Reduced E-cadherin expression correlates with increased invasiveness in colorectal carcinoma cell lines

A reduction in cell adhesiveness and cell invasion are essential steps in tumour progression to metastasis. In the present study two out of seven colorectal carcinoma cell lines exhibited reduced expression of the cell-cell adhesion molecule E-cadherin as assessed by immunofluorescence. The same two cell lines were invasive in the collagen gel and membrane invasion culture system invasion assays. Addition of anti-E-cadherin antibody to a non-invasive carcinoma cell line caused the cells to assume a dissociated morphology on plastic and to become invasive in collagen gels. This demonstrates a causal role for E-cadherin in the maintenance of intercellular adhesion and the suppression of tumour cell invasion and possibly metastasis in colorectal tumour cells.     

CDH1 gene mutation in early-onset,colorectal signet-ring cell carcinoma

AimColorectal signet-ring cell carcinomas (SRCC) are highly malignant tumours with poor prognosis that disproportionately affect younger patients. There is growing evidence of a unique set of molecular features that separate SRCC from conventional colorectal adenocarcinoma. Identification of these distinct features may have diagnostic and prognostic significance for patients and families. CDH1, which encodes E-cadherin, a cell adhesion protein, is commonly mutated in gastric SRCC and our study aimed to identify whether CDH1 mutation was also a common phenomenon in colorectal SRCC.MethodsDNA was extracted from formalin-fixed paraffin embedded tumour tissue, the CDH1 gene was analysed by next generation sequencing and the pathogenicity of mutations assessed in silico. Sections cut from the same blocks were immunostained to identify the presence of the E-cadherin protein.ResultsWe found 8 CDH1 mutations that meet our inclusion criteria in seven of 11 samples. Of these, five (from four patients), were likely to be germline mutations. E-cadherin staining was absent or markedly reduced in all of the seven samples with CDH1 mutation.ConclusionOur finding of CDH1 mutations in a proportion of signet-ring cell carcinomas and associated reduction in E-cadherin in these tumours supports previous findings of a role for mutation of this gene in the development of this disease. In addition, the finding of likely germline mutations suggests that a subset of these tumours may be familial. Loss of E-cadherin staining in the absence of CDH1 mutations however also suggests a role for environmental factors in a subset of these tumours.     

Primary colorectal signet-ring cell carcinoma in young patients: report of 3 cases

Three cases of primary signet-ring cell carcinoma of the rectum are described. They accounted for 0.2% of the 1531 cases of colorectal adenocarcinoma in the 12 yr period from 1972-1983 in the University Department of Pathology at Queen Mary Hospital. The patients were young, aged 18, 24 and 27 yr respectively, in striking contrast to the mean age of 62 in patients with the usual types of colorectal cancer. They were also younger than most patients with this tumour in the literature. They presented with alteration of bowel habit, blood and mucus in stool, and weight loss. Pathological features included constrictive narrowing of the gut lumen by intestinal wall thickened by a desmoplastic reaction to diffusely infiltrating signet-ring carcinoma cells, widespread lymph node and peritoneal metastases, and absent hepatic metastasis. Microscopically, the mucosa was largely intact, but had multifocal tumour involvement. This peculiar feature was responsible for three consecutive negative biopsies in one case. Care in distinguishing it from mucinous adenocarcinoma is emphasized. All three patients presented with Dukes' C lesions. The prognosis is poor.     

Nuclear beta-catenin expression is rare and its potential association with short survival in colorectal signet-ring cell carcinoma.

Colorectal signet-ring cell carcinoma (SRCC) is a rare cancer and the prognosis is usually very poor. The biologic pathways involved in its oncogenesis are unknown. beta-catenin, a key target in the Wnt-signaling pathway, is recognized to play an important role in the carcinogenesis in conventional colorectal carcinoma. This study explores the involvement of Wnt-signaling molecules beta-catenin and cyclin D1, cell cycle regulators cyclin D3, proliferative index Ki-67, apoptotic index, and angiogenic indicator CD31 in 20 colorectal SRCC paraffin-embedded specimens. Results showed that there were 2 specimens with nuclear beta-catenin and higher expression of cyclin D1 than the remaining 18 specimens. Surprisingly, those 2 patients had a much shorter survival of 6 months than the remaining 15 patients, who had around 24 months. Moreover, all colorectal SRCC specimens had an overexpression of cyclin D1, cyclin D3, and Ki-67, as well as much more angiogenesis and apoptosis than adjacent normal epithelial tissues. The authors make the preliminary comment that nuclear beta-catenin is a rare phenomenon in colorectal SRCC, but the involvement of it may indicate a worse prognosis with shorter survival than colorectal SRCC without nuclear beta-catenin expression. Besides, overexpression of cyclin D1, cyclin D3, Ki-67, and increased angiogenesis and apoptosis may play a vital role in promoting colorectal SRCC development.     

Nuclear localization of E-cadherin expression in Merkel cell carcinoma

CONTEXT: Cadherins are cell-cell adhesion proteins that act as tumor suppressor genes and have a critical role in cell sorting and tissue formation during organogenesis. The pattern of cadherin expression constitutes a useful diagnostic and prognostic tool in the evaluation of tumors and for determining the histogenesis of tumor cells. We have previously characterized the cell types of several tumors based on the expression of individual cadherins. OBJECTIVE: To investigate the expression of cadherins in Merkel cell carcinomas. DESIGN: Paraffin immunohistochemical analysis of the 3 best-studied cadherins was performed on 35 cases of Merkel cell carcinoma. RESULTS: E-cadherin was expressed in 34 (97%) of 35 Merkel cell carcinomas examined, N-cadherin was expressed in 22 (63%) of 35 cases, and P-cadherin was expressed in 15 (43%) of 35 cases. This frequency of cadherin expression was similar to a group of small cell and neuroendocrine tumors from other primary sites. Interestingly, the localization of E-cadherin expression was unique in Merkel cell carcinomas compared with other primary neuroendocrine tumors. Merkel cell carcinomas showed marked preference for nuclear versus membrane localization, whereas small cell tumors from other sites showed fewer cases of nuclear E-cadherin expression. The nuclear localization of E-cadherin did not correlate with cadherin-associated protein beta-catenin nuclear expression. CONCLUSIONS: Our findings show that E-cadherin is the most frequently expressed cadherin in Merkel cell carcinoma, followed in frequency by N-cadherin then P-cadherin. The pattern of nuclear E-cadherin expression is more frequent for Merkel cell carcinoma than small cell tumors of other primary sites. These observations suggest that E-cadherin expression and function are altered in Merkel cell carcinoma, and this finding has potential use in the differential diagnosis of these tumors.     

Characterization of the E-cadherin/catenin complex in colorectal carcinoma cell lines

The E-cadherin/catenin complex is a prime mediator of cell-cell adhesion. APC mutations can result in loss of beta-catenin downregulation and an accumulation of beta-catenin in the cell. Beta-CATENIN mutations can have a similar effect. The aim of this study was to investigate the effect of beta-CATENIN and APC mutations on the expression and assembly of the E-cadherin/catenin complex. Five colorectal carcinoma cell lines with different APC and beta-CATENIN gene status were selected and mutations were confirmed. The expression of members of the E-cadherin/catenin complex was studied by immunohistochemistry and Western blotting. Complex assembly was investigated by immunoprecipitation. It is shown that E-cadherin and catenins are expressed in colorectal carcinoma cell lines with the predominant complex assembly being E-cadherin/beta-catenin/alpha-catenin. The subcellular distribution of the proteins is influenced by cell-cell contact, resulting in membranous localization. The expression and assembly of the E-cadherin/catenin complex does not appear to be affected by the presence of APC and or beta-CATENIN mutations.     

Primary signet-ring cell carcinoma of the prostate

The occurrence of signet-ring cells within a mucinous prostatic carcinoma is an extremely rare finding. This cancer is characterized by both intracellular retention and extracellular secretion of mucinous material. We report a case of primary signet-ring cell carcinoma of the prostate that was confirmed by autopsy. The results of gross, microscopic, and immunohistochemical examinations are described.     

Loss of E-cadherin expression predicts disease recurrence and shorter survival in colorectal carcinoma

The traditional staging system is currently inadequate for identifying those patients with colorectal carcinoma (CRC) who carry a high risk for poor outcome. In this study, the expression of E-cadherin was evaluated in CRC to determine its correlation with clinico-pathological variables, and association with disease outcome in patients with long-term follow-up. The present series consisted of tissue samples obtained from 230 patients with stage I, II, III, or IV CRC treated during 1981-1990 at Turku University Hospital. Archival paraffin-embedded samples were used to build up tissue microarray blocks, and E-cadherin expression was assessed by immunohistochemistry using an automated staining system. Different grading systems were tested for expression of E-cadherin. Fifty-nine percent of all tumors were positive for E-Cadherin. There was no significant correlation between E-cadherin expression and gender (p < 0.83), localization (p < 0.45), tumor invasion (p < 0.32), or histologic grade (p < 0.41). However, loss of E-cadherin expression was significantly associated with older age (p < 0.03) and lymph node involvement (p < 0.02), and with borderline significance with advanced stage (p < 0.09) and tumor metastasis (p < 0.09). In univariate (Kaplan-Meier) survival analysis, positive E-cadherin significantly (p = 0.009) predicted longer disease-free survival (DFS), and the same was true with disease-specific survival (DSS) as well (p = 0.007). In multivariate (Cox) survival analysis, E-cadherin retained its significance as independent predictor of DFS (HR = 1.56; 95% CI 1.01-2.42, p = 0.043), but not DSS. A sub-group analysis revealed that E-cadherin expression also predicts DFS (p < 0.01) and DSS (p < 0.04) in stage II CRC. Our results implicate the usefulness of E-cadherin expression in predicting disease recurrence and long-term survival in CRC.     

乳腺原发性印戒细胞癌

目的：观察乳腺原发性印戒细胞癌的形态特征。方法：通过HE及AB/PAS染色,对4例乳腺原发性印戒细胞癌进行观察。结果：4例癌细胞内印戒细胞均超过205。HE染色呈典型印戒样细胞,AB/PAS染色胞质内阳性。导管内型及小叶型各1例,浸润性导管型及小叶型各1例。结论：乳腺原发性印戒细胞癌是一种特殊型癌,诊断时应排除转移性印戒细胞癌。     

E-cadherin expression in invasive urothelial carcinoma

E-cadherin (E-CD) is a transmembrane glycoprotein involved in intercellular adhesion. A loss or reduction in E-CD expression has been linked to the invasive phenotype of a wide variety of human neoplasms, including bladder tumors. The objective of this study was to compare the E-CD expression at different depths of tumor invasion below the bladder's basement membrane in high- and low-grade urothelial carcinomas to investigate whether deeper tumor invasion and higher-grade invasive urothelial carcinomas are associated with decreased E-CD expression. E-cadherin staining was performed on 29 formalin-fixed, paraffin-embedded sections from high- and low-grade urothelial carcinoma specimens using an automatic immunohistochemical stainer. The sections were divided into three categories according to the depth of invasion below the basement membrane: upper, middle, and lower. The percentage and intensity of E-CD cell membrane staining for the three categories were calculated using a quantitative automated cellular imaging system. The percentage of cells that stained for E-CD was 82.6% +/- 1.4% (mean +/- SD) in the upper layer, 59.6% +/- 2.2% in the middle layer, and 29.4% +/- 2.7% in the lower layer. The intensity of E-CD expression was 64.7 +/- 3.2 units in the upper layer, 43.3 +/- 2.9 units in the middle layer, and 26.1 +/- 3.1 units in the lower layer. There were significant differences between the three layers in both the percentage and intensity of cellular E-CD staining (P<.05). Normal urothelium, high-grade urothelial dysplasia/carcinoma in situ, and superficial noninvasive papillary urothelial carcinoma maintained E-CD expression. However, once malignant cells infiltrated through the basement membrane, E-CD expression decreased. The more poorly differentiated urothelial carcinoma, the deeper the nests, and the smaller the clusters of neoplastic cells within the tumor were, and the more decrease in E-CD expression noted. The degree of decreased E-CD expression was directly proportional to the degree of tumor differentiation and depth of infiltration in invasive urothelial carcinoma. Down-regulation of E-CD may be one of the pathways responsible for tumor differentiation and may promote deeper invasion in urothelial carcinomas.     

Exophytic signet-ring cell carcinoma of the colorectum.

Previous studies have assessed colorectal signet-ring cell carcinomas of the linitis plastica variant but not of the exophytic subtype. We retrospectively reviewed 20 cases of colorectal signet-ring cell carcinoma of the exophytic subtype (greater than 50% signet-ring cells). The patients ranged in age from 14 to 79 years (mean, 51.8 years); 10 were male; 17 were white; and three were black. Ten tumors were colonic (eight, right sided; two, left sided) and 10 were rectal; seven were stage B and 12 were stage C. One patient presented with distant metastases. Eleven of 16 tumors assessed by flow cytometry were diploid. Parenchymal hepatic metastases developed in only two patients. The overall 5-year survival rate was 36%, and matched cases did not vary significantly in survival from typical nonmucinous adenocarcinomas. There was a trend toward poorer survival for patients with advanced-stage tumor. Survival was not affected by primary site, ploidy, presence of vascular/lymphatic invasion or residual adenoma, or percentage of extracellular mucin or signet-ring cells. Our cases were somewhat lower stage than literature cases of signet-ring cell carcinoma of the lintis plastica variant.     

Primary signet-ring cell carcinoma of the urinary bladder

An unusual case of the signet-ring cell carcinoma of the bladder was reported. A 62-year-old Japanese male had a three-month history of intermittent, painless and gross hematuria. He was found to have a small egg-sized bladder tumor near the right ureteral orifice. A cytologic diagnosis of signet-ring cell carcinoma was made on a bladder washing and was confirmed by cytoscopic biopsy and surgical specimens.     

Primary signet-ring cell carcinoma of the urinary bladder

Signet-ring cell carcinoma of the urinary bladder is a rare tumour, accounting for approximately 0.24% of all bladder malignancies. In this study, the clinicopathological findings in 13 cases are described. This malignancy is far more common in men than in women (ratio 11:2). The distribution by age and clinical symptoms can not distinguish it from transitional cell carcinoma. The tumour behaves like other high grade malignancies, presenting frequently at an advanced stage, and having an unfavourable clinical outcome. No special therapy seems superior to another.     

E-cadherin expression in urothelial carcinoma in situ,superficial papillary transitional cell carcinoma,and invasive transitional cell carcinoma

Flat urothelial carcinoma in situ (CIS) is a precursor of invasive transitional cell carcinoma (TCC). High-grade TCCs frequently are accompanied by CIS in surrounding urothelium. In contrast, superficial, noninvasive papillary TCCs are often low grade and generally are unaccompanied by CIS. E-cadherin (E-CD) is a member of a family of transmembrane glycoproteins involved in intercellular adhesion. Loss or decreased expression of E-CD has been linked to the invasive phenotype of a wide variety of human neoplasms, including bladder tumors. The objective of this study was to compare the expression of E-CD in high-grade urothelial dysplasia (HD)/CIS, superficial papillary TCC, benign urothelium, and invasive TCC. Staining for E-CD was performed in formalin-fixed, paraffin-embedded sections using a Ventana NexES immunostainer (Tuscon, AZ). Percentage and intensity of cell membrane staining for E-CD was calculated for the 4 groups using the quantitative Automatic Cellular Imaging System (ChromaVision, San Juan Capistrano, CA). The results were as follows: The CIS group (n = 23) had percentage and intensity (92.8%, 120.0 U) of E-CD expression similar to the superficial noninvasive papillary TCC group (n = 16, 97.8%, 123.0 U) and the benign urothelium group (n = 17, 87.9%, 104.6 U), but it had statistically significant higher percentage and intensity than the invasive TCC group (n = 15, 45.4%, and 39.2 U, P <.05). Our data indicate that CIS and superficial, noninvasive papillary TCCs strongly express E-CD. In contrast, loss of E-CD expression is associated with the invasive TCC phenotype. Only when TCCs become invasive does E-CD expression decrease in directly proportion to the depth of invasion.