Automated quantitative analysis of E-cadherin expression in lymph node metastases is predictive of survival in invasive ductal breast cancer.

PURPOSE: The tumor suppressor adhesion molecule E-cadherin is believed to have an anti-invasive role in breast cancer. Lymph node involvement is the best prognostic marker known, yet there is variability in outcome among node-positive patients. We investigated the relationship between E-cadherin expression in primary invasive ductal tumors and corresponding nodal metastases, and determined the prognostic value of E-cadherin expression in node-positive breast cancer. EXPERIMENTAL DESIGN: Membrane E-cadherin expression was studied by immunohistochemical staining of tissue microarrays with fluorescent-labeled antibodies. An objective method of automated quantitative analysis (AQUA) was used. AQUA uses cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and measures E-cadherin expression using a Cy5-conjugated antibody within the mask. RESULTS: We employed a tissue microarray containing 207 primary and matched nodal metastases suitable for AQUA analysis. There was no significant difference in mean staining intensity between the primary and nodal specimens (P = 0.8). A scattergram was generated which identified a subset of patients (25%) with high E-cadherin expression in nodal metastases, and this top quartile had improved survival (P = 0.028). On univariate analysis, increased E-cadherin expression in nodal metastases was strongly associated with improved survival (P = 0.007), whereas expression in primary tumors was not (P = 0.13). On multivariate analysis, nodal E-cadherin expression retained its independent association with survival, as did tumor size and HER2/neu status. CONCLUSIONS: Strong E-cadherin expression in lymph node metastases was highly predictive of improved survival. This suggests that expression of adhesion molecules at metastatic sites portends less aggressive tumor behavior.     

P53 expression in squamous cell carcinomas of the supraglottic larynx and its lymph node metastases: new results for an old question

BACKGROUND: Although p53 overexpression is frequent in head and neck squamous cell carcinomas (HNSCCs), controversy remains regarding the prognostic significance of that overexpression. The objective of this study was to investigate the expression pattern and prognostic significance of p53 expression in HNSCC of the same location, treated in the same way, and with long-term follow-up. METHODS: P53 expression was determined by immunohistochemistry in paraffin-embedded tissue specimens from 107 consecutive patients (107 primary squamous cell carcinomas of the supraglottic larynx and 46 matched lymph node metastases). All patients underwent surgical resection and bilateral neck dissection. RESULTS: A strong correlation was observed between p53 expression in the primary tumor and in the matched lymph node metastases (P=.0001). P53 overexpression in the lymph nodes was an independent predictor of regional recurrence (P=.027). Likewise, expression of p53 in the lymph nodes correlated significantly with disease-specific survival (P=.018). Five years after treatment, 70% of patients with p53-negative, metastatic lymph nodes remained alive, whereas only 30% of patients with p53-positive lymph nodes remained alive. In multivariate analysis, lymph node status and p53 expression in the lymph nodes remained associated with survival. CONCLUSIONS: The current data suggested that, although p53 overexpression is common in supraglottic carcinomas, its expression in the primary tumor is of limited clinical significance. However, the results supported the role of p53 in the lymph node metastases as an independent predictor of regional failure and a poor prognosis in patients with HNSCC. A prospective trial is indicated to validate these findings.     

Expression of the E-cadherin-catenin cell adhesion complex in primary squamous cell carcinomas of the head and neck and their nodal metastases.

Reductions in cell-cell adhesion and stromal and vascular invasion are essential steps in the progression from localized malignancy to metastatic disease. In this study, changes in the expression of the components of the E-cadherin-catenin cell adhesion complex have been investigated using immunohistochemical techniques in primary tumours and nodal metastases from 36 patients with squamous cell carcinoma of the head and neck. For 14 patients the corresponding primary and nodal metastases samples were available. None of the 51 samples showed normal E-cadherin expression when compared with either the adjacent normal squamous epithelium or with normal colonic epithelium that was used as positive control material. In 88% of primary tumours fewer than 50% of cells exhibited normal membranous E-cadherin expression. Loss of membranous E-cadherin expression was more extensive in poorly differentiated carcinomas while, in individual carcinomas, membranous E-cadherin expression was stronger in those parts of the neoplasm that expressed the differentiation marker involucrin. Expression of beta-catenin generally paralleled that of E-cadherin, but in 12 cases there was strong membranous beta-catenin expression in samples that exhibited predominantly cytoplasmic E-cadherin labelling. Expression of alpha-catenin was generally weak and did not correlate with the expression of either beta-catenin or E-cadherin. Marked intratumoral heterogeneity for protein expression was evident for all antibodies, and the abnormal expression of the catenins is a novel finding. E-cadherin is expressed more intensely in cells with greater squamous differentiation, but there was no correlation between the decreased expression of any of the adhesion molecules of the E-cadherin complex tested and local recurrence, metastasis or survival. The loss of expression of components of the E-cadherin complex is a common abnormality in squamous carcinomas and, while it may be permissive for metastasis, it does not appear to be the only determinant of this process.     

E-cadherin is a selective and strongly dominant prognostic factor in squamous cell carcinoma: a comparison of E-cadherin with desmosomal components

E-cadherin-mediated and desmosomal cell-cell adhesion have been implicated in the suppression of invasive and metastatic behavior of squamous cell carcinomas. Whether the adhaerens junction represented by E-cadherin and the desmosomes interplay or have distinct and separate roles in squamous cell cancer progression is still unclear. We have studied a cohort of 200 primary tumors and 56 lymph node metastases from different anatomic sites of the head and neck region for changes in synthesis of E-cadherin, desmoplakin and desmoglein by immunohistochemistry (IHC). Selected cases were studied by indirect immunofluorescence (IIF) and electron microscopy (EM). Only frozen sections were evaluated since they gave stronger and reproducible staining results. IHC data obtained were compared to clinical parameters. While some reduction in immunostaining was found in virtually all invasive tumors, at least partial expression, including that of E-cadherin, persisted in most late stage tumors and in lymph node metastases. Reduced desmosomal staining correlated with desmosomes reduced in numbers, size or in structural defects by EM analysis. By univariate analysis, reduction in synthesis of both E-cadherin and the desmosomal components that were generally linked (i.e., they showed positive rank correlations) were significantly associated with clinical parameters including overall and disease-free survival. However, by multivariate analysis including a Cox proportional hazards regression model (backward selection), the desmosomal components were not significant as independent prognostic factors. By contrast, E-cadherin was strongly associated with patient prognosis. In line with the highly significant association of reduced E-cadherin synthesis with an increased relative risk of follow up events, i.e., regional lymph node (p = 0.0007) and distant metastasis (p < 0.0001), as well as local recurrences (p < 0.0001), the prognostic strength of E-cadherin was independent of and stronger than histological grading, N stage, tumor site, and even stronger than the TNM stage. Based on these results, evaluation of E-cadherin in squamous cell carcinomas by immunostaining is recommended as a significant prognostic marker.     

Neural-cadherin expression associated with angiogenesis in non-small-cell lung cancer patients

An immunohistochemical analysis for E(epithelial)-cadherin and N(neural)-cadherin expression in relation to tumour angiogenesis was performed in 150 patients with nonsmall cell lung cancer (NSCLC). In all, 71 carcinomas (47.3%) were E-cadherin-negative. Epithelial-cadherin-negative tumours had lymph node metastases significantly more frequently than E-cadherin-positive tumours (P=0.0100). On the other hand, 46 carcinomas (30.7%) were N-cadherin-positive. Regarding tumour vascularity, there was no significant correlation between E-cadherin expression and tumour vascular. In contrast, the frequency of hypervascular tumours was significantly higher for N-cadherin-positive carcinomas than for N-cadherin-negative carcinomas (P=0.0373). Regarding prognosis, the 5-year survival rate of patients with E-cadherin-negative NSCLCs was significantly lower than that of patients with E-cadherin-positive NSCLCs (P=0.0146). In contrast, of the patients with large cell carcinomas, the 5-year survival rate of patients with N-cadherin-positive tumours was significantly lower than that of patients with N-cadherin-negative tumours (P=0.0013). A multivariate analysis demonstrated that E-cadherin status (P=0.0339) and tumour vascularity (P=0.0295) were significant indicators for survival. In conclusion, E-cadherin expression and tumour vascularity are significant prognostic factors of NSCLC patients. Furthermore, N-cadherin expression is associated with tumour angiogenesis, and its expression is one of prognostic factors of patients with large cell carcinomas. Thus, N-cadherin also might play a specific role in undifferentiated large cell carcinomas.     

Kiss-1和E-cadherin在声门上型喉鳞状细胞癌中的表达及临床意义

目的观察Kiss-1和E钙粘蛋白(E-cadherin)在人声门上喉鳞状细胞癌组织中的表达及两者间的相互关系, 初步探讨Kiss-1、E-cadherin在人喉鳞状细胞癌发病机制中的作用及临床意义, 为喉鳞状细胞癌的预后判断提供理论依据。方法 应用免疫组化SP法检测78例声门上喉鳞状细胞癌及78例正常声门上喉组织的Kiss-1及E-cadherin蛋白的表达情况, 评估声门上喉鳞状细胞癌中Kiss-1及E-cadherin蛋白表达与临床及病理因素的关系, 并分析二者之间相关性。结果 Kiss-1和E-cadherin蛋白阳性表达主要位于细胞膜。78例声门上喉鳞状细胞癌组织中Kiss-1和E-cadherin蛋白的阳性表达率分别为32.1%和42.3%;78例喉正常组织中Kiss-1和E-cadherin蛋白的阳性表达率分别为62.8%和83.3%。两种抑癌基因在声门上喉鳞状细胞癌组织和正常喉组织中的表达有统计学差异(P＜0.01), Kiss-1和E-cadherin在喉鳞状细胞癌颈淋巴结转移、临床分期及分化程度具有统计学差异(P＜0.05), Kiss-1和E-cadherin在喉鳞状细胞癌的年龄、性别上无统计学差异(P＞0.05);Kiss-1和E-cadherin之间的表达呈正相关, 两者间差异具有统计学意义(P＜0.01)。结论 Kiss-1和E-cadherin蛋白在声门上喉鳞状细胞癌组织中的表达明显缺失, 提示Kiss-1和E-cadherin可能在喉鳞状细胞癌的发生发展中起重要作用;Kiss-1和E-cadherin蛋白表达与声门上喉鳞状细胞癌的淋巴结转移、临床分期及分化程度有关, 与患者的性别及年龄无关, Kiss-1和E-cadherin的表达存在相关性。     

Independent prognostic value of fascin immunoreactivity in stage I nonsmall cell lung cancer

Fascin-1, the most expressed form of fascin in vertebrate tissues, is an actin-bundling protein that induces cell membrane protrusions and increases motility of normal and transformed epithelial cells. Very few data are available on the role of this protein in nonsmall cell lung cancer (NSCLC). Two hundred and twenty patients with stage I NSCLC and long-term follow-up were evaluated immunocytochemically for fascin expression. Overall, variable fascin immunoreactivity was detected in 98% of 116 squamous cell carcinomas, in 78% of 96 adenocarcinomas, in 83% of six large cell carcinomas, and in the two adenosquamous carcinomas under study. Neoplastic emboli were commonly decorated by the antifascin antibody (P<0.001), also when the surrounding invasive carcinoma was unreactive. Fascin immunoreactivity correlated with high tumour grade (P=0.017) and, in adenocarcinomas, with high Ki-67 labelling index (P=0.021). Adenocarcinomas with a prevalent bronchiolo-alveolar in situ component were less commonly immunoreactive for fascin than invasive tumours (P=0.005). Contralateral thoracic or distant metastases were associated significantly with diffuse (>60% immunoreactive tumour cells) fascin expression in adenocarcinomas (P=0.043), and marginally with strong fascin immunostaining in squamous cell carcinomas (P=0.13). No associations were noted with any other clinicopathological variables tested. Patients with tumours showing diffuse (>60% immunoreactive neoplastic cells) and/or strong immunoreactivity for fascin had a shorter survival (P=0.006 for adenocarcinomas and P=0.026 for squamous cell carcinomas), even after multivariate analysis (P=0.014 and 0.050, respectively). The current study documents for the first time that fascin is upregulated in invasive and more aggressive NSCLC, being an independent prognostic predictor of unfavourable clinical course of the disease. Targetting the fascin pathway could be a novel therapeutic strategy of NSCLC.     

Altered expression of E-cadherin in breast cancer. patterns, mechanisms and clinical significance

Reduced cell adhesion brought about by altered surface expression of E-cadherin has been implicated in invasive and metastatic malignant growth. We investigated the patterns of immunohistochemical E-cadherin expression in 120 breast carcinomas. Furthermore, we analysed DNA from the same samples for loss of heterozygosity (LOH) using three separate microsatellite markers on chromosome 16q22.1. Finally, the clinical outcome was ascertained for 108 patients. 19% (18/97) of infiltrating ductal carcinomas showed complete loss of E-cadherin expression compared with 64% (9/14) of infiltrating lobular carcinomas. LOH was detected in 46% (24/52) of infiltrating ductal carcinomas and 89% (8/9) of infiltrating lobular carcinomas. In the infiltrating lobular carcinomas, LOH was associated with complete loss of cell membrane expression of E-cadherin, although a cytoplasmic expression pattern was evident. In contrast, this association was not seen in the infiltrating ductal carcinomas. In a multivariate analysis, loss of E-cadherin expression was shown to be a significant independent risk factor for a poorer disease-free survival (P=0.019), in particular in the node-negative subset of patients (P=0.029). Significance was also approached for breast cancer corrected survival (P=0.056). We conclude that different mechanisms are involved in the altered E-cadherin expression seen in different subtypes of breast carcinomas. Furthermore, we implicate loss of E-cadherin, regardless of the genetic causes, as an independent prognostic marker for disease recurrence, especially in node-negative breast cancer patients, irrespective of the histological type.     

Immunohistochemical Assessment of E-cadherin and β-catenin in the Histological Differentiations of Oral Squamous Cell Carcinoma

The aim of this study was to establish the expression and localization of E-cadherin and β-catenin inoral squamous cell carcinomas (OSCC) so that we could correlate the findings with prognostic-relevanthistopathological variables. E-cadherin and β-catenin expression in normal oral epithelia and in oral squamouscell carcinomas was examined immunohistochemically, and associations with histopathological differentiationand prognosis were then analyzed in 33 patients who had been operated on for OSCC. E-cadherin expressionwas found in (82%) of the squamous cells of well differentiated OSCC, (61%) of moderately differentiatedand (39%) of poorly differentiated. E-cadherin expression was significantly associated with histological grade(p=0.000). No nuclear staining was detected. In (19.5%) of the cells E-cadherin localized in the cytoplasm, withno correlation to the histological grade (p=0.106). β-Catenin expression was found in 87% of the squamous cellsof well differentiated OSCC, 67% of moderately differentiated and 43% of poorly differentiated, the expressionwas significantly associated with histological grade (p=0.000). the nuclear β-Catenin expression appeared in 3.3%of the cells and it was correlated to the histological grade (p=0.000). In (23.5%) of the cells β-Catenin localizedin the cytoplasm, with correlation to the histological grade (p=0.002). According to this study the expression ofβ-catenin and E-cadherin were independent prognostic factors for histological grade. E-cadherin was closelylinked to β-catenin expression in OSCC (p=0.000) and to tumor differentiation. That reflects a structuralassociation and the role of both in tumor progression.     

Expression of cyclin D1 and Ki-67 in squamous cell carcinoma of the oral cavity: clinicopathological and prognostic significance

The prognostic and clinicopathologic significance of cyclin D1 and Ki-67 expressions was studied in oral squamous cell carcinomas. We performed an immunohistochemical study to determine the level of expression of cyclin D1 and Ki-67 labelling index in tumor specimens obtained from 35 patients, of whom 14 died as a result of recurrent disease, and 20 were free of recurrence at the end of the follow-up period. Overexpression of cyclin D1 was significantly associated with regional lymph node metastases (P=0.00005) and advanced tumor stage (P=0.0007). The relative risk for nodal metastases in the cases that overexpressed cyclin D1 was 2.6. The Ki-67 labelling index was significantly (P=0.001) higher in tumors with poor histologic grade of differentiation. Our results showed that cyclin D1 is a useful prognostic factor, and suggested it could be a marker to help determine the appropriate treatment for patients with oral squamous cell carcinoma. Cyclin D1 and Ki-67 overexpression were positively correlated.     

食管癌NOS同功酶和VEGF活性表达与血管生成及其意义

 目的　研究食管癌iNOS、cNOS及VEGF表达 ,探讨NO作用双向性在食管癌发生、发展中的意义及其与VEGF的关系。方法　手术切除的食管鳞癌标本 75例 ,免疫组化法检测iNOS ,cNOS和VEGF活性表达及微血管计数 (MVD)。结果　iNOS、cNOS及VEGF阳性表达分别为 4 4 %、6 0 %及30 .7%。iNOS与组织学分级有关 ,即随着分化程度降低 ,iNOS活性越低 (P =0 .0 15 ) ;MVD在淋巴结转移者明显高于未转移者 (P =0 .0 0 3) ;iNOS与VEGF表达呈显著正相关 (P =0 .0 0 3) ;术后复发与组织学分级、iNOS表达缺失、MVD计数及淋巴结转移有关 (P值分别为 0 .0 0 3、0 .0 2 1、0 .0 4 1、0 .0 0 2 )。结论　i NOS在低分化型肿瘤的表达缺失 ,提示肿瘤预后不良。MVD计数及iNOS活性检测可作为食管癌预后判断的独立预测因素。     

The role of epidermal growth factor receptor and E-cadherin for the outcome of reduction in the overall treatment time of radiotherapy of supraglottic larynx squamous cell carcinoma

Reduction of the overall treatment time (OTT) of radiotherapy results in increased T-site control in squamous cell carcinomas of the head and neck (HNSCC). However, the response is heterogeneous and accelerated repopulation of clonogenic tumour cells during therapy may be one of the factors determining this response. The aim of the present study was to identify the influence of the epidermal growth factor receptor (EGFr) and E-cadherin for T-site control when the OTT was reduced and whether the markers add information to the histopathological grading in selecting patients for accelerated radiotherapy. A total of 209 patients from randomized DAHANCA-trials with supraglottic larynx squamous cell carcinomas treated with primary radiotherapy with different OTT of 9(1/2), 6(1/2), and 5(1/2) weeks. Available formalin-fixed paraffin embedded tumour tissues were re-evaluated for histopathological characteristics and stained for EGFr and E-cadherin. Data were correlated with patient and tumour characteristics and 5-year T-site control. EGFr and E-cadherin were not associated with patient or tumour characteristics except that EGFr correlated to carcinomas with a well to moderate histopathological feature. Tumours with high EGFr or low E-cadherin did benefit from reduced OTT, and the combination of the two (high EGFr and low E-cadherin) had the most significant acceleration of treatment effect, compared with tumours with other combinations of EGFr and E-cadherin expression. Tumours with high expression of EGFr and low expression of E-cadherin showed the most significant increase in T-site control when the overall treatment time of radiotherapy was reduced, and the markers may be useful for selecting patients who will benefit from accelerated radiotherapy.     

The role of E-cadherin/catenin complex in laryngeal cancer

In this review the role of the epithelial E-cadherin/catenin complex in cases of laryngeal cancer is discussed. Cancer of the larynx remains the second most common head and neck malignancy. The E-cadherin/catenin complex expression is abnormal in laryngeal squamous cell carcinomas. Loss or reduction of E-cadherin expression is especially observed in supraglottic larynx cancer in relation with poor histological differentiation and/or lymph nodes metastases. Controversial results in some studies regarding the role of the E-cadherin/catenin complex in various anatomical parts of the larynx have been reported. Further studies are needed to establish the importance of the E-cadherin/catenin complex as a potential biomarker in laryngeal cancer diagnosis and prognosis.     

Phospho-akt expression is associated with a favorable outcome in non-small cell lung cancer.

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.     

Loss of E-cadherin expression resulting from promoter hypermethylation in oral tongue carcinoma and its prognostic significance

BACKGROUND: E-cadherin is expressed on the surface of normal epithelial cells. Loss of E-cadherin expression has been found in cancers and is postulated to facilitate tumor cell dissociation and metastasis. This study evaluated the role of promoter dense methylation in the downregulation of E-cadherin expression in oral tongue carcinoma. METHODS: E-cadherin expression of 109 oral tongue carcinomas (93 primary tumors, 7 locally recurrent tumors, and 9 metastatic lymph nodes) was evaluated by immunohistochemical staining of tumor tissues. The methylation status of the CpG islands at the promoter region of E-cadherin which flanked five HpaII (methylation sensitive restriction enzyme) digestion sites were evaluated by methylation sensitive polymerase chain reaction in 86 tumors (70 primary tumors, 7 locally recurrent tumors, and 9 metastatic lymph nodes). RESULTS: Underexpression of E-cadherin was found in 83% of primary tumors, 86% of recurrent tumors, and 89% of nodal metastases. Hypermethylated E-cadherin promoter was found in 64% of primary tumors, 71% of recurrent tumors, and 67% of nodal metastases. Downregulation of E-cadherin expression was found to be related to promoter hypermethylation. Consistently weak expression of E-cadherin by promoter hypermethylation was observed in primary tumors, their corresponding metastatic lymph nodes, and recurrent tumors. Downregulation of E-cadherin expression was a significant poor prognostic factor for survival. CONCLUSIONS: Methylation of CpG sites at the promoter region played a key role in the inhibition of E-cadherin expression in both primary oral tongue carcinomas and their corresponding recurrences and nodal metastases. The resulting downregulation of E-cadherin expression had adverse effects on the prognosis of patients who were treated by primary surgery.     

alpha-catenin is a significant prognostic factor than E-cadherin in esophageal squamous cell carcinoma

BACKGROUND AND OBJECTIVES: The purpose of the present study was to analyze clinicopathologic variables in esophageal squamous cell carcinoma (ESCC) according to expression of E-cadherin and alpha-catenin which play an important role in cell adhesion. METHODS: We immunohistochemically examined E-cadherin and alpha-catenin in 205 patients with ESCC. The expression results were classified into two groups: preserved expression (+) and reduced expression (-). RESULTS: The incidence of E-cadherin (-) and alpha-catenin (-) was 52% and 54%, respectively and significantly related each other. For both E-cadherin and alpha-catenin, reduced expression was significantly related to tumor depth, nodal metastasis, stage, recurrence, and prognosis. In the E-cadherin (+) group, the alpha-catenin (+) and alpha-catenin (-) patients differed significantly in tumor depth, nodal metastasis, stage, hematogenous and lymphatic recurrences (P < 0.001, <0.001, <0.001, <0.001 and =0.007, respectively). According to coexpression of E-cadherin and alpha-catenin, the prognosis was best in patients with E-cadherin (+) and alpha-catenin (+), and worst in patients with E-cadherin (-) and alpha-catenin (-). Multivariate analysis revealed that alpha-catenin expression was an independent prognostic factor. CONCLUSIONS: The examination of expression of E-cadherin and especially alpha-catenin is useful for predicting lymph node metastasis and clinical outcome of ESCC.     

The relationship between Bmi-1 and the epithelial–mesenchymal transition in lung squamous cell carcinoma

This study aimed to investigate the expression of Bmi-1 in lung squamous cell carcinoma tissues and the relationship between Bmi-1 and the epithelial-mesenchymal transition. RT-PCR and western blot analysis were performed to detect the expression of Bmi-1, E-cadherin, and Vimentin in 56 cases of lung squamous cell carcinoma tissues and adjacent normal tissues. The positive rates of Bmi-1, E-cadherin, and Vimentin mRNA expression in lung squamous cell carcinoma tissues were 73.2, 42.9, and 58.9%, respectively; compared to the expression of these genes in adjacent normal tissues (14.3, 75.0, and 28.6%), the differences were significant (P < 0.05). The expression of Bmi-1 in lung squamous cell carcinoma tissues showed a negative correlation with that of E-cadherin (r = -0.372, P = 0.005) and a positive correlation with that of Vimentin (r = 0.315, P = 0.02). The expression of Bmi-1 and Vimentin mRNA and protein in lung squamous cell carcinoma tissues was significantly higher than that in adjacent normal tissues (P < 0.05), and the expression of Bmi-1 and Vimentin in patients with lymph node and distal metastasis was significantly higher than that in patients without lymph node and distal metastasis (P < 0.05). The expression of E-cadherin mRNA and protein in lung squamous cell carcinoma tissues was significantly lower than that in adjacent normal tissues (P < 0.05), and the expression in patients with lymph node and distal metastasis was significantly lower than that in patients without lymph node and distal metastasis (P < 0.05). The expression of Bmi-1, E-cadherin, and Vimentin was not associated with the patient's sex, age, tumor size or degree of tumor differentiation (P > 0.05). The increase in Bmi-1 expression was accompanied by the down-regulation of E-cadherin expression and up-regulation of Vimentin expression. Bmi-1 may be associated with the epithelial-mesenchymal transition in lung squamous cell carcinoma and the occurrence, invasion, and metastasis of lung squamous cell carcinoma.     

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.     

The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients

Epithelial ovarian cancer is the leading cause of death among female genital malignancies. Reduced expression of the cell adhesion molecule E-cadherin was previously shown to be associated with adverse prognostic features. The role of the E-cadherin repressor Snail in ovarian cancer progression remains to be elucidated. We analysed formalin-fixed and paraffin-embedded specimens of 48 primary ovarian tumours and corresponding metastases for expression of E-cadherin and Snail by immunohistochemistry. We found a significant correlation between E-cadherin expression in primary cancers and their corresponding metastases (P<0.001). This correlation was found for Snail expression as well (P<0.001). There was a significant (P=0.008) association of reduced E-cadherin expression in primary ovarian cancer with shorter overall survival. Similarly, Snail expression in corresponding metastases (P=0.047) was associated with reduced overall survival of the patients. Additionally, the group of patients showing reduced E-cadherin and increased Snail immunoreactivity in primary tumours and corresponding metastases, respectively, had a significantly higher risk of death (P=0.002 and 0.022, respectively) when compared to the patient group with the reference expression profile E-cadherin positive and Snail negative. Taken together, the results of our study show that the E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients.