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Ann Thorac Surg 2001;71:949-954
© 2001 The Society of Thoracic Surgeons

Original article: general thoracic

E-cadherin expression associated with differentiation and prognosis in patients with non–small cell lung cancer

Dage Liu, MDa, Cheng-long Huang, MDa, Kotaro Kameyama, MDa, Eiichi Hayashi, MDa, Akira Yamauchi, MDa, Shoji Kobayashi, MDb, Hiroyasu Yokomise, MDa

a Second Department of Surgery, Kagawa Medical University, Kagawa, Japan
b Department of Pathology, Kagawa Medical University, Kagawa, Japan

Accepted for publication October 18, 2000.

Address reprint request to Dr Yokomise, Second Department of Surgery, Kagawa Medical University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
e-mail: yokomise{at}kms.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. E-Cadherin plays a major role in maintaining the intercellular junctions in epithelial tissues. The reduction of E-cadherin expression in cancer cells may be associated with tumor differentiation, metastasis, and a poor prognosis.

Methods. Immunohistochemistry for E-cadherin expression was performed on 109 tumors from patients with non–small cell lung cancer who underwent operations.

Results. With respect to membranous immunostaining, 57 carcinomas were E-cadherin-positive, 39 carcinomas E-cadherin-reduced, and 13 carcinomas E-cadherin-negative. The percentage of poorly differentiated tumors in the impaired E-cadherin expression group was significantly higher than that in the E-cadherin-positive group (p = 0.005). Furthermore, the frequency of lymph node metastases in tumors with impaired E-cadherin expression was significantly higher than that in the E-cadherin-positive tumors (p = 0.011). A Cox regression analysis revealed that E-cadherin expression was a significant factor in the prediction of survival for patients with non–small cell lung cancer (p = 0.002).

Conclusions. E-Cadherin expression was associated with tumor differentiation, lymph node metastasis, and prognosis in patients with non–small cell lung cancer.


   Introduction
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 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Metastasis is specific for malignant tumors, and an understanding of the physiologic control for metastasis is very important for cancer therapy. Its initial step is the escape of cells from the primary tumor, which is believed to be dependent on the status of functioning adhesion molecules. According to previous investigations, these adhesion molecules can be grouped into four families: integrins, selectins, the immunoglobulin superfamily, and cadherins [1].

Among these adhesion molecules, E-cadherin, a member of cadherins, is widely expressed in epithelial tissues. It is a transmembrane glycoprotein that functions for homophilic cell-to-cell adhesion in the presence of calcium ions, and is linked to the actin cytoskeleton by the catenins [2, 3]. The functional disruption of the E-cadherin–catenin complex has been reported to be associated with tumor dedifferentiation and metastasis in several human cancers [4, 5]. However, only a few clinical studies on patients with non–small cell lung cancer (NSCLC) have confirmed the prognostic impact of E-cadherin expression [6, 7]. In addition, although the true mechanisms underlying these functional disruptions remain unclear, recent studies have proposed several mechanisms in human cancer. The transmembrane glycoprotein E-cadherin is principally located in the cell membrane. Recently, it was reported that the decreased tyrosine phosphorylation of E-cadherin could cause a cytoplasmic redistribution of the E-cadherin–catenin complex, resulting in its functional loss [8]. However, there have been only a few reports on E-cadherin immunohistochemistry, which focused on its immunostaining location (membranous staining and cytoplasmic staining) [4]. Therefore, we performed a retrospective clinical study on E-cadherin immunolocalization in patients with NSCLC.


   Material and methods
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 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Patients
From January 1993 to March 1997, patients with NSCLC who underwent operation at the Second Department of Surgery at Kagawa Medical University were studied. Tumor-node-metastasis (TNM) staging designations were made according to the international postsurgical pathologic staging system. Because advanced lung cancer (stage IV) involves several complicated factors and these primary tumors specimens are hard to obtain by surgical resection, these patients were excluded from this study. In total, 109 patients with lung cancer up to stage IIIB, which included 60 patients with adenocarcinoma, 39 patients with squamous cell carcinoma, and 10 patients with large cell carcinoma, were investigated. The patients’ clinical records and histopathologic diagnoses were fully documented. This report includes follow-up data as of June 30, 2000. The median follow-up period for all patients was 41.1 months.

Immunohistochemistry
Formalin-fixed paraffin-embedded tissue specimens were cut into 4-µm sections and mounted on poly-L-lysine-coated slides. The sections were deparaffinized and rehydrated. The slides were then heated in a microwave for 10 minutes in a 10 µmol/L citrate buffer solution at pH 6.0, and cooled to room temperature for 20 minutes. After quenching the endogenous peroxidase activity with 0.3% H2O2 (in absolute methanol) for 30 minutes, the sections were blocked for 2 hours at room temperature with 5% bovine serum albumin. Subsequently, duplicate sections were incubated overnight with the primary specific mouse monoclonal antibody for E-cadherin (Clone HECD-1; 1:400; Takara, Otsu, Japan). The slides were then incubated for 1 hour with biotinylated anti-mouse IgG (Vector Laboratories Inc, Burlingame, CA). The sections were incubated with the avidin-biotin-peroxidase complex (Vector Laboratories Inc) for 1 hour, and the antibody binding was visualized with 3,3'-diaminobenzidine tetrahydrochloride. Finally, the sections were counterstained with Mayer’s hematoxylin (Fig 1).



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  		Fig 1. Immunohistochemical staining of human non–small cell lung cancer tissues using the avidin-biotin-peroxidase complex procedure (original magnification, x100). (A) An adenocarcinoma with positive membranous staining for E-cadherin (E-cadherin-positive). (B) A squamous cell carcinoma with positive membranous staining for E-cadherin (E-cadherin-positive). (C) An adenocarcinoma with heterogeneous cytoplasmic staining for E-cadherin (E-cadherin-reduced). (D) A squamous cell carcinoma with heterogeneous cytoplasmic staining for E-cadherin (E-cadherin-reduced). (E) An adenocarcinoma with negative E-cadherin expression. (F) A squamous cell carcinoma with negative E-cadherin expression.

 
All of the immunostained sections were reviewed by two pathologists who had no knowledge of the patients’ clinical status. Normal bronchus epithelium and normal mucosal glands within the tumor section were used as positive internal controls, and nonepithelial cells such as infiltrating lymphocytes were used as negative internal controls. The slides were examined under low power (4x objective) to identify regions that contained weakly stained tumor cells. In the case of sections with multiple areas of low staining intensity, five random areas were selected for scoring. In the intensely stained sections, one random field was scored. The proportion of stained cells in each selected field was determined by counting individual cells at high magnification (40x). At least 200 cells were scored per high-power field. The localization of the staining (membranous and cytoplasmic pattern) and the percentage of stained tumor cells were then evaluated. Finally, the 109 NSCLC specimens we studied were classified into three groups according to the proportion of tumor cells with positive membranous staining, with or without cytoplasmic staining. When more than 50% of the tumor cells in a given specimen were positively stained, the sample was classified as E-cadherin-positive (+). When 10% to 50% of the cells were stained, it was classified as E-cadherin-reduced (±). When less than 10% of the cells were stained, it was classified as E-cadherin-negative (-). The impaired E-cadherin expression group was defined as the E-cadherin-reduced plus E-cadherin-negative samples. On the other hand, when more than 50% of the tumor cells in a given specimen had positive cytoplasmic staining, the sample was classified as cytoplasmic positive.

Statistical analysis
The overall cancer specific survival was defined from the date of the operation to the date of cancer-related death. Cancer-unrelated deaths were calculated as censored observations at the time of death. Of the 109 patients with NSCLC studied, 42 patients died of cancer-related causes and 4 patients died of cancer-unrelated causes. The statistical differences in E-cadherin expression and several other clinical and pathologic variables were assessed by the {chi}2 test and the Student’s t test. The Kaplan-Meier method was used to estimate the probability of overall survival as a function of time, and differences in the survival of subgroups of patients were compared with Mantel’s log-rank test. Cox’s proportional-hazards regression model was used to study the effects of different variables on survival, using the following seven factors: E-cadherin status defined by the percentage of tumor cells with positive membranous staining, smoking habit, age at operation, sex, differentiation, tumor status, and nodal status. All p values were based on two-tailed statistical analysis, and a p value less than 0.05 was considered to indicate statistical significance.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
E-cadherin expression in non–small cell lung cancer
With respect to membranous staining of the 109 tumors we studied, 48 carcinomas (44.0%) had membranous staining in at least 70% of the tumor cells, 9 carcinomas (8.3%) had membranous staining in 50% to 70% of the tumor cells, 13 carcinomas (11.9%) had membranous staining in 30% to 50% of the tumor cells, 26 carcinomas (23.8%) had membranous staining in 10% to 30% of the tumor cells, and 13 carcinomas (11.9%) had membranous staining in less than 10% of the tumor cells (Table 1). Thus, 57 carcinomas (52.3%) were classified as E-cadherin-positive, 39 carcinomas (35.8%) as E-cadherin-reduced, and 13 carcinomas (11.9%) as E-cadherin-negative (Fig 1 and Table 2). In total, 52 carcinomas (47.7%) had impaired E-cadherin expression. Of the 60 adenocarcinomas, 23 carcinomas (38.3%) had impaired E-cadherin. Of the 39 squamous cell carcinomas, 21 carcinomas (53.8%) had impaired E-cadherin expression.


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  		Table 1. Relationship Between the Percentage of Tumor Cells With Positive Membranous Staining and Cytoplasmic Staining

 

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  		Table 2. Distribution of 109 Patients With Non–Small Cell Lung Cancer According to Their E-Cadherin Expression

 
With respect to the cytoplasmic staining, there were various positive samples with a diffuse or spotty staining pattern. The relationship between the percentage of tumor cells with positive membranous staining and cytoplasmic staining was demonstrated in Table 1. Of the 57 E-cadherin-positive tumors, 12 tumors (21.1%) had positive cytoplasmic staining with a diffuse pattern. Of the 39 E-cadherin-reduced tumors, 35 tumors (89.7%) had positive cytoplasmic staining, which included 25 tumors with diffuse cytoplasmic staining and 10 tumors with spotty cytoplasmic staining. Of the 13 E-cadherin-negative tumors, none were positive for cytoplasmic staining. The percentage of tumor cells with positive cytoplasmic staining in the E-cadherin-reduced tumors was significantly higher than that in the E-cadherin-positive tumors (p < 0.001).

E-cadherin expression and clinicopathologic factors
The relationships between E-cadherin expression and various clinicopathologic features are shown in Table 2. With respect to tumor differentiation, 12 of the 57 E-cadherin-positive tumors (21.1%) were poorly differentiated, and 24 of the 52 carcinomas with impaired E-cadherin expression (46.2%) were poorly differentiated. The percentage of poorly differentiated tumors in the impaired E-cadherin expression group was significantly higher than that in the E-cadherin-positive group (p = 0.005). In addition, the percentage of tumor cells with positive membranous staining in the poorly differentiated tumors was also significantly lower than that in the moderately to well-differentiated tumors (42.4 ± 34.4 versus 61.9 ± 35.2, p = 0.007).

Of the 57 E-cadherin-positive tumors, 15 carcinomas (26.3%) had lymph node metastases. Of the 52 tumors with impaired E-cadherin expression, 26 carcinomas (50.0%) had lymph node metastases. Tumors with impaired E-cadherin expression had significantly more lymph node metastases than E-cadherin-positive tumors (p = 0.011). In addition, the percentage of tumor cells with positive membranous staining in those tumors with lymph node metastases was also significantly lower than that in the tumors without lymph node metastases (40.6 ± 35.5 versus 64.4 ± 33.4, p < 0.001).

Survival of patients with non–small cell lung cancer in relation to E-cadherin expression
The overall survival rate of the 109 patients with NSCLC, stratified according to their E-cadherin status, is shown in Figure 2. The survival of patients with E-cadherin-negative tumors was significantly poorer than that of patients with E-cadherin-positive tumors (11.1% versus 62.8%, 5-year survival, p < 0.001). The survival of patients with E-cadherin-negative tumors was significantly poorer than that of patients with E-cadherin-reduced tumors (11.1% versus 49.7%, 5-year survival, p = 0.037).



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  		Fig 2. Overall survival of 109 patients with non–small cell lung cancer in relation to their E-cadherin status.

 
On the other hand, of the 39 patients with the E-cadherin-reduced tumors, there was no difference of overall survival in relation to the cytoplasmic staining pattern for E-cadherin, regardless of whether it was a diffuse or spotty pattern or cytoplasmic negative (50.3%, 54.0%, and 33.3%, 5-year survival, respectively).

An analysis using Cox’s proportional-hazards regression model to predict the prognostic variables for patients with NSCLC is shown in Table 3. Three variables, E-cadherin expression, tumor status, and nodal status, were found to be significant in the prediction of survival (p = 0.002, p < 0.001, and p < 0.001, respectively). Another four variables, smoking habit, age at operation, sex, and differentiation, were found to be not significant in the prediction of survival.


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  		Table 3. Cox’s Proportional-Hazards Regression Model in Predicting Survival of 109 Patients With Non–Small Cell Lung Cancer

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
E-cadherin plays an essential role in calcium-dependent intercellular adhesion and organogenesis during embryonic development [2]. In experimental studies, transfection of E-cadherin cDNA into dedifferentiated invasive cancer cell lines resulted in phenotype reversion and a loss of their invasiveness [9, 10]. Furthermore, anti-E-cadherin antibodies can induce invasive behavior in tumor cells [9, 11].

The regulated expression of cadherins also control cell polarity and tissue morphology [2]. Many of the morphogenetic events during embryonic development are correlated with a unique spatiotemporal pattern of cadherin expression. For example, the forced expression of E-cadherin cDNA in fibroblastic cells generated epithelial structures [12]. Based on these experimental results, the E-cadherin expressed constitutively in all epithelial cells is probably required to maintain epithelial phenotype and integrity. A reduction of its expression, which occurs in a variety of human cancers, has thus been considered to be associated with tumor differentiation and metastasis [4, 5].

Previous clinical studies in cancer patients have also revealed that reduced E-cadherin expression is associated with tumor dedifferentiation and lymph node metastasis [13, 14]. In patients with NSCLC, reduced E-cadherin expression is associated with tumor dedifferentiation [8], lymph node metastasis [6, 7], and a poor prognosis [6].

However, the E-cadherin–catenin adhesion system is rather complicated, and the actual mechanisms responsible for its functional disruption in human cancers are still not clear. The cytoplasmic domain of E-cadherin interacts with catenin molecules, which establish an intracellular linkage with the actin cytoskeleton [3]. The adhesive function of E-cadherin thus depends on the integrity of the entire cadherin-catenin-actin network. A total loss of expression of the cadherin-catenin-complex is considered a rare event in human cancers [8], which might be reflected by our result that only 11.9% of NSCLCs were E-cadherin-negative. Mutations in the E-cadherin and {alpha}- and ß-catenin genes have been reported to occur infrequently in human cancers [15, 16]. Another possible mechanism for its disruption is a down-regulation of E-cadherin or the catenins. A down-regulation of E-cadherin expression could be caused by hypermethylation in its promoter region [17]. However, recent clinical studies on catenin expression in NSCLCs have yielded confusing results. Some studies reported a reduced expression of {alpha}-catenin rather than ß-catenin [18], whereas others emphasized the reduced expression of ß-catenin [19]. Another possible mechanism for its disruption is the posttranslational alteration of E-cadherin or the catenins, such as tyrosine phosphorylation [5, 8].

With respect to the evaluation of E-cadherin immunostaining, normal epithelial cells always express E-cadherin on their cell–cell boundaries. In contrast, some tumor cells with reduced E-cadherin expression had definite cytoplasmic staining for E-cadherin, as described in previous immunohistochemical studies and also demonstrated in our present study [4, 13]. This cytoplasmic expression of E-cadherin might be caused by disturbed interactions between E-cadherin and the catenins. Recently, it has been reported that a decreased tyrosine phosphorylation of E-cadherin could cause a cytoplasmic redistribution of the E-cadherin–catenin complex, resulting in its functional loss [8]. In addition, it has been reported that ß-catenin immunostaining was correlated with E-cadherin immunostaining, which supports the idea of a functional relationship between these molecules [19]. Therefore, our immunohistochemical evaluation of E-cadherin expression might offer some insight into the mechanisms of its functional and structural disruption. Our present study demonstrated that the percentage of tumor cells with positive cytoplasmic staining in the E-cadherin-reduced tumors was significantly higher than that in the E-cadherin-positive tumors. Therefore, the E-cadherin-reduced tumors with positive cytoplasmic staining could be considered to have a loss of function of the E-cadherin–catenin system, partly because of the decreased tyrosine phosphorylation of E-cadherin. Based on these results, we considered that both E-cadherin-reduced tumors and E-cadherin-negative tumors could be reclassified into one group with impaired E-cadherin expression.

Our present study of 109 patients with NSCLC showed that 47.7% of the tumors had impaired E-cadherin expression, which consisted of 35.8% of the E-cadherin-reduced tumors and 11.9% of the E-cadherin-negative tumors. We also demonstrated that the impaired E-cadherin expression was associated with tumor dedifferentiation and lymph node metastasis, as reported by previous clinical studies [6–8]. The analysis using Cox’s proportional-hazards regression model showed that E-cadherin expression was a significant factor in the prediction of survival for patients with NSCLC [6].

Although it is important for the precise understanding of the E-cadherin–catenin system to perform a complete evaluation of E-cadherin and all members of the catenin family, it is rather complicated for clinical use. In contrast, our simple immunohistochemical evaluation of membranous versus cytoplasmic staining, even for E-cadherin only, demonstrated a good correlation with the tumor differentiation, lymph node metastasis, and survival. This simple method is considered to be logistically favorable for clinical use to evaluate the biologic function of E-cadherin.

However, to evaluate the metastatic potential of NSCLCs more precisely, further investigations concerning other factors, such as adhesion molecules, will be necessary. We consider that a coevaluation of the E-cadherin and the integrin networks [20] may be useful for the treatment of patients with NSCLC. For example, NSCLCs with a normal E-cadherin–catenin complex and a normal integrin network might have low-grade malignancy, and adjuvant chemotherapy after a surgical resection of the primary tumors might not be necessary to prevent recurrence. In contrast, NSCLCs with a disruption of either of these adhesion systems might be aggressive tumors, and adjuvant chemotherapy might be necessary even at an early pathologic stage.

Furthermore, the prevention of metastasis could be a main strategy for cancer therapy. There is also the possibility of new cancer gene therapies focusing on metastasis in the future. For example, the transfection of the E-cadherin gene into cancer cells with E-cadherin dysfunction might result in phenotype reversion and a loss of tumor invasiveness [9, 10]. For this purpose, further basic studies on the E-cadherin–catenin system will be necessary.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Pignatelli M., Vessey C.J. Adhesion molecules: novel molecular tools in tumor pathology. Hum Pathol 1994;25:849-856.[Medline]
  2. Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 1991;251:1451-1455.[Abstract/Free Full Text]
  3. Aberle H., Schwartz H., Kemler R. Cadherin–catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem 1996;61:514-523.[Medline]
  4. Shiozaki H., Tahara H., Oka H., et al. Expression of immunoreactive E-cadherin adhesion molecules in human cancers. Am J Pathol 1991;139:17-23.[Abstract]
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  7. Shibanuma H., Hirano T., Tsuji K., et al. Influence of E-cadherin dysfunction upon local invasion and metastasis in non small cell lung cancer. Lung Cancer 1998;22:85-95.[Medline]
  8. Nawrocki B., Polette M., Van Hengel J., Tournier J.M., Van Roy F., Birembault P. Cytoplasmic redistribution of E-cadherin–catenin adhesion complex is associated with down-regulated tyrosine phosphorylation of E-cadherin in human bronchopulmonary carcinomas. Am J Pathol 1998;153:1521-1530.[Abstract/Free Full Text]
  9. Frixen U.H., Behrens J., Sachs M., et al. E-cadherin-mediated cell–cell-adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 1991;113:173-185.[Abstract/Free Full Text]
  10. Mbalaviele G., Dunstan C.R., Sasaki A., Williams P.J., Mundy G.R., Yoneda T. E-cadherin expression in human breast cancer cells suppresses the development of osteolytic bone metastases in an experimental metastasis model. Cancer Res 1996;56:4063-4070.[Abstract/Free Full Text]
  11. Vleminckx K., Vakaet L., Mareel M., Fiers W., van Roy F. Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991;66:107-119.[Medline]
  12. Nagafuchi A., Shirayoshi Y., Okazaki Y., Yasuda K., Takeichi M. Transformation of cell adhesion properties by exogenously introduced E-cadherin cDNA. Nature 1987;329:341-343.[Medline]
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  15. Wijnhoven B.P.L., Both N.J., Dekken H., Tilanus H.W., Dinjens W.N. E-cadherin gene mutations are rare in adenocarcinomas of the oesophagus. Br J Cancer 1999;80:1652-1657.[Medline]
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  17. Yoshiura K., Kanai Y., Ochiai A., Shimoyama Y., Sugimura T., Hirohashi S. Silencing of the E-cadherin invasion-suppressor gene by CpG methylation in human carcinomas. Proc Natl Acad Sci USA 1995;92:7416-7419.[Abstract/Free Full Text]
  18. Toyoyama H., Nuruki K., Ogawa H., et al. The reduced expression of E-cadherin, {alpha}-catenin and {gamma}-catenin but not ß-catenin in human lung cancer. Oncol Rep 1999;6:81-85.[Medline]
  19. Retera J.M., Leers M.P., Sulzer M.A., Theunissen P.H. The expression of ß-catenin in non–small-cell lung cancer: a clinicopathological study. J Clin Pathol 1998;51:891-894.[Abstract]
  20. Adachi M., Taki T., Huang C., et al. Reduced integrin {alpha}3 expression as a factor of poor prognosis of patients with adenocarcinoma of the lung. J Clin Oncol 1998;16:1060-1067.[Abstract]



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