Abstract: Carcinoembryonic antigen (CEA) was first identified over 30 years ago as a marker of malignant colonic cells, but has since been shown to be expressed by a range of normal epithelial cells. Moreover, CEA is one member of a larger gene family and shares structural homology with other family molecules. Despite this confused picture, CEA is now known to function in several biological roles, including cell-cell adhesion. Its use in the diagnostic setting has also changed over the years, where in routine immunohistochemistry, monoclonal antibodies to CEA are useful in aiding diagnosis when used as part of a panel. Here, recent advances in understanding the biological role(s) that CEA and CEA-related antigens may play in cell adhesion are highlighted, together with results from molecular studies that illustrate how structure can influence the choice of CEA antibodies for use in both the research and diagnostic laboratory.
Key words: Carcinoembryonic antigen. Cell adhesion. Neoplasms. Tumor markers, biological.
Introduction
Carcinoembryonic antigen (CEA) was first described by Gold and Freedman in 1965(1,2) as a high-molecularweight glycoprotein found in colonic tumours and fetal colon but not in normal adult colon. With the development of more sensitive immunoassays, however, raised circulating CEA was also found in cases of breast, lung and ovarian tumours, and in cases of alcoholic cirrhosis.3 Despite this, CEA continues to be of interest as a multifunctional glycoprotein capable of acting as a Ca^sup 2+^-independent homophilic and heterophilic cell-cell adhesion molecule.4,5 It plays a role in diagnostic pathology and continues to be studied as a molecule involved in metastasis and carcinogenesis. Here, the major advances which have been made in understanding CEA and CEA-related antigens are covered, including molecular study of its gene structure, how this relates to the expressed protein, and how the specificity of antibodies to CEA may be affected by the expression of homologous CEA family members.
Molecular structure
In mature form, CEA is a glycoprotein with a molecular weight (MW) of approximately 180 kDa. The protein component has an MW of 78 kDa and the majority of the molecule is carbohydrate, comprising mannose, galactose, N-acetylglucosamine, fucose and neuraminic (sialic) acid.3,6,7
It has long been recognised that CEA is a member of the immunoglobulin gene superfamily.3 This diverse family includes major histocompatibility antigens, together with cell adhesion molecules such as ICAM-1, NCAM and LFA1.8 The common structure of the immunoglobulin gene superfamily is thought to have evolved from a single ancestral unit - the proteaseresistant immunoglobulin fold - which has undergone divergence and duplication.9
The CEA gene family is clustered on chromosome 19q, within a 1.2 Mb region,lo and can be divided into two subgroups: the CEA subgroup and the pregnancyspecific glycoprotein (PSG) subgroup (Fig. 1). Within each, there is a highly conserved region of 70-90% similarity in the N-domain exons. This conservation is significantly lower (50-60%0)7 between the subgroups. The CEA gene subgroup consists of CEA and the cross-relating genes coding for non-specific crossreacting antigen (NCA) 50/90, biliary glycoproteins (BGP) and other active genes.7 The primary structure of complementary DNA (cDNA) sequences of CEA and the genes of CEArelated family members have been established.11-14 There is a close correlation between exon expression and the domain structure, with the first exon encoding the 5'-untranslated region and the first two-thirds of the leader peptide10,,4 (Fig. 2). Comparative analysis of the cDNA transcripts for CEA and NCA-50 shows that there is a high sequence homology between the two molecules. There are major differences within the 3'-untranslated region, which can be utilised in the design of specific probes for use in in situ hybridisation (ISH) and the polymerase chain reaction (PCR).'1's However, the presence of an NCA-like 3'-untranslated region may present specificity problems.14
ISH is a powerful tool for the study of gene expression and for the localisation of messenger RNA (mRNA) within cells. Using such techniques, there appears to be a relationship between mRNA expression of CEA and protein distribution. 16-20 Several studies21-23 have found that CEA mRNA expression is under both transcriptional control mechanisms, such as gene methylation, and post-translational mechanisms, such as glycosylation and several regulatory elements which bind multiple nuclear binding factors. Hauk and Stanners23 also showed that CEA and NCA mRNA expression differed in a transfected cell line (CaCo-2) when stimulated by interferon-gamma (IFN-gamma). Such observations are important when considering the biological roles) that CEA and CEA-related gene products may play.
The deduced amino acid sequences of CEA and CEA-related proteins show that CEA is synthesised as a precursor of 702 amino acids, comprising a leader peptide of 34 amino acids and a mature CEA peptide of 668 amino acids.10,4 The mature peptide is divided into structural domains based on three internal repeat regions. These are referred to as N, A1B1, A2B2 and A3B3 domains.7.10 The Fifth CD Workshop (Boston, 1993) assigned all CEA-related antigens to CD66, CEA being assigned CD66e.
The carbohydrate moieties of CEA and CEA-related antigens may be involved in cell-cell adhesion. It has been proposed that the CEA family of antigens, particularly those associated with neutrophils (e.g. NCA [CD66c]), act as presenter molecules of oligosaccharide structures.24,25 A high proportion of the carbohydrate moiety is in the form of.>acetylglucosamine, consistent with the attachment of Lewis-type antigens, which act as ligands to the selectin family of adhesion molecules.26-29 The CEA-related antigen BGP is also associated with neutrophils, and the V domain of BGPc binds to CD66-classified antibodies. This domain also mediates homotypic adhesion of the Chinese hamster ovarian cell line (CHO-BGPc) transfectants in a temperature-dependent manner.3
CEA and cell adhesion
Together with integrins, cadherins, selectins and CD44, the immunoglobulin superfamily is recognised as a group of cell adhesion molecules.31 Most cell adhesion molecule interactions are accompanied bv the transmission of signals regulating differentiation or proliferation, and allow the exchange of information mediated by other cellular components.8,32,33 Although these molecules display a diversity of functions involved with immunity and in the control of the behaviour of cells in various tissues, they share the common feature of being recognition molecules at the cell surface.34
It has been suggested that CEA plays a role in cell recognition and in the regulation of cellular interactions. Benchimol et al.35 proposed a model of the role CEA may play during the malignant transformation of colonocytes, where overexpression of CEA leads to the disruption of normal intercellular forces at both the lateral and basal surfaces, due to the reduction in strength of other adhesion molecules. This results in an undermining of the single-layer configuration seen in the normal colonic crypt. With the over-production of CEA further down the crypt, an embryonic, multilayered configuration is assumed which, together with cellular division and further genetic insult, could develop into overt malignancy.
In the colon and elsewhere, CEA is expressed along the apical border of normal epithelial cells. In well-differentiated tumour cells, there is a reported increase in CEA expression along both lateral and basal surfaces, with cytoplasmic CEA expressed in poorly differentiated cells.36-38 In vitro studies have shown an increase in cellular CEA with the loss of polarisation.39
Dysregulation of CEA-related antigen expression has been confirmed in colorectal adenomas. Scheller et al. investigated the mRNA transcript expression of BGP CGM2 and NCA in 22 colorectal adenomas, and compared it with their respective normal mucosa. BGP and CGM2 mRNA levels were down-regulated in 20 and 18 adenomas, respectively, when compared to normal mucosa. NCA mRNA was increased by up to 2.4fold in 11 adenomas, when compared to their normal mucosa. This early dysregulation in colorectal tumourigenesis suggests importance in the development of the malignant phenotype.
In cell-cell adhesion, CEA and NCA are Ca^sup 2+^-independent, homophilic and heterophilic adhesion molecules.4,5 Oikawa et al.4 found that the N-domain of NCA and the CEA family member CGM6(7) (CD66b) mediated heterotypic cell adhesion. Domain-specific antibodies inhibited homophilic cell-cell adhesion in colorectal carcinoma cell lines where the epitopes within N and A3B3 domains were reported to be responsible for CEA-CEA binding. The involvement of N and a repeated loop of the A3B3 domain in homophilic adhesion by CEA was confirmed by Kuwahara et al.40 The same antibodies failed to inhibit cell adhesion to type IV collagen and laminin.41
CEA is involved in cell-extracellular matrix (ECM) adhesion of the colonic carcinoma cell line SW1222.(42) This cell line binds to type I collagen through a receptor which recognises the Arg-Gly-Asp (RGD) tripeptide sequence.43 Cell adhesion to type I collagen matrix was inhibited by a panel of monoclonal antibodies to the 180 kDa CEA and other members of the CEA family. However, the same antibodies failed to inhibit adhesion to type I collagen in another CEAexpressing carcinoma cell line (LS 174T). This cell line does not adhere to collagen via the RGD-recognising receptor, and both cell lines failed to adhere to CEA itself. It was proposed that CEA and the RGD-recognising receptor cooperate in cell adhesion to collagen and regulate the functional activity of the SW1222 collagen receptor.
Use of CEA in diagnosis
Groups interested in using interferons (IFNs) as adjuvants in immunoscintigraphy and immunotherapy trials have identified CEA as a molecule for subsequent monoclonal antibody targeting.44 CEA expression is enhanced by IFN-gamma in cell lines derived from colon45 and lung46 carcinoma. Guadagni et al.47 found that the most responsive of the cell lines tested by IFN-y treatment were the moderately differentiated cell lines, where there was a 300-400% increase in cellular CEA content and an increase from 30-40% to greater than 80% in its cell-surface expression, as measured by flow cytometry. With one exception, those cell lines which did not constitutively express CEA were not stimulated to produce CEA by IFN-gamma treatment. Similarly, expression of CEA in patients diagnosed with gastrointestinal carcinoma is enhanced in a dose-dependent manner following intramuscular injection of IFN-alpha2, whereas CEA expression in samples of normal colonic mucosa remains low.45
For some considerable time, radiolabelled antibodies to CEA have been used in imaging tumours and localising them prior to surgery.48 However, nonspecificity and lack of characterisation in this first generation of antibodies resulted in a limited ability to resolve intrahepatic lesions, as high uptake by normal liver tissue complicated the images.49 Using internationally recognised criteria (see below), a second generation of monoclonal antibodies to CEA have been identified and are undergoing evaluation for tumour imaging and immunotherapy.50-54 Experimental models using mice that are transgenic for human CEA have been proposed.55
Despite its demise as the marker of malignancy, CEA continues to be of some value in the diagnosis and prognosis of cancer.56,57 In colorectal tumours, preoperative serum CEA levels assist in the evaluation of Duke's stage C carcinoma,58 and when used in conjunction with flow cytometry, help to predict the prognosis of patients with Duke's stage B2 and Duke's stage C carcinomas.59 In addition, a significantly higher preoperative level of serum CEA is found in patients with non-resectable tumours.60
Cellular and tissue distribution of CEA can also be useful61-63 and its staining pattern used to predict metastatic potential64 and lymph node status.65 As part of a panel of antibodies, CEA can prove useful in determining the primary site of metastatic adenocarcinoma.66,67 Similarly, in tumours of the extrahepatic biliary tract, the cellular localisation of CEA can identify foci of malignant cells.3738 PCR can be used to detect micrometastasis in specimens of bone.45
On fine-needle biopsy samples, polyclonal anti-CEA can be useful in differentiating atypical variants of hepatocellular carcinoma from metastatic tumour.68 However, because of its lack of specificity and ability to cross-react with CEA-related antigens, the polyclonal antibody was not recommended in other studies.69,70 Absorption with tissue extracts, irrespective of the source of tissue, reduces this cross-reactivity with CEA-related antigens.71 The absorption process, however, has never been standardised, with different authors recommending absorption by various tissue preparations and using different absorption procedures.71,72
Initially, monoclonal antibodies were thought to provide a means of achieving CEA specificity. Characterisation of available antibodies to CEA by an international group showed, however, that only those directed against certain domains of the CEA molecule were specific.73 This was confirmed by other groups,50,52,74-76 and has helped to classify monoclonal antibodies according to recognised standards. Fully characterised monoclonal antibodies to CEA remain important when used for diagnostic purposes. For example, in the differentiation of mesothelioma from adenocarcinoma, CEA is consistently found to be the most useful marker to identify adenocarcinoma, although the use of CEA-specific antibodies remains paramount70,77,78 especially when used as part of an antibody panel on processed tissue following heat-mediated antigen retrieval.79
Conclusions
The capacity of the CEA family of genes to undergo splice variation and post-translational change gives rise to a group of complex glycoproteins. Such variety allows the potential for CEA and CEA-related antigens to participate in many facets of cell growth and development, as well as in carcinogenesis. Well-characterised antibodies are now available and are used for both clinical and diagnostic purposes. CEA, therefore, and the CEA family of related antigens continue to provide valuable insights into carcinogenesis and are of value in diagnosis.
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[Author Affiliation]
P. MAXWELL
Immunocytochemistry and Molecular Pathology Laboratory, Institute of Pathology, Royal Group of Hospitals Trust, Belfast BT12 6BA, Northern Ireland, UK
(Accepted 9 April 1999)
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