Epithelial cell adhesion molecule

Epithelial cell adhesion molecule (EpCAM) is a is_associated_with::transmembrane is_associated_with::glycoprotein mediating Ca2+-independent is_associated_with::homotypic cell-cell adhesion in is_associated_with::epithelia. EpCAM is also involved in cell signaling, migration, proliferation, and differentiation. Additionally, EpCAM has is_associated_with::oncogenic potential via its capacity to upregulate is_associated_with::c-myc, is_associated_with::e-fabp, and is_associated_with::cyclins A & E. Since EpCAM is expressed exclusively in epithelia and epithelial-derived is_associated_with::neoplasms, EpCAM can be used as diagnostic marker for various cancers. It appears to play a role in is_associated_with::tumorigenesis and is_associated_with::metastasis of is_associated_with::carcinomas, so it can also act as a potential prognostic marker and as a potential target for immunotherapeutic strategies.

Expression pattern
First discovered in 1979, EpCAM was initially described as a dominant surface is_associated_with::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 is_associated_with::progenitor and is_associated_with::stem cells. However, EpCAM is not found in non-epithelial cells or cancers of non-epithelial origin. EpCAM is expressed on the is_associated_with::basolateral membrane of all simple (especially glandular), pseudo-stratified, and transitional epithelia. In contrast, normal is_associated_with::squamous stratified epithelia are negative for EpCAM. The level of expression may differ significantly between the individual tissue types. In the is_associated_with::gastrointestinal tract, the gastric epithelium expresses very low levels of EpCAM. Expression levels are substantially higher in is_associated_with::small intestine, and in colon EpCAM is probably expressed at the highest levels among all epithelial cell types.

EpCAM is frequently upregulated in carcinomas but is not expressed in cancers of non-epithelial origin. In cancer cells, EpCAM is expressed in a dispersed pattern across the cell membrane. 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 is_associated_with::renal cell carcinomas, and EpCAM expression increases during development of is_associated_with::androgen resistance in is_associated_with::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 is_associated_with::cell adhesion molecules, namely is_associated_with::cadherins, is_associated_with::integrins, is_associated_with::selectins, and members of the is_associated_with::immunoglobulin super-family.

EpCAM is a is_associated_with::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 is_associated_with::amino acids. EpCAM consists of an extracellular domain (242 amino acids) with is_associated_with::epidermal growth factor (EGF)- and is_associated_with::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. 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.

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/ is_associated_with::catenin complex in the is_associated_with::cytoskeleton. As EpCAM expression increases, the total amount of α-catenin decreases, whereas cellular β-catenin levels remain constant. 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.

Role in cancer
EpCAM can be cleaved which lends the molecule is_associated_with::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 is_associated_with::c-myc, is_associated_with::e-fabp, and is_associated_with::cyclins A & E. 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. The amount of β-catenin in the nucleus can modulate the expression level of EpCAM.

EpCAM may also play a role in is_associated_with::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 is_associated_with::short interfering RNA (siRNA) led to a reduction of proliferation, migration, and invasion of breast cancer cells in vitro supporting the role of EpCAM in promoting EMT. In another study, cells undergoing EMT were found to downregulate EpCAM. In one study, epithelial tumors were often strongly positive for EpCAM, but mesenchymal tumors showed only occasional and weak positivity. It has been suggested that EpCAM expression is downregulated during EMT but then upregulated once the metastasis reaches its future tumor site.

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 is_associated_with::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. 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.

is_associated_with::Edrecolomab, is_associated_with::catumaxomab and other is_associated_with::monoclonal antibodies are designed to bind to it.

Genetic disorders
EpCAM is indirectly responsible for is_associated_with::Lynch syndrome, a genetic disorder that leads to increased risk of cancer. Deletion of a portion of the 3’ end of the EpCAM gene causes is_associated_with::epigenetic inactivation of the is_associated_with::MSH2 gene by hypermethylating the promoter region of the MSH2 gene.

Mutations in EpCAM have also been associated with is_associated_with::congenital tufting enteropathy which causes intractable diarrhea in newborn children.