An Immunohistochemical Study of the Expression of Adhesion Molecules in Gallbladder Lesions
Department of Pathology (YHX,RHS,SHK), Chungbuk National University, College of Medicine, Chungbuk, Korea; Department of Pathology (Y-LC), Samsung Medical Center, Sungkyunkwan University, College of Medicine, Sungkyunkwan, Korea; Department of Pharmacy (YKS), Seoul National University, College of Pharmacy, Seoul, Korea; Department of Pathology (SWC), Sungkyunkwan University, College of Medicine, Sungkyunkwan, Korea; DiNonA, Inc. (YKS), Seoul, Korea; Department of Pathology (MCK), Seoul National University, College of Medicine, Seoul, Korea; Departments of Internal Medicine (SJY) and Surgery (JWC), Chungbuk National University, College of Medicine, and Chungbuk National University, Medical Research Institute (SHK), Chungbuk, Korea; and Department of Pathology (YHX), YanBian University, College of Medicine, YanBian, China
Correspondence to: Seok Hyung Kim, Dept. of Pathology, Chungbuk National University Hospital, 62 Kaesin-dong, Cheongju, Chungbuk, South Korea 361-763. E-mail: platoshkim{at}freechal.com
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Summary |
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(J Histochem Cytochem 52:591601, 2004)
Key Words: gallbladder catenin CD44 CD44v6 ICAM-1 CD56 CEA E-cadherin CD99 immunohistochemistry
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Introduction |
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Carcinogenesis and the formation of metastases are both multistep processes involving complex interactions between tumor cells and their environment (Liotta and Stracke 1988). Adhesion is a key component of the metastatic cascade, involving many interactions among tumor cells and between tumor cell and host cells in the processes of angiogenesis, proteolysis, motility, and invasion (Tang and Honn 199495
).
These various adhesion processes are mediated by adhesion molecules belonging to four major families: integrins, cadherins, immunoglobulins, and selectins. Altered expression of adhesion molecules such as /ß/
-catenin, CD44, ICAM-1, CD56, and E-cadherin has been implicated in various stages of tumor progression and metastasis (Tang and Honn 199495
). A striking feature of metastatic cells is the considerable flexibility of their adhesive interactions with other cells and with components of the extracellular matrix (ECM). Of these adhesion molecules, expression of
/ß/
-catenins, CD44, ICAM-1, E-cadherin, and CEA has been studied intensively in carcinomas of the gastrointestinal tract, and their diagnostic usefulness has been evaluated (Van Aken et al. 2001
). A correlation has been reported between the expression of adhesion molecules such as E-cadherin,
/ß/
-catenin, and ICAM-1 and the clinical stage or grade of cancers of the breast, stomach, and esophagus (Van Aken et al. 2001
). However, there have been few such studies of gallbladder carcinomas.
We therefore investigated the expression of a number of cell adhesion molecules (/ß/
-catenin, CD44, CD44v6, ICAM-1, CD56, E-cadherin, CEA, and CD99) in gallbladder carcinomas and in their precursor lesions.
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Materials and Methods |
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All archival materials were routinely fixed in 10% neutral-buffered formalin and embedded in paraffin. Four-µm sections were prepared on silane-coated slides (Sigma; St Louis, MO).
The immunostaining kit and all antibodies were from DiNonA (Seoul, Korea) and are listed in Table 1.
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Evaluation of Results of IHC Staining
The scoring method of Sinicrope et al. (1995) was applied to evaluate the IHC staining intensity and the proportion of stained epithelial cells. Membrane staining and nuclear staining were considered independently. The staining intensity was subclassified as 1, weak, 2, moderate, and 3, strong. The numbers of positive cells were expressed as the percentage of the total number of epithelial cells and assigned to one of five categories: 0, <5%; 1, 525%; 2, 2650%; 3, 5175%; and 4, >75%. The percentage of positivity of tumor cells and the staining intensity were multiplied to produce an immunoreactive score (IS) for each tumor specimen. Each lesion was examined and scored separately by two pathologists, and cases with discrepant scores were discussed until unity was achieved.
For the proper comparison of expression, both the frequency of expression and the mean value of the IS were analyzed. For frequency of expression, different criteria for positivity were employed for each molecule owing to the great variation in the expression of each molecule in normal gallbladder epithelium, which ranges from 0% (CD44v6, ICAM-1, CD56) to 90% (ß/-catenin, E-cadherin). In
/ß/
-catenin, CD44, and E-cadherin, we defined the cases in which tumor cells were positive in more than 50% of total tumor cells at moderate intensity as positivity. In contrast, in CD44v6, ICAM-1, CD56, CD99, and CEA, the cases with more than 5% positive cells were defined as positivity.
Statistical Analysis
Statistical analyses were performed using the Fisher's exact test, Pearson's 2 test, MannWhitney test, KruskalWallis test, and Tukey HSD, and the Duncan test as post hoc test. For comparison of means of immunoreactive scores, the MannWhitney test, KruskalWallis test, Tukey HSD, and Duncan test were used. The association of the expression rate with clinicopathological factors was assessed by cross-tabulation, and the significance of differences was determined by the Fisher's exact test and Pearson's
2 test. A p value less than 0.05 was regarded as statistically significant. All statistical analyses were performed using SPSS software (SPSS; Chicago, IL).
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Results |
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CD56 and CD99 Expression
In normal gallbladder, CD56 is expressed in ganglion cells and infiltrating NK-cells as well as in a subset of activated T-lymphocytes but is not expressed in epithelial cells. However, a basolateral pattern of CD56 expression was observed in the epithelial cells of 10.9% and 50% of the carcinomas and adenomas, respectively (Table 2; Figures 2H and 2I). Both the frequency and the mean IS were significantly higher in adenomas (50%; 3.07 ± 3.56) than in the other conditions, including carcinomas (p<0.001) (Table 2; Figure 1). Expression correlated with clinical stage of the gallbladder carcinoma, being substantially more prevalent in the earlier stages (0, I) (p<0.05) (Table 3). However, there was no correlation between CD56 expression and the other clinicopathological parameters.
Relatively weak CD99 immunoreactivity was observed in the epithelial cells of almost every normal gallbladder, with strong membrane staining in infiltrating lymphocytes and capillary endothelial cells. CD99 expression was observed less frequently in carcinomas (p<0.01) (Table 2), and the extent of its expression was found to correlate with histological differentiation and clinical stage of the carcinomas (Tables 3 and 4). Both the frequency and the mean IS were lower in poorly differentiated (20% and 1 ± 2.24, respectively) than in well-differentiated carcinomas (83.3% and 3.92 ± 3.56, respectively) (p<0.01) (Tables 3 and 4). Similarly, expression of CD99 was downregulated in advanced-stage (II, III, IV) compared with early-stage carcinoma (0, I) in terms of both frequency and IS (Tables 3 and 4).
CEA Expression
We demonstrated apical membrane staining of CEA in most carcinomas (31/46; 68.9%), but expression was relatively rare in the other pathological entities and in normal gallbladder epithelia (Table 2; Figure 2K). Overexpression in carcinoma was statistically significant in terms of both frequency and intensity of immunostaining (p<0.001) (Table 2; Figure 1). Moreover, the increased expression of CEA in carcinoma was closely related to the extent of histological differentiation (Tables 3 and 4).
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Discussion |
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E-cadherin (120 kD) is a classical cadherin forming the key component of adherens junctions that provide lateral adhesion between epithelial cells. It is bound to the actin cytoskeleton by a series of underlying proteins, the catenins (, ß, and
) (Shiozaki et al. 1996
). The resulting E-cadherin/catenin complexes serve not only to maintain adherens junctions but also to transduce signals to the nucleus and the cytoskeleton, either directly or through connections with many other complexes. Changes in the membrane expression of E-cadherin/catenin (
, ß, and
) complexes have been implicated in several malignant neoplasms, e.g., breast carcinoma, gastric carcinoma, colorectal carcinoma, and cervical adenocarcinoma (Van Aken et al. 2001
). However, there have been few studies of the expression of
/ß/
-catenins or E-cadherin in gallbladder carcinoma (Sasatomi et al. 1996
; Yanagisawa et al. 2001b
; Chang et al. 2002
; Kohya et al. 2003
). The pattern of membrane expression that we observed in adenoma and carcinoma is consistent with the finding of decreased expression of ß-catenin in moderately and poorly differentiated adenocarcinoma (Yanagisawa et al. 2001b
). With respect to nuclear staining for ß-catenin, it was largely restricted to adenoma (6/14) and was rare in other conditions (carcinoma 3/46; low-grade dysplasia 0/15; metaplasia and normal 0/29). This pattern is also compatible with those observed in previous studies (Yanagisawa et al. 2001b
; Chang et al. 2002
). This result implies that ß-catenin-related molecular events may be implicated in the pathogenesis of adenoma in gallbladder, as is true for adenoma in colon. However, when we consider the rare nuclear ß-catenin expression in gallbladder carcinoma, which is clearly in contrast to colon cancer, it is possible that the oncogenesis of gallbladder carcinoma is different from that of colon carcinoma.
The relationship between E-cadherin expression and lymph node metastasis has been studied in other organs. However, conflicting results have been obtained. Reduced expression of E-cadherin was reported to correlate with lymph node metastasis in gastric cancer, breast cancer, and esophageal cancer, whereas in colorectal carcinoma -catenin levels rather than those of E-cadherin were reported to correlate with lymph node metastasis (Oka et al. 1992
,1993
; Gofuku et al. 1999
). However, we found that the correlation between lower expression of E-cadherin and lymph node metastasis in gallbladder carcinoma did not apply to the
/ß/
-catenins. Oka and co-workers (1992)
(1993
) have reported a correlation between lower E-cadherin expression and higher-grade breast and gastric carcinomas, consistent with our results. Interestingly, downregulation of E-cadherin expression has been shown to be involved in loss of cell-to-cell contact, which is a key initial step in tumor progression and the generation of metastatic variants (Tang and Honn 199495
).
Intercellular adhesion molecule-1 (ICAM-1, CD54) is a 90-kD cell surface-bound glycoprotein belonging to the immunoglobulin superfamily. It mediates adhesion-dependent cellcell and cellECM interactions. Moreover, it plays an important role in cell adhesion and locomotion in inflammation and also in malignant disease (Dustin and Springer 1991). ICAM-1 is normally expressed by cytokine-activated endothelial cells but has also been detected in various malignant neoplasms such as pancreatic (Schwaeble et al. 1993
), colon (Dippold et al. 1993
), and gastric cancers (Nasu et al. 1997
), and its levels of expression correlate positively with the metastatic potential of neoplastic cells (Nasu et al. 1997
; Anastassiou et al. 2000
). However, no investigation of ICAM-1 expression in gallbladder cancer has been published. Despite the difference in organs, the findings just referred to are consistent with our observation that expression of ICAM-1 is positively correlated with lymph node metastasis. Moreover, in our study ICAM-1 expression turned out to be significantly higher in advanced cases (stage III, IV) than in earlier cases (stage 0, I) (p<0.05).
The neural cell adhesion molecule (NCAM, CD56), a membrane-bound glycoprotein, functions in development and in contact-mediated interactions among neural cells. CD56 (NCAM) is present in neuroendocrine and neurectodermal cells and tumors. Nevertheless, it is not absolutely specific to neuroendocrine differentiation because expression has been found in a minority of breast cancers, non-endocrine lung cancers (Zoltowska et al. 2001), colon carcinomas (Roesler et al. 1997
), and endometrial carcinomas (Arck et al. 2000
). In this study we observed CD56 expression only in gallbladder carcinoma and adenoma, and the frequency of CD56 expression was particularly high in the latter. Such a high frequency of CD56 expression has not been documented in adenomas of other gastrointestinal organs, such as stomach and colon. The control of CD56 expression in gallbladder adenoma and its implications for progression of the tumor remain to be clarified. However, CD56 is reported to be an important adhesion molecule in the colon and to act as a tumor suppressor (Roesler et al. 1997
), whereas a reduction in its expression has been shown to induce pancreatic tumor cell metastasis (Perl et al. 1999
). CD56 may therefore play a central role in the cascade of tumor progression as a tumor suppressor.
CD44 molecules are adhesion molecules involved in cell-to-cell and cell-to-matrix interactions. They are a group of transmembrane glycoproteins encoded by a single CD44 gene located on human chromosome 11. CD44 protein exists in many isoforms generated by alternative splicing. A standard 90-kD form (CD44s) is present on cells of normal epithelial and hematopoietic origin. In contrast, the alternatively spliced CD44 variants, ranging in size from 120 to 150 kD, are expressed predominantly on cells and tumors of epithelial origin and are designated as CD44v (variant). CD44 variant expression is associated with tumor metastasis and disease progression in patients with several types of tumor, such as gastric (Saito et al. 1998), gallbladder (Yamaguchi et al. 2000
; Yanagisawa et al. 2001a
), and breast carcinoma (Berner et al. 2003
).
In this study we observed CD44v6 expression only in neoplastic lesions, i.e., carcinoma and adenoma, and not in normal epithelial tissue, metaplasia, or low-grade dysplasia. This is consistent with other reports that have documented restriction of CD44v6 expression to neoplastic cells (Ishida 2000; Yanagisawa et al. 2001a
). However, we failed to find any association with clinical or histological parameters of the tumors such as metastasis to lymph nodes, histological differentiation, or tumor stage. This appears to be contrary to other reports that demonstrate a correlation between CD44v6 expression in gallbladder carcinoma and extent of histological differentiation (Yanagisawa et al. 2001a
). However, in the case of colorectal adenocarcinoma there is some disagreement regarding the clinical significance of CD44v6 expression (Ishida 2000
). Several authors report an association of CD44v6 expression with advanced stage and poor prognosis in colorectal carcinoma (Mulder et al. 1997
), whereas other investigators failed to find a correlation between expression and progression of colorectal carcinoma (Ishida 2000
).
CEA has been reported to be present in both benign and malignant gallbladder epithelia (Dowaki et al. 2000; Kanthan et al. 2000
). In the present study the expression of CEA was significantly increased in gallbladder carcinoma compared with the other lesions, consistent with these reports. CEA expression was correlated with histological differentiation (p<0.05) but not with clinical stage or lymph node metastasis, contrary to the findings of Dowaki et al. (2000)
. However, there have been very few studies of the clinical significance of CEA expression in gallbladder carcinoma, and further study of this question is called for.
CD99 (Mic2) is a 32-kD transmembrane glycoprotein involved in cell-cell adhesion during hematopoietic cell differentiation (Hahn et al. 1997), apoptosis of immature thymocytes (Bernard et al. 1997
), and transport of transmembrane proteins (Choi et al. 1998
). It is expressed in most human tissues, especially in cortical thymocytes, pancreatic islet cells, and Leydig and Sertoli cells. It is also found in tumor cells, including Ewing's sarcoma/primitive neuroectodermal tumors (Folpe et al. 2000
), lymphoblastic lymphoma/leukemia (Dworzak et al. 1999
), some rhabdomyosarcomas (Folpe et al. 2002
), some ovarian tumors (Choi et al. 2000
), and in stomach cancer (Jung et al. 2002
). Our results suggest that loss of CD99 expression is a common event in the evolution of gallbladder carcinomas. Downregulation of CD99 was significantly associated with poorly differentiated and advanced-stage tumor cells, in agreement with previous reports in gastric cancer (Jung et al. 2002
). Loss of CD99 expression may alter the cytoskeletal system and the expression of other adhesion molecules and may thus lead to morphological and behavioral changes of the tumor cells. Kim et al. (2000)
have reported that the loss of CD99 plays a critical role in the formation of Hodgkin's and ReedSternberg lesions. These results indicate that CD99 is related to gallbladder tumor progression.
In conclusion, we have first examined the expression of adhesion molecules such as -catenin, ICAM-1, CD56, and CD99 expression in gallbladder tumors. There were extensive changes in the expression of various adhesion molecules in carcinoma and adenoma, some of which were related to clinicopathological parameters. Our results suggest that downregulation of
/ß/
-catenin is a relatively early event in tumor progression, whereas aberrant expression of ICAM-1 and downregulation of CD99 and E-cadherin occur later.
The expression of CD44v6 and CEA is relatively specific to neoplastic lesions, but its implications for tumor progression remain to be determined. Knowledge of the expression profile of adhesion molecules in gallbladder lesions obtained by IHC should be of considerable help in the diagnosis of neoplastic gallbladder lesions and the prediction of outcomes.
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Acknowledgments |
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Footnotes |
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