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© 2002 American Society for Clinical Oncology
CEACAM1: A Marker With a Difference or More of the Same?Guy’s Hospital, London, United Kingdom LUNG CANCER IS the most common cause of cancer death in the Western world. There have been considerable advances in our understanding of the pathogenesis of lung cancer in recent years, which have identified many potential molecular prognostic markers including, eg, p53, HER2, EGFR, FOS, JUN, and cyclin A.1,2 In this issue of the Journal of Clinical Oncology, a new molecule is added to the burgeoning list of such markers: CEACAM1. In a retrospective study of 93 patients with primary adenocarcinoma of the lung, the expression of CEACAM1 was determined by immunohistochemical analysis of paraffin-embedded sections of tumor.3 Approximately two thirds of tumors were considered positive for CEACAM1. In a multivariate analysis CEACAM1 was identified as an independent marker of poor prognosis. So what is CEACAM1, and what is the potential role of it and other prognostic markers in the management of patients with lung cancer? The human carcinoembryonic antigen (CEA) family is composed of 29 genes tandemly arranged on chromosome 19q13.2. These genes have been classified into two major subfamilies, the CEACAM and the pregnancy-specific glycoprotein subgroups. Protein structural analysis indicates that the CEACAM subgroup members belong to the immunoglobulin superfamily of adhesion molecules. The CEACAM-encoded proteins include CEA, CEACAM1, and CEACAMs 3, 4, 7, and 8.4,5 CEACAM1 is expressed on the epithelium and endothelium of various tissues, monocytes, granulocytes, activated T cells, B cells, and a subset of natural killer cells.4-6 Alternative splicing of the cytoplasmic exons generates CEACAM1 variants with either a long (L; 73 amino acid) or a short (10 amino acid) cytoplasmic tail. The cytoplasmic domain of the L isoform contains tyrosine residues that potentially interact with protein tyrosine kinases of the Src family as well as an immunoreceptor tyrosine inhibition motif.7 The expression pattern, relationship to the immunoglobulin superfamily, and presence of signal transduction motifs in the L cytoplasmic domain suggest a potential diverse function for CEACAM1 as a homophilic and heterophilic adhesion molecule and as a regulator of signal transduction. Given this complexity, it is not surprising that a variety of functions that may be important in tumor growth, some apparently contradictory of each other, have been ascribed to CEACAM1. The expression of CEACAM1 has been demonstrated to be lower in tumor compared with normal tissue in cancers of the breast,8 colon,9 prostate,10 and endometrium.11 These findings, and the observation that CEACAM1 is a negative regulator of tumor cell growth in breast and prostate cancer models,12,13 suggested that CEACAM1 may be a tumor suppressor gene. The inhibition of tumor growth in vitro is dependent on the L cytoplasmic domain of CEACAM1, and recent work has demonstrated the phosphorylation of a specific serine residue to be crucial.14,15 However, in contrast to the tissues described above, CEACAM1 is not expressed in normal lung. CEACAM1 is therefore unlikely to have tumor suppressor activity in the pathogenesis of lung cancer. Similarly, CEACAM1 is not expressed by normal melanocytes, but has been demonstrated in malignant melanoma cells, with expression associated with a worse prognosis.16 Some of the other activities described for CEACAM1 may be relevant in lung cancer. For example, in endothelial cells CEACAM1 exhibits angiogenic properties and acts as a major effector of vascular endothelial growth factor.17 CEACAM1 associates with the cytoskeleton,18 is coexpressed with integrin ß3, and is localized to maternal-fetal interface during placental development and at the invading front of primary melanomas.19 These data suggest a possible role for CEACAM1 in angiogenesis, tumor invasion, and metastasis. CEACAM1 also has a role in the immune system. It is expressed on activated human T cells, and antibodies to CEACAM1 have been reported to increase20,21 or decrease6 T-cell activation in response to T-cell receptor cross-linkage in vitro. In a recent study, the binding of Neisseria gonorrhoeae Opa proteins to CEACAM1 on primary CD4+ T cells suppressed their activation and proliferation.22 These apparent differences may reflect different in vitro culture systems, but also the potential for the cytoplasmic domain of the L isoform of CEACAM1 to generate both stimulatory and inhibitory intracellular signals. Expression of CEACAM1 by MHC class I–deficient tumor cells has also been reported to inhibit tumor cell lysis by natural killer cells.23 It is, therefore, possible that the expression of CEACAM1 by tumor cells may suppress both the adaptive and innate immune response to the tumor. CEACAM1, in common with many other reported prognostic factors, has diverse physiological roles and many possible effects on tumor cells. Tumor development and progression is a complex process, and it is too simplistic to consider one possible prognostic factor in isolation from others. The breast cancer literature should act as a guide to us on the perils of identifying single factors of prognostic significance and overinterpreting their clinical relevance. Perhaps the most encouraging recent development in this area has been the application of array technology to the clinical arena. The use of cDNA microarrays and the serial analysis of gene expression have extended our ability to determine the expression of large numbers of genes within a tumor.24,25 Two recent studies used cDNA microarrays to determine gene expression in lung cancer.26,27 Distinct patterns of gene expression were demonstrated for small-cell cancers, squamous carcinomas, and adenocarcinomas. In addition, the adenocarcinomas were divided by gene expression into three26 or four subtypes.27 Although there were some similarities between the adenocarcinoma subtypes identified in these studies, there were also significant differences, which are exemplified by reference to the results on CEACAM1. In the first study the expression of CEACAM1 was associated with a good prognosis,26 whereas in the second study CEACAM1 expression was associated with lung metastases from colon cancer and not with primary lung adenocarcinoma.27 These results are at odds with each other and with those of Laack et al.3 These differences probably reflect the small number of cases in each study, but also the potential difficulties in interpreting microarray data. The RNA was extracted from frozen samples of tumor, which will vary in the proportions of tumor cells, stroma, blood vessels, and inflammatory or lymphoid cells. Therefore, variations in gene expression between samples may not reflect differences solely in the phenotype of the malignant cells, and interpretation may be especially difficult for molecules such as CEACAM1 that are expressed by a wide variety of tissues. Although new methods are being devised to interpret microarray data, they are not yet applicable to routine clinical practice.28 Given these potential difficulties, perhaps the optimal use of cDNA microarrays may be to identify gene products of potential significance that can be further analyzed by immunohistochemistry to determine tissue expression.29 A recent such study in the Journal used tissue microarrays to analyze rapidly and reproducibly the expression of E-cadherin and associated proteins in a large number of primary lung tumors.30 Tissue microarrays could be used to analyze the expression of many different prognostic markers from a large number of samples relatively easily. Until studies analyzing the expression of multiple prognostic markers in large numbers of lung cancers can be performed, the identification of single molecular prognostic markers, such as that documented by Laack et al,3 while of interest in generating hypotheses, will have little practical role in the management of patients with non–small-cell lung cancer. REFERENCES 1. Yip D, Harper PG: Predictive and prognostic factors in small cell lung cancer: Current status. Lung Cancer 28: 173-185, 2000[CrossRef][Medline] 2. Koutsami MK, Gorgoulis VG, Kastrinakis NG, et al: Prognostic factors in non–small cell lung carcinoma. Anticancer Res 22: 347-374, 2002[Medline]
3. Laack E, Nikbakht H, Peters A, et al: Expression of CEACAM1 in adenocarcinoma of the lung: A factor of independent prognostic significance. J Clin Oncol 20: 4279-4284, 2002 4. Obrink B: CEA adhesion molecules: Multifunctional proteins with signal-regulatory properties. Curr Opin Cell Biol 9: 616-626, 1997[CrossRef][Medline] 5. Beauchemin N, Draber P, Dveksler G, et al: Redefined nomenclature for members of the carcinoembryonic antigen family. Exp Cell Res 252: 243-249, 1999[CrossRef][Medline]
6. Morales VM, Christ A, Watt SM, et al: Regulation of human intestinal intraepithelial lymphocyte cytolytic function by biliary glycoprotein (CD66a). J Immunol 163: 1363-1370, 1999 7. Hauck CR, Meyer TF, Lang F, et al: CD66-mediated phagocytosis of Opa52 Neisseria gonorrhoeae requires a Src-like tyrosine kinase- and Rac1-dependent signalling pathway. EMBO J 17: 443-454, 1998[CrossRef][Medline]
8. Riethdorf L, Lisboa BW, Henkel U, et al: Differential expression of CD66a (BGP), a cell adhesion molecule of the carcinoembryonic antigen family, in benign, premalignant, and malignant lesions of the human mammary gland. J Histochem Cytochem 45: 957-963, 1997
9. Neumaier M, Paululat S, Chan A, et al: Biliary glycoprotein, a potential human cell adhesion molecule, is down-regulated in colorectal carcinomas. Proc Natl Acad Sci U S A 90: 10744-10748, 1993
10. Kleinerman DI, Troncoso P, Lin SH, et al: Consistent expression of an epithelial cell adhesion molecule (C-CAM) during human prostate development and loss of expression in prostate cancer: Implication as a tumor suppressor. Cancer Res 55: 1215-1220, 1995 11. Bamberger AM, Riethdorf L, Nollau P, et al: Dysregulated expression of CD66a (BGP, C-CAM), an adhesion molecule of the CEA family, in endometrial cancer. Am J Pathol 152: 1401-1406, 1998[Abstract] 12. Luo W, Wood CG, Earley K, et al: Suppression of tumorigenicity of breast cancer cells by an epithelial cell adhesion molecule (C-CAM1): The adhesion and growth suppression are mediated by different domains. Oncogene 14: 1697-1704, 1997[CrossRef][Medline] 13. Luo W, Tapolsky M, Earley K, et al: Tumor-suppressive activity of CD66a in prostate cancer. Cancer Gene Ther 6: 313-321, 1999[CrossRef][Medline] 14. Fournes B, Sadekova S, Turbide C, et al: The CEACAM1-L Ser503 residue is crucial for inhibition of colon cancer cell tumorigenicity. Oncogene 20: 219-230, 2001[CrossRef][Medline]
15. Estrera VT, Chen DT, Luo W, et al: Signal transduction by the CEACAM1 tumor suppressor: Phosphorylation of serine 503 is required for growth-inhibitory activity. J Biol Chem 276: 15547-15553, 2001
16. Thies A, Moll I, Berger J, et al: CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol 20: 2530-2536, 2002 17. Ergun S, Kilik N, Ziegeler G, et al: CEA-related cell adhesion molecule 1: A potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell 5: 311-320, 2000[CrossRef][Medline]
18. Schumann D, Chen CJ, Kaplan B, et al: Carcinoembryonic antigen cell adhesion molecule 1 directly associates with cytoskeleton proteins actin and tropomyosin. J Biol Chem 276: 47421-47433, 2001
19. Brummer J, Ebrahimnejad A, Flayeh R, et al: cis Interaction of the cell adhesion molecule CEACAM1 with integrin beta(3). Am J Pathol 159: 537-546, 2001 20. Kammerer R, Hahn S, Singer BB, et al: Biliary glycoprotein (CD66a), a cell adhesion molecule of the immunoglobulin superfamily, on human lymphocytes: Structure, expression and involvement in T cell activation. Eur J Immunol 28: 3664-3674, 1998[CrossRef][Medline] 21. Donda A, Mori L, Shamshiev A, et al: Locally inducible CD66a (CEACAM1) as an amplifier of the human intestinal T cell response. Eur J Immunol 30: 2593-2603, 2000[CrossRef][Medline] 22. Boulton IC, Gray-Owen SD: Neisserial binding to CEACAM1 arrests the activation and proliferation of CD4+ T lymphocytes. Nat Immunol 3: 229-236, 2002[CrossRef][Medline]
23. Markel G, Lieberman N, Katz G, et al: CD66a interactions between human melanoma and NK cells: A novel class I MHC-independent inhibitory mechanism of cytotoxicity. J Immunol 168: 2803-2810, 2002 24. Bamberger AM, Kappes H, Methner C, et al: Expression of the adhesion molecule CEACAM1 (CD66a, BGP, C-CAM) in breast cancer is associated with the expression of the tumor-suppressor genes Rb, Rb2, and p27. Virchows Arch 440: 139-144, 2002[CrossRef][Medline]
25. Ramaswamy S, Golub TR: DNA microarrays in clinical oncology. J Clin Oncol 20: 1932-1941, 2002
26. Garber ME, Troyanskaya OG, Schluens K, et al: Diversity of gene expression in adenocarcinoma of the lung. Proc Natl Acad Sci U S A 98: 13784-13789, 2001
27. Bhattacharjee A, Richards WG, Staunton J, et al: Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 98: 13790-13795, 2001 28. Mills JC, Roth KA, Cagan RL, et al: DNA microarrays and beyond: Completing the journey from tissue to cell. Nat Cell Biol 3: E175-E178, 2001[CrossRef][Medline]
29. Volm M, Koomagi R, Mattern J, et al: Expression profile of genes in non–small cell lung carcinomas from long-term surviving patients. Clin Cancer Res 8: 1843-1848, 2002
30. Bremnes RM, Veve R, Gabrielson E, et al: High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non–small-cell lung cancer. J Clin Oncol 20: 2417-2428, 2002
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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