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Carcinoembryonic antigen (CEA), also known as CEACAM5 or CD66e, is a kind of adhesion molecule on the surface of immunoglobulin superfamily (Ig-SF). CEA contains 702 amino acids and has a molecular weight of approximately 150 kDa. The protein molecule consists of: N-terminal intrachain disulfide bond lacked Immunoglobulin variable-like (IgV-like) domain and six immunoglobulin type 2 constant region-like (IgC2-like) domains. CEA is highly glycosylated and contains many Glc-NAc-AsN bond type and ploy mannose type multiantennary carbohydrate chains.

Figure 1. Molecular model of CEA based on cDNA structures

Note: Arrows indicate the connection GPI between CEA and cell membrane; N indicates the N-terminal IgV-like domain; A1-A3, B1-B3 indicate the IgC-like A and B domains; lollipop structures represent potential glycosylated sites.

Biological functions of Carcinoembryonic antigen (CEA)

CEA has the function of inhibiting cell anoikis, inhibiting cell differentiation and preventing cell polarization. CEA also plays an important role in cell adhesion, intracellular signaling conduction and tumor progression.

A. Mediating cell adhesion

CEA can act as an adhesion molecule by mediating homogeneous and heterogeneous cell adhesion through its N-terminus when expressed on the surface of tumor cells. This may be related to the anti-parallel and parallel binding properties of CEA immunoglobulin superfamily (lg-SF) single-chain molecules. lg-SF single-chain molecules can bind with each other to form homo/hetero dimmers and higher-order complexes.

B. Inhibition of cell anoikis

CEA is anchored to the lipid rafts of cell membrane and bound to the integrin receptor α5β1 via the structure of glycosyl phosphatidylinositol (GPI). α5β1 localizes the cytoskeleton to adhesion site after binding to the ligand fibronectin (FN). When CEA is overexpressed, CEA-GPI anchored lipid rafts aggregate, leading to the aggregation and activation of integrin a5. Then, PI3-K/Akt and MAPK signaling pathways are activated and survival signal is transmitted from extracellular to intracellular, and CEA exerts its inhibitory function to anoikis. Thus, tumor cells can survive and proliferate out of the plane of monolayer in absence of basement membrane adhesion. In addition, inhibition of anoikis can also inhibit cell differentiation and further aggravate cancer.

Clinical significance of Carcinoembryonic antigen (CEA)

CEA is a stable molecule selectively expressed by the epithelium, with limited expression in healthy tissues and high expression levels in tumors, and its expression level is positively correlated with cell differentiation status.
In healthy people, CEA is mainly produced by colonic goblet cells and exists in the outer mucus layer of the apical glycocalyx and is finally excreted with feces. So the content of CEA in blood of healthy human is very low. "WS/T 645.2-2018 Commonly used clinical immunology test items reference interval part 2: Serum AFP, CEA, CA19-9, CA15-3, CA125" pointed out that the reference interval of serum carcinoembryonic antigen (CEA) in Chinese adults is ≤5 ng/mL.

In cancer patients (eg. colorectal cancer), CEA expression is upregulated and overexpressed in the apical lumen of tumor cells. Thus, the normal cells lose their polarity, components from the plasma membrane are continuously shed from the surface and CEA-coated vesicles are formed, which pass through the lymphangion and blood vessels and finally enter the blood. Along with the development of tumors, the content of CEA in the blood increases. Currently, CEA is mainly used for postoperative monitoring of colon cancer in clinical, and CEA monitoring provides patients with a lead time for secondary surgery or other treatments. Generally, CEA is a broad-spectrum biomarker and be used for various cancers. However, unlike other typical carcinoembryonic antigens, CEA has relatively poor tumor specificity and it needs to be combined with other indicators in clinical diagnosis to improve the specificity and sensitivity of detection.

References

[1]S, Hammarstrom. The carcinoembryonic antigen(CEA) family: structures, suggested functions and expression in normal and malignant tissues[J]. Seminars in cancer biology, 1999, 9(2): 67-81.
[2]C Ordoez, RA Screaton, C Ilantzis, et al. Human carcinoembryonic antigen functions as a general inhibitor of anoikis[J]. Cancer Res, 2000, 60(13): 3419-3424.
[3]P Camacho-Leal, CP Stanners. The human carcinoembryonic antigen (CEA) GPI anchor mediates anoikis inhibition by inactivation of the intrinsic death pathway[J]. Oncogene, 2008, 27: 1545-1535