Analysis of the E-cadherin repressor Snail in primary human cancers

Epithelial-mesenchymal transition (EMT), a normal developmental process, is known to play a crucial role in tumor progression. Molecules involved in this process, such as the E-cadherin repressor Snail, facilitate migration and invasion of carcinoma cells. A growing number of studies addressing the expression of Snail in clinical samples have been reported and are discussed in this review. A total of 2,112 cases from 9 different tumor types were evaluated. So far, a clear picture has emerged only in some cancer types analyzed with regard to overexpression of Snail and clinical-pathological parameters. Currently, it seems that Snail may play a role in hormone-dependent carcinomas but may be of minor importance in gastrointestinal cancers for tumor dedifferentiation and the maintenance of the invasive phenotype. It should be kept in mind, however, that the threshold for Snail activity does not have to be the same in every tumor type analyzed. The recent introduction of well-characterized novel monoclonal antibodies reacting with the short-lived nuclear Snail protein may help to establish a potential clinical usefulness for this master molecule of EMT, at least for certain types of cancer.     

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.     

转录因子Snail及黏附分子E-cadherin在胃癌中的表达及意义

目的探讨转录因子Snail及黏附分子E—cadherin在胃癌中的表达及意义。方法采用免疫组化sP法检测96例胃癌组织和80例癌旁组织中Snail、E—cadherin的表达,分析两者在不同组织类型与分化程度胃癌中的表达,以及与临床病理因素之间的关系。结果胃癌组织E—cadherin的阳性率（37．5％）显著低于癌旁组织（100％）（P〈0．05）,E—cadherin的表达与胃癌不同分化程度、组织学类型、浸润深度、淋巴结转移、临床分期及远处转移有关（P〈0．05）。胃癌组织Snail阳性率（83．3％）显著高于癌旁组织（41．25％）（P〈0．05）,Snail的表达与胃癌不同分化程度、组织学类型、浸润深度、淋巴结转移及远处转移有关（P〈0．05）。胃癌组织中E—cadherin与Snail的表达呈负相关（P〈0．05）。结论E—cadherin蛋白低表达与Snail蛋白高表达可能是胃黏膜恶性转变以及胃癌发生浸润转移的重要生物学标志。联合检测E—cadherin及Snail对预测胃癌浸润转移有重要意义。     

Tumor expression of Integrin-linked kinase (ILK) correlates with the expression of the E-cadherin repressor Snail: an immunohistochemical study in ductal pancreatic adenocarcinoma

Integrin-linked kinase (ILK) is a key molecule involved in mediating several biological functions including cell-matrix interactions, angiogenesis, and invasion, as well as playing a role in epithelial to mesenchymal transition (EMT) in cancer cells. In ductal pancreatic adenocarcinoma, increased expression of ILK has been linked to tumor prognosis and correlated with increased chemoresistance to drugs, such as gemcitabine. However, the precise relationship between ILK, Snail, E-cadherin, and N-cadherin expression on the stepwise development of pancreatic cancer is unknown. Hence, the purpose of this work was to investigate levels of expression of ILK, Snail, and the cadherins in pancreatic intraepithelial neoplasia (PanIN), and cancer. Resection specimens of 25 randomly selected patients, who underwent a pyloric preserving pancreatoduodenectomy for ductal pancreatic adenocarcinoma, were utilized for this study. Formalin-fixed paraffin embedded pancreatic tissue was immunostained for ILK, E-cadherin, N-cadherin, and Snail by standard techniques. The extent of staining positivity was scored and the results correlated with clinicopathological parameters. In 23 of 25 cases, ILK expression showed extensive positivity (>50%), while two cases did not demonstrate any ILK staining. PanIN grades 1 (n = 16), 2 (n = 11), and 3 (n = 19) lesions demonstrated only focal positivity (<10%) for ILK. E-cadherin showed a reciprocal staining pattern to ILK in 21 of 25 cases, with only focal expression of the marker in pancreatic adenocarcinoma. Interestingly, 15 of 19 PanIN-3 lesions expressed extensive E-cadherin staining. N-cadherin, however, was moderately expressed in the majority of cases (n = 18). Snail expression (n = 22) correlated with ILK expression in ductal pancreatic adenocarcinoma (ρ = 0.8168, p = 0.02), but only minimal Snail staining activity was detected in PanIN lesions. The increase in expression of the E-cadherin repressor Snail, as well as the related increase in the ILK expression, may point towards an ILK-mediated induction, opening possible avenues for targeted drug therapy.     

Snail和E-cadherin在人乳腺癌的表达及临床意义

目的探讨Snail和E-cadherin在乳腺癌组织中的表达及其临床意义。方法采用免疫组织化学方法检测199例乳腺癌组织和60例乳腺腺瘤组织中的Snail和E-cadherin蛋白的表达,分析其表达与临床病理参数及预后的相关性,并分析二者表达的相关性。同时采用Real-time PCR法检测20例乳腺癌组织和20例乳腺腺瘤组织中Snail和E-cadherin mRNA的表达,并分析二者表达的相关性。结果 Snail在乳腺癌组织中的表达水平明显高于乳腺腺瘤组织,E-cadherin在乳腺癌组织中的表达水平明显低于乳腺腺瘤组织(0.05)。Snail的表达与乳腺癌组织学分级、组织学类型、TNM分期及淋巴结转移密切相关(0.05);E-cadherin的表达与乳腺癌组织学分级和淋巴结转移密切相关(0.05)。Snail高表达的患者预后明显差于低表达的患者(0.05);而E-cadherin高表达的患者预后明显优于低表达的患者(0.05)。乳腺癌组织中Snail和E-cadherin表达具有显著负相关(0.05)。结论乳腺癌组织中Snail和E-cadherin表达呈负相关,与组织学分级等临床病理参数密切相关。     

Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma

Ohishi Y, Oda Y, Kurihara S, Kaku T, Kobayashi H, Wake N & Tsuneyoshi M
(2011) Histopathology 58 , 423–432
Nuclear localization of E‐cadherin but not beta‐catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma Aims: The role of misregulated Wnt/beta‐catenin signalling in human ovarian granulosa cell tumour (GCT) has not been well characterized. The aim of this study was to confirm subcellular localization of key molecules of Wnt signalling (beta‐catenin and E‐cadherin) in human ovarian GCTs. Methods and results: Tissue samples taken from 32 human ovarian GCTs and 19 human normal ovaries containing 68 follicles were stained immunohistochemically using monoclonal anti‐beta‐catenin and anti‐E‐cadherin antibodies. None of the 32 GCTs and none of the 68 ovarian follicles showed beta‐catenin nuclear expression (0%). On the other hand, 28 of 32 GCTs (88%) and 53 of 68 normal ovarian follicles (78%) showed nuclear expression of E‐cadherin in granulosa cells. The ovarian stroma in all 19 normal ovaries showed nuclear expression of E‐cadherin but not beta‐catenin. Membranous and cytoplasmic expression was observed variously in ovarian GCT, follicles and stroma. Conclusions: We have confirmed frequent nuclear localization of E‐cadherin but not beta‐catenin in human ovarian GCT, ovarian follicles and stroma. There is no evidence of misregulated Wnt/beta‐catenin signalling (represented by nuclear expression of beta‐catenin) in human ovarian GCT. Nuclear translocation of E‐cadherin might contribute to ovarian folliculogenesis or granulosa/stromal cell differentiation.