β-连接素在胃癌的表达及其与患者生存的关系

背景与目的:细胞粘附功能下降是恶性肿瘤发展的关键因素。作为粘附分子的E-钙粘蛋白在维持正常组织结构方面具有非常重要的作用,但其功能的发挥,需要配体-连接素(α-、β-连接素等)的调节。为探讨β-连接素在胃癌发病机制中的作用,我们研究β-连接素在胃癌的表达情况,并分析其与临床病理特征及生存期的关系。方法:采用免疫组织化学法检测148例胃癌石蜡标本β-连接素和E-钙粘蛋白的表达水平。结果:胃癌组织β-连接素和E-钙粘蛋白的异常表达率分别为43.2%和44.6%;胃癌β-连接素和E-钙粘蛋白其中一种或二种表达异常者达63%。β-连接素和E-钙粘蛋白在低分化癌的异常表达率显著高于高分化癌(均P<0.005)。β-连接素表达异常与胃癌浸润深度密切相关(P<0.025);淋巴结转移阳性(45/84,53.6%)及发生远处转移(21/31,67.7%)的β-连接素异常表达率显著高于淋巴结转移阴性(19/64,29.7%)(P<0.005)及无远处转移者(43/117,36.8%)(P<0.005)。β-连接素正常表达比异常表达具有生存优势(P<0.005),且独立于浸润深度、淋巴结转移及分化程度。结论:胃癌广泛存在E-钙粘蛋白复合体表达异常;β-连接素异常表达是对胃癌生存期具有预测价值的重要指标。     

Clinicopathological variables associated with lymph node metastasis in submucosal invasive gastric cancer

Background We aimed to elucidate clinicopathological variables associated with lymph node metastasis of submucosal invasive gastric cancer. Methods Specimens were surgically resected from 201 patients who had primary submucosal gastric cancer. We studied 39 consecutive patients with lymph node metastasis and 162 patients without lymph node metastasis. We compared the following clinicopathological characteristics of the patients in relation to lymph node metastasis: age, sex, tumor size, histology, extent of submucosal invasion, lymphatic and venous invasion, and ulceration of the tumor. Submucosal invasion was divided subjectively into sm1, sm2, and sm3 (representing invasion of the upper-, middle-, and lower-third of the submucosa, respectively). We also studied the relationship between lymph node metastasis of submucosal gastric cancer and immunohistochemistry for p53, Ki67, vascular endothelial growth factor (VEGF), α-fetoprotein, sLe^a, and dendritic cells (DCs). Results In terms of conventional pathological factors, lymph node metastasis in submucosal gastric cancer was related to tumor size (P = 0.002), depth of submucosal invasion (P = 0.001), lymphatic invasion (P < 0.0001), and venous invasion (P = 0.012). Lymph node metastasis in sm1 gastric cancer was significantly related to VEGF expression (P = 0.047). Also, lymph node metastasis in sm3 gastric cancer was significantly correlated with DC expression (P = 0.016). Multivariate analysis showed that tumor size, tumor invasion depth in the submucosal layer, and lymphatic invasion were independent predictors of nodal metastasis in submucosal gastric cancer. Conclusion Conventional pathological factors, such as tumor size, depth of submucosal invasion, and lymphatic invasion, have a significant influence on lymph node metastasis. VEGF expression and DC expression may be helpful predictors of lymph node metastasis in patients with sm1 and sm3 gastric cancer, respectively.     

Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer

Background. E-cadherin has been recognized as an impor-tant factor associated with tumor metastasis. However, the relationship between micrometastasis in the lymph nodes and the expression of E-cadherin in the primary tumor in gastric cancer remains unclear. Methods. Two consecutive sections of 4522 lymph nodes from 162 patients with early gastric cancer were prepared for simultaneous hematoxylin and eosin (H&E) and cytokeratin (CK) staining. Sections of primary tumors from 135 of these patients were prepared for E-cadherin immunostaining. Results. The incidence of lymph node involvement was significantly increased, from 6.8% (11/162 patients) by H&E staining, to 27% (43/162 patients) by CK immunostaining ( P < 0.0001). Micrometastasis in the lymph node was found in 32 of 151 (21%) patients who had no lymph node metastasis evidenced by H&E staining. Micro-lymph node metastasis was frequently found in tumors with a diameter more than 1.0 cm, of those that were poorly differentiated, deeply invaded, showed lymphatic on vascular invasion, and in those that showed reduced expression of E-cadherin. Loss of expression of E-cadherin in the primary tumor was closely correlated with micro-lymph node metastasis. Patients with tumors with micro-lymph node metastasis detected by CK immunostaining had a significantly lower 5-year survival rate ( P < 0.01) than those without such metastases. Conclusion. Tumors more than 1.0 cm in diameter and those that exhibit poor differentiation, deep invasion (i.e., to the submucosa), lymphatic or vascular invasion, and reduced expression of E-cadherin are risk factors for lymph node metastasis in early gastric cancer. Thus, it is recommended that cancers confined to the mucosa (m-cancers) that are more than 1.0 cm in diameter should not be treated with limited surgery without lymphadenectomy. Received: March 27, 2001 / Accepted: May 10, 2001     

胃癌组织Snai2和E-cadherin表达及其与淋巴结转移关系的研究

目的:观察E-cadherin蛋白和Snai2蛋白在胃癌组织中的表达及其与淋巴结转移的关系.方法:采用免疫组织化学方法(SP法)检测54例胃癌组织和癌旁组织中E-cadherin蛋白和Snai2蛋白的表达情况.结果:E-cadherin蛋白在胃癌组织中表达率(33.33％)明显低于癌旁组织(100.00％,P＜0.05),而Snai2蛋白在胃癌组织中表达率(61.11％)明显高于癌旁组织(20.37％,P＜0.05);两者表达呈负相关(r=-0.564,P＜0.01)且均与胃癌浸润深度和淋巴结转移明显相关,P＜0.05.淋巴结转移阳性胃癌组织中Snai2蛋白阳性表达且E-cadherin蛋白阴性表达者为78.57％,而淋巴结转移阴性者为26.92％,两者差异有统计学意义,P＜0.01,Snai2蛋白阳性且E-cadherin蛋白阴性与淋巴结转移阳性呈显著正相关,P＜0.01.结论:Snai2和E-cadherin在胃癌发生演进过程中有重要作用,Snai2可能抑制E-cadherin表达导致上皮—间质转化而促进胃癌浸润转移.联合检测Snai2与E-cadherin表达情况对术前评估胃癌琳巴结转移状况有一定临床意义.     

Heterogeneous expression and association of beta-catenin, p16 and c-myc in multistage colorectal tumorigenesis and progression detected by tissue microarray

Most colorectal carcinomas (CRCs) arise from adenomas through an archetypal pathogenic pathway, the adenoma-carcinoma-metastasis sequence. Aberrant expression of beta-catenin, p16, E-cadherin and c-myc appears to have played important roles in the development and/or progression of CRC, but their precise distribution pattern and associations in different pathologic loci along CRC's pathogenic pathway have not been thoroughly examined. In this study, a tissue microarray (TMA) containing 85 advanced CRCs in different Dukes stages was constructed. In each of 85 cases, tissue specimens from normal mucosa and primary carcinomas in different layers of the bowel wall were included in the TMA. Tissue specimens from matched adenoma, lymph node metastases and distant metastases were obtained from 22, 21 and 21 cases, respectively. Expression patterns of beta-catenin, p16, E-cadherin and c-myc were evaluated by immunohistochemistry. The results revealed that nuclear expression of beta-catenin, p16 and c-myc was quantitatively increased from normal mucosa to premalignant adenoma, primary carcinoma and lymph node metastatic carcinoma; the frequency of nuclear overexpression of beta-catenin and p16 in lymph node metastases was significantly higher than that in distant metastases (p < 0.05). These results suggest an association between nuclear overexpression of beta-catenin and/or p16 and CRC lymph node metastasis but not distant metastasis. The results also showed that correlative high nuclear expression of beta-catenin and c-myc was observed in primary carcinomas involving the serosa and lymph node metastases (p < 0.05) but not in other pathologic regions of CRCs, suggesting that the tumor microenvironment in different pathologic loci of colorectal tumorigenesis and progression may influence c-myc responsiveness to beta-catenin/Tcf activation.     

Alteration of the E-cadherin/beta-catenin cell adhesion system is common in pulmonary neuroendocrine tumors and is an independent predictor of lymph node metastasis in atypical carcinoids

BACKGROUND: To the authors' knowledge, little is known regarding the role of E-cadherin/beta-catenin system dysregulation in pulmonary neuroendocrine tumors. METHODS: E-cadherin and beta-catenin immunoreactivity was evaluated in 10 hyperplastic neuroendocrine tumorlets and 210 neuroendocrine tumors, including 96 typical carcinoids (CTs), 35 atypical carcinoids (ACTs), 49 large cell neuroendocrine carcinomas (LCNECs), and 30 small cell lung carcinomas (SCLCs). RESULTS: Normal and hyperplastic bronchial neuroendocrine cells expressed E-cadherin/beta-catenin with an orderly distribution along the cell membrane. Neuroendocrine tumors retained beta-catenin expression in all tumors and E-cadherin in most tumors, with the exception of 2% of LCNECs, 3% of SCLCs and 9% of ACTs. E-cadherin showed a prevalent membrane-associated, linear immunoreactivity in CTs, whereas membrane-disarrayed and cytoplasmic staining was seen in most ACTs, LCNECs, and SCLCs (P < 0.001). beta-Catenin exhibited similar immunoreactivity patterns according to tumor type and a close association with E-cadherin subcellular distribution (P < 0.001). Nuclear accumulation of beta-catenin was found only in seven LCNECs and in two SCLCs. In ACTs, disarrayed immunoreactivity for E-cadherin and/or beta-catenin was associated with a nontrabecular growth pattern, altered expression of the cell-motility marker fascin, and lymph node metastases. Furthermore, a disarrayed E-cadherin distribution pattern was associated with the pathologic lymph node classification and the number of involved lymph nodes. Multivariate analysis confirmed that a disarrayed E-cadherin or beta-catenin pattern was an independent predictor of lymph node metastases in patients with ACT. CONCLUSIONS: The subcellular compartmentalization of the E-cadherin/beta-catenin complex was altered in pulmonary neuroendocrine tumors. This likely affects the tumor growth pattern and cell motility of ACT and was correlated with the occurrence of lymph node metastases.     

Reduction in membranous expression of beta-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer

beta-catenin, a component of the E-cadherin-catenin cell adhesion complex, also plays a separate intracellular signalling role, interacting with APC protein. Intracellular accumulation of beta-catenin is common in colorectal neoplasia. beta-catenin abnormalities are associated with poor survival in gastric cancer, but previous studies do not differentiate between membrane-associated and intracellular beta-catenin. In this study we aimed to determine which type of expression abnormalities for E-cadherin, beta-catenin and alpha-catenin correlate with clinico-pathological features and survival in gastric cancer. Immunoperoxidase staining of paraffin-embedded sections from 40 gastric cancers was performed for E-cadherin, alpha- and beta-catenins using microwave unmasking and an avidin-biotin technique. Clinical data were obtained from case records and cancer registry records. Reduced membranous expression of beta-catenin occurred in 10/12 (83%) diffuse and 8/28 (29%) intestinal tumours (P= 0.0014), and was associated with poor differentiation (P= 0.0015) and short survival (P= 0.032), but not with age, sex, tumour size or nodal status. Nuclear expression of beta-catenin was uncommon; cytoplasmic expression was observed in 13/40 cases (33%) but did not correlate with histology, tumour grade or survival. Reduced E-cadherin membrane expression was associated with lymph node metastasis (P= 0.02). Neither E-cadherin or alpha-catenin expression correlated with survival. Reduced membranous expression of beta-catenin predicts poor prognosis in gastric cancer, whilst ectopic intracellular expression is relatively rare. The apparent differences in beta-catenin expression from those found in colon cancer merit further study.     

LGR5和E-cadherin在胃癌组织中的表达及临床意义

目的 探讨富含亮氨酸重复序列G蛋白偶联受体5（leucine-rich repeat-containing G protein-coupled receptor 5,LGR5）和 E-钙粘蛋白（E-cadherin）在胃癌组织中的表达及其临床意义。方法 收集2014年8月—2016年5月在中南大学湘雅医学院附属株洲医院手术切除的115例胃癌组织及相应20例癌旁正常组织标本。采用免疫组化SP法检测LGR5和E-cadherin的表达水平,分析LGR5与E-cadherin表达的相关性及其与胃癌患者临床病理特征和预后的关系。结果 LGR5和E-cadherin在胃癌组织中阳性表达率分别为62.6%和53.9%,与癌旁正常组织相比,差异有统计学意义（P<0.05）;LGR5和E-cadherin表达均与肿瘤大小、TNM分期、浸润深度、淋巴结转移及远处转移有关（P<0.05）;相关分析显示,LGR5与E-cadherin表达呈负相关（r=-0.318,P=0.001）。LGR5阴性表达患者的1年、3年总生存率高于阳性表达患者（P<0.001）,E-cadherin阳性表达患者的1年、3年总生存率亦高于阴性表达患者（P<0.001）;多因素Cox回归分析显示,TNM分期Ⅲ~Ⅳ期、淋巴结转移、远处转移、LGR5表达阳性及E-cadherin表达阴性是影响胃癌患者预后的独立危险因素（P<0.05）。结论 LGR5在胃癌组织中高表达而E-cadherin表达缺失,可能导致胃癌的发生发展及不良预后。     

The loss of E-cadherin, alpha- and beta-catenin expression is associated with metastasis and poor prognosis in invasive breast cancer

Loss of E-cadherin and catenin expression may be associated with distant and lymph node metastases in breast cancer. Heterogeneity of E-cadherin expression is associated with poor prognosis, suggesting that E-cadherin and catenins may serve as useful prognostic markers for invasive breast carcinoma. Reduction or loss of expression of either E-cadherin or catenins is associated with invasion, metastasis and poor prognosis in several types of human malignancies. We investigated the expression of E-cadherin, and alpha- and beta-catenins by immunohistochemistry in 171 cases of primary invasive breast cancer, and compared the expression with clinicopathological parameters to define the relationship between expression and prognosis. E-cadherin immunoreactive protein was shown to be expressed in 97 cases. Reduction or lack of expression of E-cadherin was associated with distant metastasis. Based on immunohistochemical heterogeneity, E-cadherin-positive tumors were classified into heterogeneous, homogeneous and intermediate types. Interestingly, although patients with heterogeneous type demonstrated the lowest incidence of distant metastasis at diagnosis, they showed a higher incidence of subsequent distant metastasis, after surgery, and a lower survival rate than those with homogeneous type (p<0.05). E-cadherin expression was reduced or negative in metastatic axillary lymph nodes regardless of the expression in the primary tumor, suggesting that changes in E-cadherin expression are associated with not only distant metastasis but also lymph node metastasis. Tumors negative for either alpha- or beta-catenin expression demonstrated a higher incidence of distant metastasis than those expressing both catenins, suggesting that the expression of catenins is involved in breast cancer metastasis. Reduction or loss of E-cadherin and catenin expression may be associated with distant and lymph node metastases in invasive breast cancer, and the heterogeneous type may be associated with poor prognosis.     

Re-expression of the cadherin-catenin complex in lymph nodes with metastasis in advanced gastric cancer: the relationship with patient survival

The cadherin-catenin complex has been recognized as an important factor associated with tumor metastasis. However, the clinical significance of the expression of adhesion molecules in lymph nodes with metastasis remains unclear. The aim of this study was to investigate the clinical significance of the re-expression of the cadherin-catenin complex in metastatic lymph nodes in patients with advanced gastric cancer. Immunohistochemical expression of E-cadherin, alpha- and beta-catenin were analyzed in 96 primary gastric cancers with serosal invasion and in 79 lymph nodes with metastasis. The expression levels of these adhesion molecules in primary tumors and lymph nodes with metastasis were compared. Ninety-four out of 96 primary tumors (98%) showed reduced expression of adhesion molecules. Out of 79 cases with lymph node metastasis, increased expression of one or more adhesion molecules in metastatic foci as compared with primary tumors was detected in 52 cases (66%). Re-expression of adhesion molecules in metastatic lymph nodes was detected in a more advanced stage. The overall 5-year survival rate of the 52 patients who had lymph nodes with metastasis with re-expression of adhesion molecules (8%) was significantly poorer than that of the 27 who had lymph nodes with metastasis without re-expression of adhesion molecules (33%, P = 0.0012). The re-expression of the cadherin-catenin complex in lymph nodes with metastasis may play an important role in the growth of cancer cells in metastatic foci. A comparison of the expression patterns of adhesion molecules between the primary tumor and metastatic lymph nodes may provide new prognostic information for patients with advanced gastric cancer.     

Overexpression of EphA2 correlates with epithelial–mesenchymal transition-related proteins in gastric cancer and their prognostic importance for postoperative patients

The expression of EphA2 and three epithelial-mesenchymal transition-related proteins (E-cadherin, β-catenin and vimentin) was detected by immunohistochemistry in human gastric cancer and normal gastric mucosa. The expression of EphA2 and vimentin was significantly higher in gastric cancer tissues than in normal gastric mucosa tissues, and similar results were found for negative E-cadherin expression and ectopic β-catenin expression. Further analysis showed that the expression of EphA2 was closely correlated with the depth of tumor invasion, tumor-node-metastasis (TNM) stages and lymph node metastasis. Down-regulated expression of the epithelial protein E-cadherin, overexpression of the mesenchymal protein vimentin and ectopic expression of β-catenin were associated with the depth of tumor invasion, tumor differentiation, TNM stages and lymph node metastasis. The Spearman rank test indicated that the positive expression of EphA2 was negatively associated with E-cadherin expression and was positively correlated with β-catenin ectopic expression and vimentin expression. In addition, the Kaplan-Meier survival analysis showed that the overexpression of EphA2 and vimentin, ectopic expression of β-catenin and down-regulation of E-cadherin indicate a poor outcome. Moreover, multivariate Cox analysis showed that TNM stages, lymph node metastasis, EphA2 expression, E-cadherin expression and β-catenin ectopic expression were independent prognostic factors for postoperative gastric cancer. These findings indicate that the overexpression of EphA2 correlates with the loss of epithelial proteins and the appearance of mesenchymal proteins. Therefore, EphA2 may play a role in epithelial-mesenchymal transition in gastric cancer.     

Decrease in ICAM-1 expression on gastric cancer cells is correlated with lymph node metastasis

Background. Lymph node metastasis is a frequent type of metastasis in patients with gastric cancer. The mechanisms responsible for this type of metastasis, however, are not clearly understood. We hypothesize that the immunosurveillance system between cancer cells and lymphocytes may be associated with the lymph node metastatic process. In this study, we examined the correlation between lymph node metastasis and intercellular adhesion molecule-1 (ICAM-1), which mediates the immunosurveillance system between tumor cells and cytotoxic lymphocytes, in gastric cancer. Methods. One hundred and forty-three specimens resected from patients with gastric cancer were investigated by staining with a monoclonal antibody against ICAM-1. We studied the correlation between the expression of ICAM-1 and various clinicopathologic factors, as well as infiltration of tumor-infiltrating lymphocytes (TILs). Results. ICAM-1 expression on gastric cancer cells was significantly decreased in patients with lymph node metastasis. The infiltration of TILs was associated with ICAM-1 expression level. The prognosis of patients with ICAM-1-negative tumors was poorer than the prognosis of those with ICAM-1-positive tumors. Conclusions. These findings suggest that ICAM-1 expression on cancer cells is closely associated with lymph node metastasis in gastric cancer, under the influence of the host immunosurveillance system. Received on Aug. 20, 1999; accepted on Jan. 5, 2000     

The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer

Triple-negative breast cancer (TNBC) has a poor prognosis and lacks prognostic indicators. The androgen receptor (AR) and E-cadherin are involved in the pathogenesis of breast cancer, but their roles are not clearly defined. We designed this study to evaluate AR and E-cadherin expression and to determine their relationships with the clinicopathologic parameters of triple-negative breast cancer. The present study included 127 TNBC patients. Immunohistochemical stains for AR and E-cadherin were performed, and the relationships between AR and E-cadherin expression and clinicopathologic data and prognosis were analyzed. We found that in TNBC patients, AR was expressed in 16(12.6%) cases, and E-cadherin was expressed in 41(33.0%) cases. AR expression was associated with tumor grade (P = 0.004) and menopausal status (P = 0.017), and E-cadherin expression was associated with node status (P= 0.016). A multivariate analysis demonstrated that tumor size, tumor grade, lymph node status, and E-cadherin were of prognostic significance for disease-free interval and overall survival. Compared with AR-positive patients, AR-negative patients showed significantly poorer outcomes with respect to the disease-free interval (P = 0.047) and overall survival (P = 0.038). E-cadherin-negative patients experienced shorter disease-free interval (P = 0.016) and poorer overall survival (P = 0.012) than did E-cadherin-positive patients. An AR-positive and E-cadherin-negative expression profile was associated with recurrence or metastasis (P = 0.036). Moreover, as the expression of nuclear AR increased (25% vs. 33.3%, P = 0.361), less E-cadherin staining was observed in TNBC samples. This finding suggested that AR and E-cadherin expression could be a useful prognostic marker for classifying subgroups of TNBC.     

乙酰肝素酶、E-cadherin、N-cadherin和vimentin蛋白在胃癌中的表达及其意义

目的： 探讨人胃癌组织中乙酰肝素酶（HPA）、上皮标志物E-cadherin、间质标志物N-cadherin和vimentin蛋白的表达及其与人胃癌临床病理指标的关系,以及HPA与E-cadherin、N-cadherin、vimentin蛋白之间的关系。方法： 应用免疫组织化学方法检测91例人胃癌组织中HPA、E-cadherin、N-cadherin和vimentin蛋白表达情况;采用卡方检验,检测这几种蛋白阳性表达率与人胃癌不同病理指标的关系;同时采用Spearman等级相关分析HPA与E-cadherin、N-cadherin、vimentin蛋白之间的关系。结果： 人胃癌组织中HPA、E-cadherin、N-cadherin和vimentin蛋白阳性表达率为75.82%、51.65%、54.95%和23.08%。91例人胃癌组织中HPA、E-cadherin、N-cadherin和vimentin蛋白的阳性表达率与胃癌患者年龄、性别、胃癌大小均无明显相关（P > 0.05）,而与人胃癌发生部位、分化程度和有无淋巴结转移、侵袭程度有关（P < 0.05）。HPA、N-cadherin和vimentin蛋白在贲门部阳性表达率明显高于胃体、幽门及胃窦胃癌;低分化者、有淋巴结转移者和胃癌侵袭深处这3种蛋白阳性表达率明显高于高分化者、无淋巴结转移者和胃癌起始部位;E-cadherin蛋白在幽门及胃窦部胃癌阳性表达率明显高于贲门和胃体胃癌;高中分化者、无淋巴结转移者明显高于低分化者和有淋巴结转移者。E-cadherin蛋白阳性表达率在侵袭深处明显低于起始部位。经Spearman等级相关分析显示,人胃癌组织中HPA与E-cadherin蛋白的阳性表达率呈负相关（r=-0.341,P < 0.05）;而与N-cadherin（r=0.366,P < 0.05）和vimentin（r=0.284,P < 0.05）蛋白阳性表达率呈正相关。结论： 人胃癌组织中HPA、N-cadherin和vimentin蛋白在低分化者、有淋巴结转移者和胃癌侵袭深处高表达;E-cadherin蛋白在高中分化胃癌,无淋巴结转移者和起始部位高表达。HPA与N-cadherin、vimentin蛋白阳性表达率呈正相关,HPA与E-cadherin蛋白的阳性表达率呈负相关,可见HPA蛋白与间质标志物N-cadherin和vimentin蛋白表达增强有关,而与上皮标志物E-cadherin蛋白缺失或减少有关,因此HPA可能诱导人胃癌组织发生上皮间质转化。     

E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis

OBJECTIVE: Abnormal expression of E-cadherin plays an important role in the differentiation and progression of gastric carcinoma. However, the relationship between molecular changes in E-cadherin and metastasis in early gastric carcinoma (EGC) is poorly understood. MATERIALS AND METHODS: Sixty cases of EGC with or without lymph node metastasis (30 node-positive cases and 30 node-negative cases) were investigated to evaluate hypermethylation status using bisulfate-MSP and immunohistochemistry using antibody against E-cadherin. RESULTS: Twenty-seven (45.0%) of 60 primary EGCs exhibited methylation in the CpG island of E-cadherin. Abnormal expression of E-cadherin was significantly correlated with patient age, tumor size, Lauren classification, differentiation, and lymph node metastasis. Using multiple logistic regression analysis, two factors were independent, statistically significant parameters associated with lymph node metastasis: abnormal expression of E-cadherin (risk ratio, 2.62; 95% confidence interval, 0.917-7.457; P < 0.05) and lymphatic invasion (risk ratio, 8.11; 95% confidence interval, 1.612-40.766; P < 0.05). CONCLUSION: Our results suggest that methylation of E-cadherin is a frequent, early event in gastric carcinoma progression, and is correlated significantly with downregulated E-cadherin expression. Inactivation of E-cadherin might be involved in metastasis in EGC and play an important role in microscopic differentiation.     

Immunohistochemical evaluation of cadherin and catenin expression in early gastric carcinomas: correlation with clinicopathologic characteristics and Helicobacter pylori infection.

Dysfunction of E-cadherin and catenin has been linked to invasiveness and differentiation of tumors. This study aimed to characterize the expression of cadherins and catenins in early gastric carcinoma and their relationship to clinicopathologic characteristics and Helicobacter pylori infection. E-cadherin and alpha-, beta- and gamma-catenins were strongly expressed in normal epithelium but abnormal immunoreactivity of at least one of these four proteins was noted in 48 (90.6%) of 53 early gastric carcinomas. Only 5 cases with intestinal-type tumors had intact expression of E-cadherin and alpha-, beta-, and gamma-catenins. Abnormal immunoreactivity in the tumor tissue was observed in 18 patients (34.0%) for E-cadherin, in 35 (66.0%) for alpha-catenin, in 20 (37.7%) for beta-catenin, and in 37 (69.8%) for gamma-catenin. In diffuse-type tumors, abnormal expression of E-cadherin (60.9 vs. 13.3%, p < 0.0005), alpha-catenin (82.6 vs. 53.3%, p < 0.05) and gamma-catenin (91.3 vs. 53.3%, p < 0.005) was more frequent than in the intestinal type. Ten tumors with lymph node metastasis showed a relatively higher frequency of abnormal expression of E-cadherin (70 vs. 25.6%, p < 0.05) but a lower frequency of abnormal expression of beta-catenin (10 vs. 44.1%, p = 0.07) than those without metastasis. No significant association was found between cadherin/catenin expression and the depth of invasion or the H. pylori status. It was concluded that abnormal expression of E-cadherin and the catenin-mediated cell-cell adhesion system occurs frequently in early gastric carcinogenesis and may play an important role in the genesis of histologic differentiation and in the mode of metastasis of early gastric carcinomas.     

Expression of EphA2 and E-cadherin in Gastric Cancer: Correlated with Tumor Progression and Lymphogenous Metastasis

In this study, gastric cancer progression was correlated with the over-expression of erythropoietin-producing hepatocellular (Eph)A2 receptor and down-expression of epithelial cadherin (E-cadherin). Immunohistochemistry of EphA2 and E-cadherin were performed on these tumor samples from 165 primary lesions of gastric cancer. The results showed that expression of EphA2 was obviously increased in gastric cancer tissues (P < 0.01), which was positively correlated with the depth of cancer invasion, tumor-node-metastasis (TNM) stage and lymph node metastasis (P < 0.05). Meanwhile, the expression of E-cadherin was significantly reduced (P < 0.01), which was negatively correlated with the depth of cancer invasion, grade of tumor differentiation, TNM stage and lymph node metastasis (P < 0.05). The correlation between EphA2 and E-cadherin expression was negative (r = −0.198, P = 0.011). In conclusion, either the over-expression of EphA2 or the down-expression of E-cadherin is correlated with cancer progression and lymphogenous metastasis in gastric cancer, suggesting that both of them may play an important role in tumor progression and metastasis.     

Clinical significance of E-cadherin-catenin complex expression in metastatic foci of colorectal carcinoma.

BACKGROUND AND OBJECTIVES: Reduced expressions of cell adhesion molecules (E-cadherin, alpha-catenin, and beta-catenin) has been reported to be associated with tumor metastasis. However, the clinical significance of such adhesion molecules in the metastatic foci remains unclear. In this study, we evaluated the prognostic significance of E-cadherin, alpha-catenin, and beta-catenin expressions in the metastatic foci of patients with colorectal carcinoma. METHODS: The expressions of E-cadherin, alpha-catenin, and beta-catenin were detected immunohistochemically in 105 primary tumors, in 30 metastatic lymph nodes, and 13 metastatic liver tumors from consecutive patients with colorectal carcinoma. RESULTS: Reduced normal expression of E-cadherin, alpha-catenin, and beta-catenin in comparison with normal epithelium was detected in 78 primary tumors, respectively. Patients who had tumors with reduced expression of adhesion molecules showed unfavorable prognosis and the reduced expression of adhesion molecules was detected as one of the independent prognostic factors for patients with colorectal carcinoma. In 30 patients with lymph node metastasis, the increased expression of adhesion molecules in metastatic lymph nodes compared with primary tumors was detected in 13 patients. The prognosis of these 13 patients was poorer than that of remaining 17 patients (P = 0.0296). Also, in 13 patients with liver metastasis, even no significant difference was observed, the mean survival time of 6 patients who had metastatic liver tumors with increased expression of adhesion molecules (10 months) was shorter than that of the remaining 7 patients (16 months; P = 0.1718). CONCLUSIONS: These results suggest that increased expression of the cadherin-catenin cell-cell adhesion system in metastatic foci may play an important role in progression of metastatic colorectal carcinomas.     

Expression of E-cadherin,alpha-catenin,and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma

Regional lymph node metastasis is a very important prognostic indicator. In the metastatic process, reduction in cell to cell adhesion including E-cadherin-catenin cell adhesion complex is an essential step. We investigated immunohistochemical expression of E-cadherin, alpha-catenin and beta-catenin in 159 tissue samples from patients with oral squamous cell carcinoma and examined the correlation between their expressions and the presence of regional lymph node metastasis. Significantly greater reduction in expression levels of E-cadherin, alpha-catenin and beta-catenin was found in the metastatic group (n=64) compared to the nonmetastatic group (n=95) (P=0.007, 0.001, 0.001, respectively). However, there was no significant correlation between their expressions and the features of the regional metastasis, the number of metastatic lymph nodes or the presence of extracapsular metastasis. These data suggest that evaluation of the immunohistochemical expression of E-cadherin, alpha-catenin and beta-catenin is extremely valuable for the diagnosis of metastatic occurrence.