Immunohistochemical Expression Of E-cadherin Research Articles

Correlation between the expression abnormalities of E-cadherin-β-catenin complex and lymph node metastasis (LNM) in early gastric cancer

15105 Background: Therapy for early gastric cancer (GC) varies according to risk of LNM. When the possibility of LNM is very remote, the primary lesion can be resected by the minimally invasive endoscopic surgery only. Therefore, useful parameters predicting LNM are needed. E-cadherin, a component of the cell-cell junctional structure, is known to correlate with GC. In vitro, previous studies elucidated that disorders of cell-cell junction increased the potential of metastasis, and that phosphorylation of β-catenin by c-erbB-2 induced loss of membranous E-cadherin and β-catenin, resulting in junctional structure disorders. Here we evaluated significance of analysis of these molecules in LNM prediction in early GC. Methods: The clinicopathological features and immunohistochemical expressions of E-cadherin, β-catenin, and c-erbB-2 in the primary lesion were studied in 28 patients (LNM +ve group: 14, LNM1 -ve group: 14) selected from 272 patients who underwent radical surgery for early GC between April 2000 to March 2004 at our hospital. All the patients consented to use of their stomach tissues for the clinical study afterwards. Statistical analysis was performed by t-test or χ2 test. Results: The clinicopathological features showed no significant differences between both groups. Loss of the membranous E-cadherin was noticed in 12 (85%) of the 14 LNM +ve patients, and in 8 (57%) of the 14 LNM -ve patients (p=0.209). This result was more remarkable in the intestinal type GC as the corresponding figures were 83% (5 of 6 ) and 16% (1 of 6) (p=0.083), respectively. Loss of the membranous β-catenin also showed a remarkable similar trend in the intestinal type GC, and the corresponding figures were 100% (6 of 6) and 50% (3 of 6) (p=0.182), respectively. Two patients showed over-expression of c-erbB2 and nuclear accumulation of β-catenin, and both had intestinal type GC with LNM. Conclusions: These results suggested that the same molecular signal pathway - as in vitro - including E-cadherin, β-catenin, and c-erbB2 induced LNM in early GC (intestinal type). We concluded that analysis of the expressions of these molecules is useful for not only LNM prediction but also determination of the therapeutic modality especially in intestinal type early GC. No significant financial relationships to disclose.

A new concept of melanocytic neoplasia pathogenesis based on the phenotype of common acquired nevi

Common melanocytic nevi are ubiquitous lesions which in some cases constitute a risk factor for the development of melanoma. To date, despite long term research there are no known molecular hallmarks for nevus development. We have observed that common acquired nevi excised from the same individual share remarkable similarity in their microscopic appearance and in the immunohistochemical expression of E-cadherin. Based on these observations, we hypothesize that all melanocytes are genetically similar in the same individual and changes predisposing to neoplasia are a global melanocytic event characteristic for each person and propose a microgenomics/proteomics approach to test this hypothesis.

Robinson Cytologic Grading in Invasive Ductal Carcinoma of the Breast

To correlate the cytologic grade of breast carcinoma with the expression of E-cadherin/catenin system molecules and the presence of metastasis in regional lymph nodes.Aspirate smears were examined together with histologic sections from the corresponding neoplasms taken from 100 patients with invasive ductal carcinoma. In 50 cases, > or = 1 metastatic nodes were identified. Cytologic grading of the smears was performed using the Robinson method. Immunohistochemical expression of E-cadherin and of alpha-, beta- and gamma-catenin was studied.A statistically significant relationship was observed between E-cadherin/catenin expression and cytologic grade (p < 0.0005). This association was particularly relevant to the cell dissociation parameter (p < 0.0005).The cytological grade established in preoperative studies may provide relevant information on the aggressiveness of invasive ductal carcinoma and its tendency to produce regional metastasis. This finding could be particularly useful in cases of breast carcinoma in which neoadjuvant therapy is the method of choice.

Decreased E-Cadherin but not β-Catenin Expression is Associated With Vascular Invasion and Decreased Survival in Head and Neck Squamous Carcinomas

We wished to correlate the expression of E-cadherin and beta-catenin in squamous carcinomas of the head and neck to outcome and other clinicopathologic variables. This retrospective study was carried out in a tertiary care setting. The tumors of 45 patients who had their head and neck squamous carcinoma primarily treated by resection were evaluated immunohistochemically with antibodies to E-cadherin and beta-catenin. Thirty-two tumors arose in the oral cavity, 9 tumors originated in the larynx, and 4 tumors began in the hypopharynx. Patient outcome and the clinicopathologic variables of tumor site, tumor stage, cervical lymph node status, tumor differentiation, perineural invasion, and vascular invasion were correlated to immunohistochemical expression of E-cadherin and beta-catenin. Low expression of E-cadherin in the tumors was significantly associated with decreased overall survival (P = 0.004), disease-free survival (P = 0.007), and vascular invasion (P = 0.02) but not with other clinicopathologic variables. beta-catenin expression was not significantly associated with any of the studied clinicopathologic variables. Decreased E-cadherin but not beta-catenin expression is associated with decreased survival in patients with head and neck squamous carcinomas. Detection of loss of E-cadherin expression may help predict which patients with head and neck squamous cell carcinoma will experience a worse outcome compared to patients whose tumors have not lost this tumor suppressor. C-4.

Importance of P-Cadherin, β-Catenin, and Wnt5a/Frizzled for Progression of Melanocytic Tumors and Prognosis in Cutaneous Melanoma

It has been proposed that melanoma cells shift from E-cadherin to N-cadherin expression during tumor development, and recent gene profiling has shown increased expression of Wnt5a/Frizzled in aggressive melanomas possibly by interactions with beta-catenin. We therefore wanted to investigate the role of cadherin subtypes, beta-catenin, and Wnt5a/Frizzled in melanocytic tumors, with focus on prognosis in nodular melanomas. The immunohistochemical expression of E-cadherin, N-cadherin, P-cadherin, beta-catenin, and Wnt5a/Frizzled was examined using tissue microarrays of 312 melanocytic tumors. Cytoplasmic expression of P-cadherin was associated with increasing tumor thickness (P=0.005) and level of invasion (P=0.019), whereas membranous staining was associated with thinner (P=0.012) and more superficial (P=0.018) tumors. Increased cytoplasmic P-cadherin was associated with reduced survival (P=0.047). Lack of nuclear beta-catenin expression was related to increased tumor thickness (P=0.002) and poor patient survival in univariate (P=0.0072) and multivariate (P=0.004) analyses. Membranous expression of N-cadherin was significantly increased from primary tumors to metastatic lesions, whereas E-cadherin staining tended to be decreased. Wnt5a and its receptor Frizzled were highly coexpressed, and nuclear expression of both markers was significantly reduced from benign nevi to melanomas, with a shift from nuclear to cytoplasmic expression in malignant tumors. In addition, Wnt5a expression was significantly associated with nuclear beta-catenin expression. Alterations in the expression and subcellular localization of cell adhesion markers are important in the development and progression of melanocytic tumors, and strong cytoplasmic P-cadherin expression and loss of nuclear beta-catenin staining were associated with aggressive melanoma behavior and reduced patient survival.

E-cadherin and β-catenin expression in early stage cervical carcinoma: a tissue microarray study of 147 cases

BackgroundThe disruption of intercellular adhesions is an important component of the acquisition of invasive properties in epithelial malignancies. Alterations in the cell-cell adhesion complex, E-Cadherin/β-Catenin, have been implicated in the oncogenesis of carcinomas arising from various anatomic sites and have been correlated with adverse clinico-pathologic parameters. In this study, the authors investigated the immunohistochemical expression of E-Cadherin and β-Catenin in a cohort of early stage cervical cancers to determine its prognostic significance and to investigate differences between the three major histological subtypes.Patients and methodsA tissue microarray of 147 cases of FIGO stage 1A and 1B cervical carcinomas [96 squamous cell carcinomas (SCC), 35 adenocarcinomas (AC), 12 adenosquamous carcinomas (ASQ), 4 miscellaneous types] was constructed from our archived surgical pathology files and stained with monoclonal antibodies to E-Cadherin and β-Catenin. Cases were scored by multiplying the intensity of staining (1 to 3 scale) by the percentage of cells stained (0–100%) for a potential maximum score of 300. For both markers, "preserved" expression was defined as bright membranous staining with a score of 200 or above. "Impaired" expression included any of the following: negative staining, a score less than 200, or exclusively cytoplasmic or nuclear delocalization.ResultsImpaired expression of β-Catenin was found in 85.7%, 66.7%, & 58.3% of AC, SCC & ASQ respectively. Impaired expression of E-Cadherin was found in 94.3%, 86.5% & 100% of cases of AC, SCC, & ASQ respectively. The differences between the histologic subtypes were not significant. For the whole cohort, a comparsion of cases showing impaired versus preserved of E-Cadherin and β-Catenin expression showed no significant differences with respect to recurrence free survival, overall survival, patient age, histologic grade, and frequency of lymphovascular invasion or lymph node involvement. There was no correlation between the status of both markers for all three histological subtypes (overall spearman correlation co-efficient r = 0.12, p = 0.14)ConclusionImpairment of E-Cadherin and β-Catenin expression is very frequent in early stage cervical cancers, and alterations in the E-Cadherin/β-Catenin cell adhesion complex are therefore likely involved in the pathogenesis of cervical carcinomas even at their earliest stages. None of the three major histological subtypes of cervical carcinoma (SCC, ADCA, ADSQ) is significantly more likely than the others to show impairment in E-Cadherin and β-Catenin expression. Overall, the expression of both markers does not significantly correlate with clinico-pathological parameters of prognostic significance.

Evaluation of Tumor Cell Dissociation as a Predictive Marker of Lymph Node Metastasis in Submucosal Invasive Colorectal Carcinoma

Tumor cell dissociation-the histologic finding of small solid carcinoma cell clusters and groups of dissociated dedifferentiated carcinoma cells at the invasive front-is related to tumor metastasis and patient prognosis. However, few previous reports have examined tumor cell dissociation in submucosal invasive colorectal carcinoma. We investigated the relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. We also examined immunohistochemical expression of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma. Submucosal invasive colorectal carcinoma tissue samples from 20 patients with lymph node metastasis and 100 patients without lymph node metastasis were evaluated. Sections stained with hematoxylin and eosin were evaluated for tumor cell dissociation. Immunohistochemistry was used to determine the expression and cellular distribution of E-cadherin and beta-catenin. Tumor cell dissociation was more frequently identified in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.0001). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with lymph node metastasis than in those without lymph node metastasis (P = 0.025). Nuclear expression of beta-catenin tended to be present in submucosal invasive colorectal carcinoma cases with lymph node metastasis (P = 0.063). Decreased membranous expression of E-cadherin occurred more frequently in submucosal invasive colorectal carcinoma cases with tumor cell dissociation than in those without tumor cell dissociation (P = 0.0023). Our results suggest that there is a relation between tumor cell dissociation and lymph node metastasis in submucosal invasive colorectal carcinoma. Tumor cell dissociation formation might be related to abnormal expression patterns of E-cadherin and beta-catenin in submucosal invasive colorectal carcinoma. Tumor cell dissociation and decreased membranous expression of E-cadherin would be important predictive markers for lymph node metastasis in submucosal invasive colorectal carcinoma.

Elevated expression of E-cadherin and α-, β-, and γ-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas

E-cadherin and catenins play key roles in cell adhesion and motility. Little is known about the changes in expression of these molecules in the progression of ovarian carcinomas. In the present study, the immunohistochemical expression of E-cadherin and α-, β-, and γ-catenins was examined in 77 cases of ovarian carcinoma. In addition, the expression of these molecules was evaluated in 26 matched pairs of primary and metastatic lesions of advanced ovarian carcinomas. Of the 77 primary lesions, positive staining for E-cadherin and α-, β-, and γ-catenin was observed in 75 (97%), 63 (82%), 71 (92%) and 57 (74%) cases, respectively. Positivity for E-cadherin and α-, β-, and γ-catenin was significantly decreased in stage III and IV tumors compared with stage I and II tumors, suggesting that expression of the cadherin-catenin complex is reduced with the advancing stages of a tumor. Interestingly, expression of E-cadherin and α-, β-, and γ-catenin in the lesions of peritoneal dissemination was significantly increased compared with the primary lesions. These findings suggest that expression of the cadherin-catenin complex changes markedly and that reexpression may occur during the peritoneal dissemination of ovarian carcinoma cells.

Relation of E-cadherin and β-catenin expression to pit pattern in colorectal cancer

To investigate the usefulness of pit pattern to estimate depth of submucosal invasion and the mechanism of change in pit pattern by tumor character in colorectal cancer, we investigated the relation between pit pattern and immuno-histochemical E-cadherin and beta-catenin expression. Fifty-seven colorectal tumors including 37 submucosal invasive carcinomas, 10 high-grade adenomas and 10 cases of advanced carcinomas invading into the muscularis propria were divided into a non-VN and VN group according to a modification of the Kudo classification system. In addition, distance between the invasive front and muscularis mucosae was measured, and histological and immunohistochemical expression of E-cadherin and beta-catenin in the superficial portion and invasive portion were examined. Many tumors with deep invasion were classified in the VN group. Among the submucosal invasive carcinomas in the VN group, there was a significantly higher number with deep invasion than with slight invasion. All submucosal invasive cancers with lymphatic invasion also had deep submucosal invasion. Immunohistochemical analysis revealed significant loss of normal membrano-cytoplasmic beta-catenin expression in the superficial area of cancers in the VN group. Submucosal carcinoma with deep invasion also had significant loss of membrano-cytoplasmic expression of beta-catenin in the superficial area. Pit pattern is useful not only to predict tumor character but also to estimate depth of invasion. Change in pit pattern may be associated with abnormality of beta-catenin expression.

E-cadherin expression in canine mammary carcinomas with regional lymph node metastases.

E-cadherin (E-cad) is a cell adhesion molecule known for its tumour invasion-suppressor function. This study investigated the immunohistochemical expression of E-cadherin in 19 cases of malignant mammary tumours of the dog and the relationship between E-cadherin expression in primary tumours and in regional lymph node metastases. E-cadherin expression is not always parallel in the primary tumour and in the lymph node metastasis. One year follow-up was available in 12 of 19 cases. Three different patterns of expression were revealed in the lymph node metastases compared with the primary tumour: downregulation when the protein expression was weaker in the metastasis than in the primary tumour; upregulation when E-cadherin was stronger in the lymph node than in the primary tumour, and a similarly intense expression when it was equal in the metastasis and in the tumour. The lymph node pattern revealed a prevalent upregulation or downregulation with respect to the primary tumour, whereas a similar expression of E-cadherin was encountered in less than 50% of cases.

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, α-catenin and β-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, α-catenin and β-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, α-catenin and β-catenin is extremely valuable for the diagnosis of metastatic occurrence.

Mature adipocytes, but not preadipocytes, promote the growth of breast carcinoma cells in collagen gel matrix culture through cancer-stromal cell interactions.

Interaction between cancer and stromal cells is critical for tumour cell growth and invasion. It has recently been suggested that mature adipocytes, a specific type of stromal cell that is abundant in the breast, affect the biological behaviour of some epithelial cell types. However, the nature of the interaction between mature adipocytes and breast cancer cells remains unclear. The present study has examined the effects of mature rat adipocytes, as the main cell type in adipose tissue, on the growth, apoptosis, and cell adhesion of breast carcinoma cell lines [human oestrogen receptor (ER)-positive cell lines MCF-7, ZR75-1, and T47-D; and the ER-negative mouse cell line MMT 060562] by analysing bromodeoxyuridine (BrdU) uptake, apoptotic indices, and immunohistochemical expression of E-cadherin. As a reference, the effects of rat preadipocytes (immature adipocytes) on the behaviour of the cell lines were examined. The cell lines were cultured in a three-dimensional collagen gel matrix with mature adipocytes or preadipocytes. Mature adipocytes significantly promoted BrdU uptake by all cell lines other than MMT 060562 cells. Preadipocytes decreased the uptake of T47-D cells and had no effect on that of MCF-7, ZR75-1 or MMT 060562 cells. Mature adipocytes or preadipocytes did not affect the apoptotic indices of any of the cell lines. Mature adipocytes did not influence E-cadherin expression in any of the cell lines, but preadipocytes clearly promoted E-cadherin expression by MCF-7 and T47-D cells, but not by R75-1 and MMT 060562 cells. These data suggest that mature adipocytes may be involved in the mechanisms regulating the growth of breast cancer mass through their growth-promoting effect on ER-positive tumour cells.

Immunohistochemical expression of E-cadherin in metastatic brain tumors.

The adhesion molecule E-cadherin has been shown to influence malignant transformation of tumors, including local and distant metastases. We examined the expression of E-cadherin to determine its relationship to the development of metastasis in metastatic brain tumors. Immunohistochemistry for E-cadherin and Ki-67 was carried out in 76 formalin-fixed, paraffin-embedded archival specimens of metastatic brain tumors and in 14 corresponding available primary tumors from patients who received treatment for metastatic brain tumors. The primary tumors were mainly lung cancers (51.3%), followed by gastrointestinal tumors (28.9%). E-cadherin was expressed in 62 (81.5%) of 76 cases examined. In metastatic adenocarcinomas, a consistent tendency for E-cadherin expression was noted, regardless of the degree of differentiation or the extent of spread of the disease (P = 0.04). There was a direct correlation between E-cadherin expression and high MIB-1 index in all metastatic brain tumors (P = 0.0007). Pairwise analysis in 14 primary tumors and the corresponding metastatic specimens revealed high E-cadherin and MIB-1 staining in metastatic brain tumors. These results provide a unique association between E-cadherin, systemic metastasis, and proliferation potential in metastatic brain tumors.

Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis

Various types of cell adhesion molecules and matrix metalloproteinases (MMPs) seem to play an important role in the invasion process of endometriosis; however, limited investigation has focused on their gene expression in human peritoneal endometriotic lesions. A total of 63 endometriotic tissues were surgically obtained from 35 women with endometriosis, which included 43 pigmented and 20 non-pigmented lesions. Gene expression levels of E-cadherin, α- and β-catenin, MMP-2, MMP-9 and membrane-type 1 (MT1)-MMP in these endometriotic lesions were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. MMP-2, MMP-9 and MT1-MMP mRNA expression in pigmented lesions was significantly higher than that in normal endometrium (p < 0.05), whereas E-cadherin, α- and β-catenin mRNA expression was not suppressed in endometriotic lesions. There was a close correlation between MMP-2 or MT1-MMP and E-cadherin, α- or β-catenin gene expression in 63 endometriotic tissues examined (p < 0.01). Immunohistochemical expression of E-cadherin, α- and β-catenin in glandular epithelial cells was positive not only for all of seven cases with normal eutopic endometrium but also for 9 of 11 with ovarian endometriosis. MMP expression in ectopic endometrium was much greater than that in eutopic endometrium. These results suggest that endometriotic tissues expressing MMPs might be invasive and simultaneously possess cell-to-cell adhesion property in pelvic peritoneal foci.

Gene expression of adhesion molecules and matrix metalloproteinases in endometriosis

Various types of cell adhesion molecules and matrix metalloproteinases (MMPs) seem to play an important role in the invasion process of endometriosis; however, limited investigation has focused on theirgene expression in human peritoneal endometriotic lesions. A total of 63 endometriotic tissues were surgically obtained from 35 women with endometriosis, which included 43 pigmented and 20 non-pigmentedlesions. Gene expression levels of E-cadherin, α- and β-catenin, MMP-2, MMP-9 and membrane-type 1 (MT1)-MMP in these endometriotic lesions were compared with those in normal eutopic endometriumobtained from 12 women without endometriosis. MMP-2, MMP-9 and MT1-MMP mRNA expression in pigmented lesions was significantly higher than that in normal endometrium (p < 0.05), whereas E-cadherin,α- and β-catenin mRNA expression was not suppressed in endometriotic lesions. There was a close correlation between MMP-2 or MT1-MMP and E-cadherin, α- or β-catenin gene expressionin 63 endometriotic tissues examined (p < 0.01). Immunohistochemical expression of E-cadherin, α- and β-catenin in glandular epithelial cells was positive not only for all of sevencases with normal eutopic endometrium but also for 9 of 11 with ovarian endometriosis. MMP expression in ectopic endometrium was much greater than that in eutopic endometrium. These results suggest thatendometriotic tissues expressing MMPs might be invasive and simultaneously possess cell-to-cell adhesion property in pelvic peritoneal foci.

Expression of E-Cadherin and α-, β-, γ-Catenin Proteins in Endometrial Carcinoma

Loss of the cell adhesion molecule E-cadherin is suggested to promote tumor invasion and distant metastasis in tumor development. Recently, it has been proposed that E-cadherin function requires its linkage to the cytoskeleton through catenins. We evaluated the expression of E-cadherin and alpha-, beta-, gamma-catenins in tissues of human endometrial carcinoma, analyzed the patterns of cell adhesion molecules' expression in endometrial carcinoma and investigated the relationship between the statuses of cell adhesion molecules and various clinicopathological factors. This study investigated the immunohistochemical expression of E-cadherin and alpha-, beta-, gamma-catenins in 33 paraffin embedded formalin fixed tissues of endometrial carcinomas. Aberrant E-cadherin, and alpha-, beta-, gamma-catenin expression was observed in 33.3 (11 of 33), 27.3 (9 of 33), 18.2 (6 of 33), and 51.5 (17 of 33) % of the specimens, respectively. Statistically significant correlation was found between aberrant expression of E-cadherin and lymph node metastasis and cell types other than endometrioid adenocarcinoma. Aberrant pattern of gamma-catenin expression was also correlated with deep myometrial invasion. However, alpha-, and beta-catenin expression was not correlated with any clinicopathological parameters. Using the Kaplan-Meier method and log-rank comparison test, abnormal expression of E-cadherin was correlated closely with poor survival (p < 0.05), but cases with loss of both E-cadherin and catenin expression predicted even poorer survival than cases with only one or no aberrant expression in E-cadherin and catenins. We revealed aberrant expression of these cell adhesion molecules among patients with endometrial carcinoma. Aberrant expression of E-cadherin was correlated with lymph node metastasis and cell types other than endometrioid adenocarcinoma, while aberrant expression of gamma-catenin was related with deep myometrial invasion. The expression of E-cadherin might be a possible prognostic factor for endometrial cancer while the expression of catenins may help predict patient's survival.

Immunohistochemical analysis of candidate gene product expression in the duodenal epithelium of children with coeliac sprue.

Coeliac sprue is a chronic disease, in which there is a characteristic mucosal lesion of the small intestine and impaired nutrient absorption, which improves upon the withdrawal of wheat gliadins and related grain proteins from the diet. Biopsy specimens demonstrate diffuse enteritis with pronounced atrophy or total loss of villi. There is also a long term risk of malignant disease. To compare the immunoexpression of DCC (deleted in colon cancer), p53, E-cadherin, and beta-catenin in the duodenal mucosa of children with coeliac disease with that seen in children with no evidence of small intestinal disease. To gain more insight into the genetic and immunohistochemical alterations of the duodenal epithelium in coeliac disease, 21 endoscopic biopsies from children with coeliac disease and 10 duodenal biopsies from children without coeliac disease were immunohistochemically evaluated for p53, DCC, E-cadherin, and beta-catenin. DCC expression was not reduced in patients with coeliac disease compared with those without coeliac disease. p53 positive nuclear immunostaining was seen in seven of the 21 patients with coeliac disease. Positive nuclear staining was seen mainly in the deep and the lateral aspects of the crypts. All patients in the control group were negative for p53. In nine and three of the 21 patients with coeliac disease, respectively, the immunohistochemical expression of E-cadherin and beta-catenin was reduced. However, both E-cadherin and beta-catenin immunostaining in the control group was not altered. E-cadherin and beta-catenin were reduced in the duodenal epithelium of children with coeliac disease when compared with normal mucosa. p53 was overexpressed in the duodenal mucosa of patients with coeliac disease. The reduced expression of E-cadherin and beta-catenin and p53 overexpression may contribute to the morphological changes seen in the small intestinal mucosa in coeliac disease.

Co-expression of N-cadherin and alpha-fetoprotein in stomach cancer.

Although N-cadherin is necessary for organ formation originating in the endoderm, the expression of N-cadherin in gastric carcinoma and its role has not yet been reported. The present study was conducted to determine the pattern of immunohistochemical expression of E-cadherin and N-cadherin, using formalin-fixed, paraffin-embedded tissues from 97 primary gastric carcinomas, including 17 which were producing alpha-fetoprotein (AFP). Samples were subdivided into 50 tubular adenocarcinomas and 47 poorly differentiated adenocarcinomas. Results showed that E-cadherin was expressed in varying degrees in areas of cell adhesion between tumor cells, in 94 out of 97 cases studied. Three cases which showed no expression of E-cadherin were diagnosed as AFP-producing tumors by immunohistochemistry. Expression of N-cadherin was observed in varying degrees in the intercellular spaces between tumor cells in 11 tubular adenocarcinomas and in six poorly differentiated adenocarcinomas, including E-cadherin-negative cases, all of which were AFP positive. The present findings suggest a possible role for N-cadherin in gastric carcinoma.

E-cadherin gene mutations in human intrahepatic cholangiocarcinoma.

Deletions or mutations of the E-cadherin gene may result in reduced cell adhesiveness. In particular, conservative point mutations within the N-terminal calcium-binding pocket (including exons 7, 8, and 9) are frequently detected in several cancers and are enough to abolish cell-cell adhesion. There have been no studies on E-cadherin gene mutations in human intrahepatic cholangiocarcinoma (ICC). Human ICCs were therefore investigated for E-cadherin gene mutations within exons 7, 8, and 9. In addition, the relationships were analysed between their mutations and the immunohistochemical expression of E-cadherin, histological grade, and clinicopathological parameters. The E-cadherin gene was analysed in 34 tumours by nested polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) followed by DNA sequencing. In four of the 34 cases (11.8%), tumour-restricted mobility shifts were observed; two cases harboured a single shift, one case presented two different mobility shifts, and one case presented three different mobility shifts within exons 7 and 8, encoding extracellular domains of E-cadherin. Polymorphism as previously reported was not identified and all seven new DNA alterations were not present in genomic DNA of non-tumour origin. The E-cadherin gene mutations correlated significantly with down-regulated E-cadherin protein expression and high ICC histological grade. These data suggest that E-cadherin gene mutations in ICC are associated with reduced cell adhesiveness and high histological grade.

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.