EPCAM - epithelial cell adhesion molecule |Elisa - Clia - Antibody - Protein

Background

Epithelial Cell Adhesion Molecule (EpCAM), also known as CD326 or TACSTD1 (tumor-associated calcium signal transducer 1), is a transmembrane glycoprotein prominently expressed on the surface of epithelial cells in various tissues. EpCAM plays a dual role in cellular adhesion and signaling, as well as in the regulation of cell proliferation and differentiation. Originally identified as a marker on cancer cells, EpCAM is also a vital component in normal epithelial physiology, where it participates in maintaining cell-cell adhesion and the structural integrity of epithelial layers.

EpCAM has become a major focus in cancer research due to its high expression in numerous epithelial tumors, including colorectal, breast, lung, and ovarian cancers. It is frequently upregulated in cancer, where it contributes to cell proliferation, migration, and invasion, as well as tumor growth and metastasis. Its presence on circulating tumor cells has made EpCAM a promising biomarker for early cancer detection and prognosis. Beyond its role in oncogenesis, EpCAM is involved in regenerative processes in epithelial tissues, influencing stem cell behavior and tissue repair.

Protein Structure

EpCAM is a single-pass transmembrane protein with a unique structure that contributes to its diverse functional roles. The structure of EpCAM can be divided into three major domains:

Extracellular Domain (N-terminal):

• The extracellular domain of EpCAM is composed of two subdomains: a signal peptide (cleaved during maturation) and an EGF-like repeat domain. The EGF-like repeat includes a cysteine-rich motif responsible for mediating adhesive interactions, particularly through homophilic binding with EpCAM molecules on neighboring cells.
• This domain also contains N-glycosylation sites, which are important for protein stability, surface expression, and function. Glycosylation influences how EpCAM interacts with other molecules and contributes to its role in cell adhesion and signaling.

Transmembrane Domain:

• The transmembrane domain of EpCAM consists of a hydrophobic region that anchors the protein within the cell membrane. This domain is critical for positioning EpCAM on the cell surface and ensuring that the extracellular and intracellular domains maintain their specific functions.

Intracellular Domain (C-terminal):

• The intracellular domain of EpCAM contains a short, proline-rich region that participates in intracellular signaling cascades. This domain has binding sites for various signaling molecules, such as β-catenin, which link EpCAM to pathways that regulate cell proliferation, migration, and differentiation.
• EpCAM’s C-terminal domain also interacts with the actin cytoskeleton through the interaction with adapter proteins, allowing it to influence cytoskeletal dynamics and cell morphology.

The structure of EpCAM, particularly its interaction with β-catenin, plays a crucial role in its ability to act as both an adhesion molecule and a signaling receptor, facilitating cross-talk between the cell surface and intracellular pathways that regulate cell behavior.

Classification and Subtypes

EpCAM belongs to the TACSTD (tumor-associated calcium signal transducer) family and is classified as a type I transmembrane glycoprotein. EpCAM is generally considered a unique protein without known subtypes, though its expression levels and functional state vary across tissues and cellular conditions. Unlike classical cadherins, EpCAM does not belong to the cadherin or integrin families of cell adhesion molecules, although it contributes to cellular cohesion in epithelial layers.

Function and Biological Significance

EpCAM functions as a cell adhesion molecule and is involved in several crucial biological processes:

Cell-Cell Adhesion:

• EpCAM mediates homophilic cell adhesion between epithelial cells, thereby contributing to the structural integrity of epithelial tissues. It enhances cell-cell adhesion by interacting with other EpCAM molecules on adjacent cells, although it does not function through classical cadherin-dependent mechanisms.
• EpCAM’s adhesive role is particularly significant in tissues undergoing rapid cell turnover or repair, as it provides stability to proliferative cell populations within the epithelial lining.

Cell Signaling and Proliferation:

• EpCAM is also involved in intracellular signaling, particularly through its interaction with β-catenin. Upon proteolytic cleavage, the intracellular domain of EpCAM can translocate to the nucleus, where it participates in β-catenin signaling, influencing the expression of genes involved in cell proliferation and survival.
• This signaling capacity is critical in cancer, where overexpressed EpCAM can promote uncontrolled cell growth and survival, contributing to tumor formation and progression.

Epithelial Tissue Maintenance and Regeneration:

• EpCAM plays a role in the maintenance and regeneration of epithelial tissues, particularly in organs that require constant repair, such as the intestine. In this context, EpCAM contributes to stem cell proliferation and differentiation, supporting tissue homeostasis and repair mechanisms.
• EpCAM has been identified as a marker of stem and progenitor cells within epithelial tissues, where it regulates the balance between stem cell renewal and differentiation.

Cancer Stem Cell Marker and Tumor Progression:

• In cancer, EpCAM is commonly upregulated and is associated with tumor-initiating cells, also referred to as cancer stem cells. It contributes to the self-renewal and maintenance of these cells, which play a critical role in cancer progression, metastasis, and resistance to therapy.
• EpCAM expression on circulating tumor cells has made it a valuable biomarker in detecting metastatic cells in the bloodstream, aiding in early cancer diagnosis, prognosis, and monitoring of treatment efficacy.

Clinical Issues

Cancer Progression and Metastasis:

• EpCAM overexpression is strongly associated with cancer progression in epithelial tumors. Its upregulation is observed in colorectal, breast, lung, ovarian, and other epithelial cancers, where it contributes to increased tumor cell proliferation, migration, and invasion.
• The ability of EpCAM to facilitate cell signaling related to β-catenin pathways is linked to increased cell survival and tumor aggressiveness. High EpCAM expression correlates with poor prognosis in several cancers, making it a target of interest for anticancer therapies.

Target for Cancer Therapy:

• Due to its specific overexpression in various cancers, EpCAM is a promising therapeutic target. Monoclonal antibodies targeting EpCAM, such as catumaxomab, have been developed for cancer treatment, particularly in targeting metastatic and treatment-resistant tumor cells.
• Immunotherapy approaches using EpCAM-targeting strategies are being explored to selectively eliminate tumor cells, as EpCAM’s expression on normal epithelial cells is often lower than in tumor tissues, providing a therapeutic window to reduce off-target effects.

Biomarker for Circulating Tumor Cells (CTCs):

• EpCAM’s presence on CTCs in blood has made it a useful biomarker for non-invasive cancer diagnosis and monitoring. EpCAM-based capture methods allow for the isolation and analysis of CTCs, which can provide insights into disease progression and treatment response in real time.
• The detection of EpCAM-positive CTCs has become a valuable tool in personalized oncology, aiding in early detection of metastasis and in assessing the effectiveness of therapies.

Role in Regenerative Medicine and Tissue Engineering:

• Beyond cancer, EpCAM’s role in tissue regeneration and stem cell regulation has implications in regenerative medicine. Its expression in progenitor cells in organs like the liver, intestine, and kidney makes it a marker of interest for identifying and isolating stem cells for therapeutic purposes.

Summary

EpCAM (CD326) is a multifunctional transmembrane glycoprotein expressed on epithelial cells, involved in cell-cell adhesion and intracellular signaling. Structurally, EpCAM is composed of an extracellular domain containing glycosylation sites and an EGF-like repeat for adhesion, a transmembrane domain for membrane anchoring, and a cytoplasmic tail that mediates signaling pathways critical for cell proliferation and differentiation. Its role in cell adhesion is distinct from that of classical cadherins, as it enhances cell cohesion through homophilic interactions without relying on catenin linkage for adhesion.

Functionally, EpCAM plays a significant role in epithelial cell adhesion, proliferation, and tissue maintenance. In normal tissues, it maintains epithelial integrity and supports tissue repair and regeneration, particularly in rapidly renewing tissues. In cancer, EpCAM is frequently overexpressed and is involved in tumor cell proliferation, survival, and metastasis, with its upregulation often correlating with aggressive tumor behavior and poor prognosis.

Clinically, EpCAM serves as a target for cancer therapies, with EpCAM-specific antibodies like catumaxomab being explored for their therapeutic potential. Its use as a biomarker for CTCs also provides a minimally invasive method for cancer diagnosis and treatment monitoring, offering valuable insights into metastatic potential and treatment efficacy. EpCAM’s role in regenerative medicine further highlights its significance beyond oncogenesis, as its expression in progenitor cells supports the exploration of tissue engineering and regenerative therapies.

In summary, EpCAM is a critical player in epithelial biology, acting as both an adhesion molecule and a signaling receptor that regulates cell behavior. Its involvement in cancer progression and regenerative processes makes it an important target in both therapeutic development and clinical diagnostics.