This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laack, E. Articles by Hossfeld, D. K. Search for Related Content PubMed PubMed Citation Articles by Laack, E. Articles by Hossfeld, D. K.

Expression of CEACAM1 in Adenocarcinoma of the Lung: A Factor of Independent Prognostic Significance

From the Departments of Oncology and Hematology and Clinical Chemistry, and Institute for Anatomy, University Hospital Hamburg-Eppendorf; Departments of Pathology and Surgery, General Hospital Harburg, Hamburg; and German Cancer Research Center, Heidelberg, Germany.

Address reprint requests to Eckart Laack, MD, Clinic of Internal Medicine, Department of Oncology and Hematology, University Hospital Hamburg-Eppendorf, Martinistr 52, D-20246 Hamburg, Germany; email: laack{at}uke.uni-hamburg.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the prognostic relevance of CEACAM1 and sialyl Lewis X expression in adenocarcinomas of the lung.

PATIENTS AND METHODS: Paraffin wax sections of 93 patients with adenocarcinomas of the lung who underwent surgery between 1990 and 1995 were immunohistochemically investigated using monoclonal anti-CEACAM1 and sialyl Lewis X antibodies. The clinical course of all patients was followed up for a minimum of 5 years.

RESULTS: Sixty-one tumors were classified as CEACAM1-positive, and 32 were classified as CEACAM1-negative. Patients with CEACAM1-positive tumors had a significantly poorer overall (P = .00025) and relapse-free (P = .00029) survival than those with CEACAM1-negative tumors. Only three patients did not express the sialyl Lewis X glycotope, whereas 90 tumors (97%) were sialyl Lewis X–positive. In multivariate Cox regression analysis, next to tumor stage and sex, only the expression of CEACAM1 was a significant independent prognostic factor for survival.

CONCLUSION: Expression of CEACAM1 was an independent prognostic factor in our patient population and can be used to stratify patients with adenocarcinomas of the lung into low-risk and high-risk groups. In contrast, the expression of sialyl Lewis X was of no prognostic relevance because it was expressed in 97% of all investigated tumors, and most likely has no influence on the function of CEACAM1 in this tumor entity.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
LUNG CANCER IS a particular challenge in oncology, because more than 1 million new cases occur worldwide every year, with an increasing incidence in women and in the younger population. In the United States alone, approximately 160,000 lung cancer deaths are registered each year. The prognosis for patients with lung cancer is poor, with a survival rate between 8% and 15%. From a histologic point of view, lung cancer is a heterogeneous group of tumors, with three-quarters being non–small-cell lung cancer (NSCLC). In NSCLC, surgical resection is the therapy of choice in early stages of the disease. However, even in this selected group of patients, about half of the patients relapse after complete resection, indicating that the tumor has already spread beyond its anatomic site at the time of surgery. At present, the prognostic "gold standard" is staging of patients according to the tumor-node-metastasis classification.^1,2 Patients with early disease (stages I and II) have a 5-year survival rate between 30% and 75% after complete resection. Patients with locally advanced disease (stage IIIA/B disease) have a 5-year survival rate between 5% and 15%, and patients with metastatic disease (stage IV disease) have a 5-year survival rate of less than 2%.^2,3

Histologically, NSCLCs can be subdivided into adenocarcinomas, squamous cell carcinomas, and large-cell carcinomas. Adenocarcinomas have been increasing in incidence during the past decades and have become the most common type of NSCLC in the United States and in western Europe.^4,5 Despite the clinical need to stratify adenocarcinomas of the lung with regard to prognosis beyond the classical tumor-node-metastasis classification, no satisfactory prognostic marker has emerged yet. The classic tumor-node-metastasis classification rests on the anatomic description of the tumor spread. The inherent disadvantage of such a classification is that it does not allow any biologic insight into the metastatic potential, which might lead to new therapeutic strategies in the future.

As in most other cancers, the formation of metastases accounts for most lung cancer deaths. The biologic mechanisms leading to the spread of tumor cells are complex and not entirely understood. However, cell-to-cell and cell-to-matrix interactions play an important role in this process, and several cell adhesion molecules mediating these interactions are involved in the metastatic spread of tumors.⁶

This study focuses on the cell adhesion molecule CEACAM1, formerly known as CD66a or biliary glycoprotein 1, which belongs to the carcinoembryonic antigen family, which itself is a subgroup of the immunoglobulin superfamily.⁷ CEACAM1 is the human homologue of the adhesion molecule Cell-CAM of the rat. It is known to mediate both homophilic and heterophilic adhesion⁷ and is expressed in normal human epithelial tissues such as the colonic mucosa, mammary gland, bile ducts and gallbladder, pancreatic ducts, proximal tubules of the kidney, prostate, esophagus, endometrium, and certain endothelia and cells of the myeloid lineage.⁸ A loss or downregulation of the expression of CEACAM1 in tumor tissues of the breast,⁹ colon,^10,11 prostate,^12,13 and endometrial cancer¹⁴ suggests the hypothesis that CEACAM1 expression may play an important role in the metastatic process through decreasing adhesive interactions with surrounding cells, especially with tumor cells.

CEACAM1 is highly glycosylated and is the main carrier of the selectin-binding carbohydrate groups Lewis X and sialyl Lewis X on human granulocytes.¹⁵ As sialyl Lewis X is a ligand of the endothelial selectin, the glycosylated CEACAM1 itself can act as a ligand and can thus further be involved in the metastatic cascade. In addition to being the main carbohydrate determinant of CEACAM1, sialyl Lewis X has been reported as a prognostic marker in its own right in a number of tumor entities, such as colorectal,^16-18 gastric,¹⁹ lung,^20-23 prostate,^24,25 head and neck,²⁶ breast,²⁷ and pancreatic cancer.²⁸ Its presence has been correlated with advanced disease, decreased disease-free survival, and greater metastatic potential.^16-28

The aim of the present investigation was to analyze the prognostic relevance of CEACAM1 expression in adenocarcinomas of the lung in order to possibly identify a new prognostic marker in this clinically important tumor entity. The expression of CEACAM1’s main carbohydrate determinant, sialyl Lewis X expression, was also investigated, as it has been shown to be a prognostic marker in its own right and may in addition be functionally involved in CEACAM1-mediated adhesion (see above).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The complete series of paraffin wax blocks retrieved from the files of the Department of Pathology (General Hospital Harburg, Hamburg, Germany) consisted of samples from 103 resected specimens of adenocarcinomas of the lung. All patients who underwent surgery between 1990 and 1995 in the General Hospital Harburg, Hamburg, Germany, were consecutively included in the series. Of these, a complete follow-up could be retrieved from 93 patients, whose tissue blocks were further investigated. No other selection criteria were applied.

Immunohistochemistry
To determine the expression and localization of CEACAM1, immunohistochemistry was performed on paraffin-embedded specimens with the monoclonal antibody 4D1/C2,^29,30 which had previously been used to study CEACAM1 expression in several normal human and malignant tissues.⁸ Serial sections (5 µm) were deparaffinized in xylene and rehydrated in a series of graded ethanols to Tris-buffered saline (TBS) (50 mmol/L Tris, 150 mmol/L NaCl, pH 7.6) with 0.1% Tween 20 added. The slides were microwaved for 5 x 2 minutes in 10 mmol/L citrate buffer, pH 6.0. After cooling for 20 minutes, the slides were washed three times in TBS plus 0.1% Tween 20 for 5 minutes, blocked for 30 minutes at room temperature with normal rabbit serum (Dako, Glostrup, Denmark), diluted 1:20 in TBS, and incubated overnight at 4°C with the monoclonal CEACAM1 antibody 4D1/C2 (in-house preparation by C. Wagener) at 8 µg/mL in TBS. The next morning, the sections were washed three times in TBS for 5 minutes and then incubated with a 1:40 diluted biotinylated rabbit antimouse antibody (Dako) for 40 minutes at room temperature. After further washes in TBS, the sections were incubated with 2.5 µg/mL streptavidin-horseradish peroxidase complex (Calbiochem, Nottingham, United Kingdom) for 30 minutes followed by additional washes in TBS. Diaminobenzidine and hydrogen peroxide were used for visualization. Negative controls were treated the same way except for incubation with the primary antibody. Sialyl Lewis X expression was determined similarly using the 1:40 diluted 2H5 monoclonal antibody (Pharmingen, Hamburg, Germany).

In addition to CEACAM1 and sialyl Lewis X histochemistry, hematoxylin and eosin–stained slides were used for a general overview and for identification of tumor areas. The staining of the cancer cells was recorded as follows: negative indicated no staining or weak staining of single tumor cells (< 5%), and positive indicated that at least 6% of the tumor cells were stained (Fig 1). The classification into negative or positive was achieved independently by two observers who agreed in more than 95% of the cases; in the remaining cases, consensus was achieved after discussion. The slides were examined under a Zeiss Axioplan photomicroscope (Carl Zeiss, Jena GmbH, Jena, Germany) and photographed with a Kodak Ektachrome 64T color film (Eastman Kodak Company, Rochester, NY).

View larger version (152K): [in this window] [in a new window]   Fig 1. CEACAM1-positive (A) and CEACAM1-negative (B) adenocarcinoma of the lung (x200).

The results of the expression of CEACAM1 and sialyl Lewis X pattern and of the clinical data were assessed for their predictive value for patient survival by the proportional hazards model (Cox regression model).³³ First, the candidate factors were investigated for their prognostic value in a univariate analysis using the Cox regression model, which is equivalent to the evaluation of each factor separately using the log-rank test for differences between prognostic groups determined by the respective levels of one factor. Variables with sufficient statistical prognostic power (P < .1) were investigated by further analysis in a multivariate Cox regression model, and a model selection approach was applied in order to determine a final parsimonious prognostic model. Forward and backward variable selection and the likelihood ratio statistic were used with the SAS system (SAS Institute, Inc, Cary, NC).³⁴ The outcome of the Cox regression was described quantitatively by the statistical estimate of the regression parameter beta and its SE, its risk ratio exp (beta), and the respective P value obtained from the Wald test statistic.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
The tumor tissues of 93 patients with adenocarcinomas of the lung were investigated. The majority of patients (68%) were male (Table 1). Patients had a median age of 59 years (range, 27 to 81 years). Seventy-two patients (78%) were pathologically staged as having early disease (stage I and II disease) with negative mediastinal lymph nodes, and 19 (20%) were staged as having locally advanced disease with positive lymph nodes of the ipsilateral mediastinum (stage IIIA disease). No patient had tumor-positive lymph nodes of the contralateral mediastinum or distant metastases. Nevertheless, one patient with a pulmonary metastasis of the same lobe as the primary tumor (stage IIIB disease) was included, as was one patient with a pulmonary metastasis of another lobe of the same side (stage IV disease). Patients with positive mediastinal lymph nodes received radiotherapy after surgery. The predominant grade of tumor differentiation was moderately differentiated (40%) followed by poorly differentiated (35%). The most common blood group was type A (45%).

Tumor stage (P < .000005, log-rank test) (Fig 2), grade of tumor differentiation (P = .0254), and sex (P = .04) had a significant influence on overall survival. The blood group showed no statistical association with prognosis (P = .36).

View larger version (17K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of overall survival by tumor stage of 93 patients with resected adenocarcinomas of the lung.

View larger version (17K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plot of overall survival for CEACAM1 expression. Patients (n = 61) whose tumors expressed CEACAM1 had a significantly poorer survival than patients (n = 32) whose adenocarcinomas were CEACAM1-negative.

The predictive value of CEACAM1 expression was not restricted to the overall prognosis but was also related to the relapse-free interval. Those patients whose tumors did not express CEACAM1 had a significantly longer relapse-free survival than those patients whose tumors expressed this adhesion molecule (P = .00029) (Fig 4). Forty-one (67%) of the 61 patients with CEACAM1-positive tumors developed a recurrence of the disease. All 41 patients had distant metastases, and 19 of these patients also had a local relapse. A correlation between the presence of CEACAM1 expression and the site of recurrence (distant metastases v local relapse) was not significant (P = .18).

View larger version (17K): [in this window] [in a new window]   Fig 4. Kaplan-Meier plot of relapse-free survival for CEACAM1 expression. Those patients (n = 32) whose tumors did not express CEACAM1 had a significantly longer relapse-free survival than those patients (n = 61) whose tumors expressed CEACAM1.

Prognostic Impact
Tumor stage, grading, age, sex, blood group, and expression of CEACAM1 and sialyl Lewis X were included in the univariate Cox regression model (Table 2). Next to stage and sex, only the expression of CEACAM1 was identified as a significant independent prognostic factor in multivariate analysis (Table 3).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

It is interesting to note that CEACAM1 is not expressed in the normal bronchial or alveolar epithelium.⁸ This upregulation of CEACAM1 in the malignant tissue is a novel finding and differs from the expression pattern of CECAM1 in other epithelial neoplasias investigated so far. In breast,⁹ colorectal,^10,11 prostate,^12,13 and endometrial cancer,¹⁴ a downregulation of CEACAM1 has been observed in the tumor tissue compared with the nonmalignant epithelia from which the cancer cells are derived. Likewise, in hepatocellular carcinoma, a decreased expression level of CEACAM1 was found in comparison with the adjacent nonmalignant regions.³⁵

Hence, from a tumor biologic point of view, two types of neoplasias have to be distinguished. In the first type of tumors, CEACAM1 is expressed in the normal epithelium, and its loss of expression during the malignant transformation may enable the tumor cell to loosen from the primary tumor, thus facilitating metastasis by enabling migration. In the second type of tumors, exemplified by the bronchial mucosa, CEACAM1 expression is not observed in the normal mucosa but occurs in the metastatic subtype of tumors derived from this epithelium. This observation seems to be counterintuitive at first sight. However, CEACAM1 may not only be functionally involved at the site of the primary tumor, where its downregulation facilitates detachment of tumor cells from the primary tumor itself, but may also play a functional role at the evasion front and the site of the future metastatic deposit where it mediates tumor cell adhesion. At this site, an upregulation of CEACAM1 would increase the metastatic capabilities of a tumor. This upregulation of CEACAM1 expression is not unique to adenocarcinomas of the lung, but was also observed in gastric adenocarcinomas.³⁶ Thus, the interpretation of the functional significance of CEACAM1 expression in neoplastic tissue always has to be viewed in the context of its normal expression.

In our investigation, no significant correlation between CEACAM1 expression and the site of recurrence (distant metastases v local relapse) could be detected, indicating that CEACAM1 expression does not differentiate between lymphatic versus hematogenous spread. The same finding was reported in cutaneous malignant melanoma, where CEACAM1 expression was associated with metastatic spread irrespective of its mode of spread.³⁷ As normal melanocytes and melanoma cells are not attached by means of cell junctions to neighboring cells, the authors concluded that CEACAM1 expression must play a functional role in cell-to-matrix interaction at the invasion front or in melanoma cell–to–endothelial cell adhesion at the site of the evasion from the circulation.

CEACAM1 occurs as several splice isoforms, the majority of which differ only in their cytoplasmic domains. The longer domain contains two phosphorylable tyrosine residues in immunoreceptor-based inhibition motifs. These motifs are lacking the short domain.³⁸ It has been shown that the CEACAM1 isoform with the longer domain can inhibit tumor growth in vivo. In contrast, the isoform with the short domain cannot inhibit tumor growth on its own, but it seems to influence the inhibitory activity of the longer domain isoform. If one assumes a causal relationship between the expression level of CEACAM1 and the phenotypic characteristics of tumors, the differential expression of the longer domain and short-domain isoforms may explain the finding that CEACAM1 is downregulated in some tumor types but upregulated in others.³⁹ In addition, the function of CEACAM1 may depend on the direct or indirect interaction with other molecules that may be differentially expressed in different tumor entities.

In contrast to CEACAM1, sialyl Lewis X expression is of no prognostic significance in adenocarcinomas of the lung, as 97% of the tumors of this patient cohort expressed this glycotope. Thus, the functional properties of CEACAM1 required for metastasis formation in adenocarcinomas of the lung are not altered by the presence or absence of this carbohydrate determinant present on CEACAM1. This is in contrast to normal granulocytes, where CEACAM1 is the main carrier of sialyl Lewis X.¹⁵ Thus, the CEACAM1 adhesion mechanisms between normal granulocytes and future metastatic cells differ, and adhesion processes mediated by CEACAM1 appear to be far more complex than formerly assumed.

Future larger studies are needed to corroborate our finding that CEACAM1 expression is a new additional powerful prognostic marker stratifying patients with adenocarcinomas of the lung into low- and high-risk groups. Furthermore, patients with resectable stage IB to IIIA disease should be stratified for an adjuvant chemotherapy within studies according to their CEACAM1 expression. Other investigations should evaluate the prognostic value of CEACAM1 expression in the other histologic subtypes, such as squamous cell carcinomas and large-cell carcinomas, of NSCLC. Furthermore, CEACAM1 expression in cells of the primary tumor and in the tumor cells forming metastases are needed to further clarify the role of CEACAM1 expression at the metastatic site.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Sobin LH , Wittekind CH, (eds): TNM Classification of Malignant Tumors (ed 5). New York NY, Wiley, 1997

2. Clifton F, Mountain MD: Revisions in the international system for staging lung cancer. Chest 111: 1711-1717, 1997

3. Bülzebruck H, Bopp R, Drings P, et al: New aspects in the staging of lung cancer. Cancer 70: 1102-1110, 1992[CrossRef][Medline]

4. Franceschi S, Bidoli E: The epidemiology of lung cancer. Ann Oncol 10: 3-6, 1999[Free Full Text]

5. Liu NS, Spitz MR, Kemp BL, et al: Adenocarcinoma of the lung in young patients: The M. D. Anderson experience. Cancer 88: 1837-1841, 2000[CrossRef][Medline]

6. Hart IR, Saini A: Biology of tumour metastasis. Lancet 339: 1453-1461, 1992[CrossRef][Medline]

7. Thompson JA, Grunert F, Zimmermann W: Carcinoembryonic gene family: Molecular biology and clinical perspectives. J Clin Lab Anal 5: 344-366, 1991[Medline]

8. Prall F, Nollau P, Neumaier M, et al: CD66a (BGP), an adhesion molecule of the carcinoembryonic antigen family, is expressed in epithelium, endothelium, and myeloid cells in a wide range of normal human tissues. J Histochem Cytochem 44: 35-41, 1996[Abstract]

9. Riethdorf L, Liboa 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[Abstract/Free Full Text]

10. 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[Abstract/Free Full Text]

11. Brümmer J, Neumaier M, Gopfert C, et al: Association of pp60c-src with biliary glycoprotein (CD66a), an adhesion molecule of the carcinoembryonic antigen family downregulated in colorectal carcinomas. Oncogene 11: 1649-1655, 1995[Medline]

12. 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[Abstract/Free Full Text]

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. 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 153: 1401-1406, 1998[Abstract/Free Full Text]

15. Stocks SC, Kerr MA: Neutrophil NCA-160 (CD66) is the major protein carrier of selectin binding carbohydrate groups LewisX and sialyl LewisX. Biochem Biophys Res Commun 195: 478-483, 1993[CrossRef][Medline]

16. Nakagoe T, Fukushima K, Nanashima A, et al: Expression of Lewis (a), Lewis (x) and sialyl Lewis (x) antigens as prognostic factors in patients with colorectal cancer. Can J Gastroenterol 14: 753-760, 2000[Medline]

17. Nakagoe T, Sawai T, Tsuji T, et al: Circulating sialyl Lewis(x), sialyl Lewis(a), and sialyl Tn antigens in colorectal cancer patients: Multivariate analysis of predictive factors for serum antigen levels. J Gastroenterol 36: 166-172, 2001[CrossRef][Medline]

18. Yamada N, Chung YS, Maeda K, et al: Increased expression of sialyl Lewis A and sialyl Lewis X in liver metastases of human colorectal carcinoma. Invasion Metastasis 25: 95-102, 1995

19. Tatsumi M, Watanabe A, Sawada H, et al: Immunohistochemical expression of the sialyl Lewis x antigen on gastric cancer cells correlates with the presence of liver metastasis. Clin Exp Metastasis 16: 743-750, 1998[CrossRef][Medline]

20. Satoh H, Ishikawa H, Kamma H, et al: Serum sialyl Lewis X-i antigen levels in non-small cell lung cancer: Correlation with distant metastasis and survival. Clin Cancer Res 3: 495-499, 1997[Abstract]

21. Satoh H, Ishikawa H, Yamashita YT, et al: Predictive value of preoperative serum sialyl Lewis Xi antigen levels in non-small cell lung cancer. Anticancer Res 18: 2865-2868, 1998[Medline]

22. Satoh H, Ishikawa H, Kamma H, et al: Elevated serum sialyl Lewis X-i antigen levels in non-small cell lung cancer with lung metastasis. Respiration 65: 295-298, 1998[CrossRef][Medline]

23. Fukuoka K, Narita N, Saijo N: Increased expression of sialyl Lewis (x) antigen is associated with distant metastasis in lung cancer patients: Immunohistochemical study on bronchofiberscopic biopsy specimens. Lung Cancer 20: 109-116, 1998[CrossRef][Medline]

24. Jorgensen T, Kanagasingam Y, Kaalhus O, et al: Prognostic factors in patients with metastatic (stage D2) prostate cancer: Experience from the Scandinavian Prostatic Cancer Group Study-2. J Urol 158: 164-170, 1997[CrossRef][Medline]

25. Idikio HA: Sialyl-Lewis-X, Gleason grade and stage in non-metastatic human prostate cancer. Glycoconj J 14: 875-877, 1997[CrossRef][Medline]

26. Farmer RW, Richtsmeier WJ, Scher RL: Identification of sialyl Lewis-x in squamous cell carcinoma of the head and neck. Head Neck 20: 726-731, 1998[CrossRef][Medline]

27. Yamaguchi A, Ding K, Maehara M, et al: Expression of nm23-H1 gene and sialyl Lewis X antigen in breast cancer. Oncology 55: 357-362, 1998[CrossRef][Medline]

28. Nakamori S, Nishihara S, Ikehara Y, et al: Molecular mechanism involved in increased expression of sialyl Lewis antigens in ductal carcinoma of the pancreas. J Exp Clin Cancer Res 18: 425-432, 1999[Medline]

29. Drzeniek Z, Lamerz R, Fenger U, et al: Identification of membrane antigens in granulocytes and colonic carcinoma cells by a monoclonal antibody specific for biliary glycoprotein, a member of the carcinoembryonic antigen family. Cancer Lett 56: 173-179, 1991[CrossRef][Medline]

30. Stoffel A, Neumaier M, Gaida FJ, et al: Monoclonal, anti-domain and anti-peptide antibodies assign the molecular weight 160,000 granulocyte membrane antigen of the CD66 cluster to a mRNA species encoded by the biliary glycoprotein gene, a member of the carcinoembryonic antigen gene family. J Immunol 150: 4978-4984, 1993[Abstract]

31. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef]

32. Kalbfleisch JD, Prentice RL: Analysis of Failure Time Data. New York NY, Wiley, 1980

33. Cox DR: Regression models and life tables. J R Stat Soc B 72: 187-220, 1972

34. SAS Institute, Inc: SAS/STAT Software, Release 6.12. Cary NC, SAS Institute Inc, 1996

35. Tanaka K, Hinoda Y, Takahashi H, et al: Decreased expression of biliary glycoprotein in hepatocellular carcinomas. Int J Cancer 74: 15-19, 1997[CrossRef][Medline]

36. Kinugasa T, Kuroki M, Takeo H, et al: Expression of four CEA family antigens (CEA, NCA, BGP and CGM2) in normal and cancerous gastric epithelial cells: Up-regulation of BGP and CGM2 in carcinomas. Int J Cancer 76: 148-153, 1998[CrossRef][Medline]

37. Thies A, Moll I, Berger J, et al: CEACAM1 expression in cutaneous malignant melanoma predicts the development of metastatic disease. J Clin Oncol 20: 2530-1536, 2002[Abstract/Free Full Text]

38. 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]

39. Singer BB, Scheffrahn I, Obrink B: The tumor growth-inhibiting cell adhesion molecule CEACAM1 (C-CAM) is differently expressed in proliferating and quiescent epithelial cells and regulates cell proliferation. Cancer Res 60: 1236-1244, 2000[Abstract/Free Full Text]

Submitted August 8, 2001; accepted July 16, 2002.

This article has been cited by other articles:

				G. Markel, R. Seidman, N. Stern, T. Cohen-Sinai, O. Izhaki, G. Katz, M. Besser, A. J. Treves, R. S. Blumberg, R. Loewenthal, et al. Inhibition of Human Tumor-Infiltrating Lymphocyte Effector Functions by the Homophilic Carcinoembryonic Cell Adhesion Molecule 1 Interactions J. Immunol., November 1, 2006; 177(9): 6062 - 6071. [Abstract] [Full Text] [PDF]

				L. Lucka, M. Fernando, D. Grunow, C. Kannicht, A. K. Horst, P. Nollau, and C. Wagener Identification of Lewis x structures of the cell adhesion molecule CEACAM1 from human granulocytes Glycobiology, January 1, 2005; 15(1): 87 - 100. [Abstract] [Full Text] [PDF]

				A. Ebrahimnejad, T. Streichert, P. Nollau, A. K. Horst, C. Wagener, A.-M. Bamberger, and J. Brummer CEACAM1 Enhances Invasion and Migration of Melanocytic and Melanoma Cells Am. J. Pathol., November 1, 2004; 165(5): 1781 - 1787. [Abstract] [Full Text] [PDF]

				G. Markel, R. Gruda, H. Achdout, G. Katz, M. Nechama, R. S. Blumberg, R. Kammerer, W. Zimmermann, and O. Mandelboim The Critical Role of Residues 43R and 44Q of Carcinoembryonic Antigen Cell Adhesion Molecules-1 in the Protection from Killing by Human NK Cells J. Immunol., September 15, 2004; 173(6): 3732 - 3739. [Abstract] [Full Text] [PDF]

				I. S. Aljada, N. Ramnath, K. Donohue, S. Harvey, J. J. Brooks, S. M. Wiseman, T. Khoury, G. Loewen, H. K. Slocum, T. M. Anderson, et al. Upregulation of the Tissue Inhibitor of Metalloproteinase-1 Protein Is Associated With Progression of Human Non-Small-Cell Lung Cancer J. Clin. Oncol., August 15, 2004; 22(16): 3218 - 3229. [Abstract] [Full Text] [PDF]

				G. Markel, H. Mussaffi, K.-L. Ling, M. Salio, S. Gadola, G. Steuer, H. Blau, H. Achdout, M. de Miguel, T. Gonen-Gross, et al. The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients Blood, March 1, 2004; 103(5): 1770 - 1778. [Abstract] [Full Text] [PDF]

				T. Ruggiero, M. Olivero, A. Follenzi, L. Naldini, R. Calogero, and M. F. Di Renzo Deletion in a (T)8 microsatellite abrogates expression regulation by 3'-UTR Nucleic Acids Res., November 15, 2003; 31(22): 6561 - 6569. [Abstract] [Full Text] [PDF]

				P. Jantscheff, L. Terracciano, A. Lowy, K. Glatz-Krieger, F. Grunert, B. Micheel, J. Brummer, U. Laffer, U. Metzger, R. Herrmann, et al. Expression of CEACAM6 in Resectable Colorectal Cancer: A Factor of Independent Prognostic Significance J. Clin. Oncol., October 1, 2003; 21(19): 3638 - 3646. [Abstract] [Full Text] [PDF]

				T. A. Plunkett and P. A. Ellis CEACAM1: A Marker With a Difference or More of the Same? J. Clin. Oncol., November 1, 2002; 20(21): 4273 - 4275. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laack, E. Articles by Hossfeld, D. K. Search for Related Content PubMed PubMed Citation Articles by Laack, E. Articles by Hossfeld, D. K.