. The diagnosis of such conditions can therefore be assisted by immunohistochemistry using BerEp4, which is an antibody to EpCAM. 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 which causes intractable diarrhea in newborn children. == References ==