Carcinoembryonic antigen (CEA), also named CD66 or CEACAM5, is a glycophosphatidylinositol-(GPI-) linked membrane-anchoring protein. The structure of CEA protein includes an N-terminal sequence followed by three disulfide-linked repeats of 178 amino acids and a hydrophobic C-terminal domain. This structure is similar to that of the immunoglobulins and has established CEA as a member of the superfamily of immunoglobulin genes. The membrane-anchoring region of CEA is cleaved by phospho-inositol specific phospholipases C and D to release CEA in a soluble form. The molecular weight of CEA protein in normal cells is 72 kDa. However, CEA is expressed on the cellular surface of multiple cancers with a molecular weight of about 180 kDa depending on the extent of its glycosylation.
Fig.1 Structure of CEA. (Horig, 2000)
CEA behaves as an intercellular adhesion molecule connecting adjacent epithelial cell membranes, particularly in both embryonic intestine and colonic tumors, resulting in the aggregation of CEA-expressing cells. In addition, CEA plays a significant role in other cellular processes including the inhibition of differentiation programs, inhibition of anoikis and apoptosis in colon cells, disruption of cell polarization and tissue architecture, and promotion of liver metastasis. CEA regulates these activities by activating integrin signaling pathways in lipid raft subdomains where it colocalizes and clusters with the α5β1 integrin, thus triggering integrin-linked kinase, phosphatidylinositol 3-kinase (PI3K), and protein kinase B (AKT) activities.
CEA may also be involved in the enhancement of metastatic disease. Many clinical studies have shown correlations between serum CEA levels and advanced colorectal cancer (CRC), in particular the presence of liver metastasis. Experimentally, poorly metastatic CRC cell lines can become highly metastatic following transfection with CEA cDNA. This may be due to adhesion between circulating CEA in the liver and CEA bound to metastatic tumor cells. The release of the anti-inflammatory cytokine IL-10 by Kupffer cells activated by CEA also plays a role in tumor cell survival by inhibiting inducible nitric oxide synthetase (iNOS) and the production of NO and ROS, thus aiding tumor cell survival. In addition, the direct association of CEA with the death receptor 5 (DR5) receptor expressed on CRC cells leads to decreased anoikis and, as a consequence, increased metastasis. CEA inhibits transforming growth factor (TGF) signaling through an unknown mechanism and increases tumor cell proliferation. This suggests an additional mechanism by which CEA may promote tumor survival at the metastatic site.
CEA is one of the oldest and most widely used tumor markers. Circulating CEA in the serum has long been used as a biomarker. Most modern assays for detecting CEA use a monoclonal technique that has a low false-positive rate. The experimental generation of monoclonal antibodies against CEA paved the way for a variety of diagnostic approaches based on the detection and targeting of CEA.
Several studies have shown that CEA can be envisaged as a target for cancer immunotherapy protocols. The goal of cancer immunotherapy is to disrupt the immune tolerance to tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs), thus inducing a strong immune response to these antigens expressed by cancer cells. Vaccination with viral or yeast vectors expressing CEA, dendritic cells (DCs) pulsed with CEA-peptides, CEA plasmid DNA, or with recombinant CEA has been proven to be successful in inducing a potent anti-tumor immunity in animal models.
CEA was one of the first tumor antigens to be isolated from cancer patients and is expressed on many different types of tumors. CEA and its receptor involved in the progression of colorectal cancer hepatic metastasis may, therefore, provide a new therapeutic target. Creative Biolabs provides a comprehensive CEA assay portfolio service, including but not limited to:
As a biotechnological leader specializing in customized services, Creative Biolabs focuses on providing a full range of tumor marker assay services (e.g., CEA assay portfolio service). Operating in state-of-the-art laboratories, our scientists are fully equipped to provide a broad array of services to meet the needs of different clients. Please feel free to contact us.
Reference
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