Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer

The prognostic value of the immunohistochemical expression of epithelial and stromal syndecan-1 was evaluated in 296 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with mouse monoclonal antibody B-B4 against human syndecan-1. Loss of immunoreactivity (syndecan-1 immunoreactivity correlated with a higher stage of disease (stages II-IV), tumour location in the upper third of the stomach, nodal metastases (N1 or N2), positive stromal syndecan-1 staining, deep tumour penetration (to subserosa or deeper = T2-T4), larger tumour size (> or = 5 cm) and intestinal type of cancer. No correlation between epithelial syndecan-1 immunoreactivity and age, gender, distant metastases, grade of differentiation or Borrmann classification was observed. Positive stromal syndecan-1 immunoreactivity correlated with decreased epithelial syndecan-1 expression, intestinal type of cancer and Borrmann type I. Patients with low epithelial syndecan-1 expression in cancer cells had worse overall survival than patients with strong epithelial syndecan-1 staining (p = 0.0012). Stromal syndecan-1-positive patients had a worse outcome than patients with syndecan-1-negative stroma (p = 0.0193). In Cox multivariate analysis, stromal syndecan-1 immunoreactivity was a prognostic factor independent of TNM stage, surgery for cure and tumour size. Thus, the immunohistochemical expression of syndecan-1 might be a predictor of outcome in patients with gastric adenocarcinoma.     

Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget

Epithelial mesenchymal transition (EMT) is proposed as a critical mechanism for the acquisition of malignant phenotypes by epithelial cells. In colorectal cancer, tumor cells having undergone EMT are histologically represented by the presence of tumor buds defined as single cells or small clusters of de-differentiated tumor cells at the invasive front. Tumor budding is not a static, histological feature rather it represents a snap-shot of a dynamic process undertaken by an aggressive tumor with the potential to disseminate and metastasize. Strong, consistent evidence shows that tumor budding is a predictor of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival time and an independent prognostic factor. Moreover, the International Union against Cancer (UICC) recognizes tumor budding as a highly relevant, additional prognostic parameter. The aim of this review is to summarize the evidence supporting the implementation of tumor budding into diagnostic pathology and patient management and additionally to illustrate its worthiness as a potential therapeutic target.     

Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients

Introduction  

Epithelial to mesenchymal transition (EMT) is considered an essential process in the metastatic cascade. EMT is characterised by upregulation of vimentin, Twist, Snail, Slug and Sip1 among others. Metastasis is also associated with the presence of circulating tumour cells (CTCs) and disseminated tumour cells in the blood and bone marrow, respectively, of breast cancer patients, but the expression of EMT markers in these cells has not been reported so far.     

Host microenvironment in breast cancer development: Epithelial–mesenchymal transition in breast cancer development

The epithelial–mesenchymal transition (EMT) is a developmental mechanism of crucial importance in establishing the body plan in many multicellular organisms. Several transduction pathways controlling the various steps of the morphological transition have been identified by molecular analyses of this process in cell lines and in vivo. The newly formed mesenchymal cells can exhibit locomotory and invasive phenotypes, suggesting that EMTs contribute to the progression of carcinoma. Diverse evidence indicates that EMT subprograms are involved in the appearance of different breast carcinoma types. Several normal and malignant breast cell lines are currently being analyzed to define key steps in EMT and to identify candidate genes. DNA profiling technology is also being applied to uncover pathways that lead to a metastatic phenotype.     

Epithelial mesenchymal transition from a natural gestational orchestration to a bizarre cancer disturbance

The epithelial to mesenchymal transition (EMT), a pathologic phenomenon in cancer, has a twin in the embryonic period of life. In the first one, its promotion will cause metastasis to become a life‐threatening stage of cancer, while in the second it will lead to organogenesis, which is necessary for all living creatures. There is one more from this phenomenon, which occurs during the wound healing process and if dys‐regulated can lead to fibrosis. In both there are stimulants in common and one that are different. Stages start from cell–cell junction dissociation followed by morphological changes and behavioral and essence alterations. To control the EMT as a bizarre disturbance in cancer and metastasis, initially it is better to understand the wonder of natural gestational orchestration in early life. In this review, first the structure of the two heads of the spectrum is described followed by the cellular and micro‐environmental alterations during this phenomenon. Understanding cellular behavior in this process and what makes them invasive resistant stemness cells will be of great importance in highlighting roads to cancer treatment. (Cancer Sci 2013; 104: 28–35)     

lncRNA-ATB介导的上皮间质转化在胃癌进展中的机制研究

目的 探讨lncRNA-ATB介导的上皮间质转化在胃癌进展中的可能机制。方法 采用生物信息学分析预测lncRNA-ATB的下游结合分子并采用荧光素酶报告基因验证。收集联勤保障部队第九八〇医院2017年1月—2019年12月胃癌及癌旁组织标本56例,采用qRT-PCR分析lncRNA-ATB及下游结合分子在胃癌及癌旁组织中的表达水平及二者之间的相关性,并分析二者与胃癌临床病理特征的相关性;在敲降lncRNA-ATB前后的胃癌BGC-823细胞系中,采用qRT-PCR及Western blot实验验证miR-200a、β-catenin、vimentin、E-cadherin表达水平的变化。结果 生物信息学分析发现lncRNA-ATB与miR-200a有直接结合位点,miR-200a与β-catenin能直接结合并采用荧光素酶报告基因验证。lncRNA-ATB在胃癌组织中较癌旁组织中明显高表达(P＜0.001),miR-200a在胃癌组织中较癌旁组织中明显低表达,差异有统计学意义(P＜0.001)。在胃癌组织中lncRNA-ATB与miR-200a表达水平呈负相关(r=-0.317,P=0.017)。lncRNA-ATB在Ⅲ、Ⅳ期胃癌较Ⅰ、Ⅱ期表达水平明显升高,淋巴结转移阳性组、脉管内癌栓阳性及肿瘤低分化组lncRNA-ATB表达水平更高,差异有统计学意义(P＜0.001)。miR-200a在Ⅲ、Ⅳ期胃癌患者较Ⅰ、Ⅱ期患者表达水平明显降低,淋巴结转移阳性组、脉管内癌栓阳性及肿瘤低分化组miR-200a表达水平明显降低,差异有统计学意义(P＜0.05)。在胃癌BGC-823细胞系中敲降lncRNA-ATB后β-catenin和vimentin表达降低、E-cadherin表达升高,差异有统计学意义(P＜0.05)。结论 lncRNA-ATB通过与miR-200a结合,影响β-catenin的表达促进上皮间质转化进程从而影响胃癌进展。     

Risk groups as related to gastric cancer

Under examination were the features of life, labour, habits, inheritance pattern, a type of diet, the course of the disease in 440 gastric cancer patients. The most typical and frequently observed factors were singled out. The material obtained was processed by an electronic computer. The informative value of the risk factors was checked by selection, using questionnaires of patients irrespective of the reason of their referring to the clinic. The age of patients over 40 and the character of work should become the basic indication for limiting the number of persons subject to a gastrological examination.     

胃癌患者营养不良相关因子研究进展

胃癌患者的预后与营养不良密切相关,导致胃癌患者营养不良的机制目前并不十分明确,除了厌食、进食困难等,胃癌患者营养不良可能与宿主-肿瘤相互作用产生具有代谢活性的因子如肿瘤坏死因子-α、白细胞介素-1、白细胞介素-6、干扰素、瘦素、核因子-κB等。相关因子之间关系复杂,相互调控,构成一个精密的调控网络。因此,进一步探索胃癌患者营养不良与相关因子之间的关系,可能为改善患者营养状况及预后提供一定的研究基础。     

子宫内膜异位症相关卵巢癌患者上皮-间充质转化相关蛋白的表达及其影响因素

目的 探讨子宫内膜异位症相关卵巢癌(EAOC)患者上皮-间充质转化(EMT)相关蛋白的表达及其影响因素分析.方法 取60例EAOC患者及60例单纯子宫内膜异位症(EMS)患者的EAOC组织和EMS组织采用免疫组织化学法检测,比较各组织中EMT相关蛋白[上皮钙黏蛋白(E-cadherin)、神经钙黏蛋白(N-cadherin)及锌指转录因子Snail]的阳性表达情况,分析EAOC组织中EMT相关蛋白阳性表达的影响因素及其相关性.结果 EAOC组织中E-cadherin蛋白阳性表达率低于EMS组织(P﹤0.05),N-cadherin及Snail蛋白阳性表达率均高于EMS组织(P﹤0.05).临床分期为Ⅰ～Ⅱ期、无淋巴结转移的EAOC患者EAOC组织中E-cadherin蛋白阳性表达率均高于临床分期为Ⅲ～Ⅳ期、有淋巴结转移的患者(P﹤0.05);临床分期为Ⅰ～Ⅱ期、无淋巴结转移的EAOC患者EAOC组织中N-cadherin蛋白阳性表达率均低于Ⅲ～Ⅳ期、有淋巴结转移的患者(P﹤0.05);无淋巴结转移的EAOC患者EAOC组织中Snail蛋白阳性表达率低于有淋巴转移患者(P﹤0.05).多因素Logistic回归分析结果显示,临床分期为Ⅲ～Ⅳ期、有淋巴结转移均是E-cadherin蛋白阳性表达的独立危险因素(P﹤0.05),无淋巴结转移是N-cadherin、Snail蛋白阳性表达的独立危险因素(P﹤0.05).Spearman相关性分析显示,EAOC患者EAOC组织中E-cadherin蛋白阳性表达与其临床分期及淋巴转移情况呈负相关(r=-0.36、-0.44,P﹤0.05),而N-cadherin蛋白阳性表达与其临床分期及淋巴转移情况呈正相关(r=0.42、0.37,P﹤0.05),Snail蛋白阳性表达与其淋巴转移情况呈正相关(r=0.34,P﹤0.05).结论 EAOC患者临床分期及淋巴转移与其病灶组织中E-cadherin、N-cadherin及Snail蛋白阳性表达存在相关性,提示EAOC的进展可能与EMT相关蛋白间有密切联系.     

Epithelial mesenchymal transition in early invasive breast cancer: an immunohistochemical and reverse phase protein array study

Epithelial mesenchymal transition (EMT), as defined by loss of epithelial characteristics and gain of a mesenchymal phenotype, has been reported in vivo although the occurrence of events remains unclear. This study aims at exploration of EMT portraits of breast cancer (BC) with relevance to different molecular pathways, especially potential EMT triggers and BC molecular subtypes. Immunohistochemical (IHC) expression of markers/triggers of EMT was studied on a well-defined cohort of invasive non-lobular BC (n = 1,035), prepared as tissue microarrays. IHC panel of biomarkers included cadherins (cad; E-cad and N-cad), TGFβ1, PIK3CA, pAkt, and others. Reverse phase protein array (RPPA) was performed for quantitative analysis of proteins extracted from formalin fixed paraffin embedded tissues of a subset of cases from this cohort. Four combinatorial phenotypic groups representing cadherin switch were defined, including E-cad⁺/N-cad^?, E-cad^?/N-cad^?, E-cad⁺/N-cad⁺, and E-cad^?/N-cad⁺. Statistically significant association was noticed between these phenotypes and histological tumour grade, tumour type and size and NPI staging classes. The E-cad/N-cad switch occurred more frequently in the triple negative molecular class, both basal and non-basal, and in the HER2⁺ subtype than in luminal BC. Significant outcome differences were observed between cadherin switch combinatorial groups regarding BCSS and DMFS (p < 0.001). Results of RPPA confirm those observed using IHC regarding differential expressions of EMT markers/triggers. EMT/cadherin switch programs in BC appear to occur in synergy with TGFβ1 and PIK3/Akt pathways activation. These data explain, at translational proteomic level, the molecular heterogeneity and in turn the varied clinical behaviour of BC molecular subtypes. RPPA is a promising high-throughput technique in monitoring subtle quantitative changes in protein expression in archival material.     

Epithelial mesenchymal transition in colorectal cancer: Seminal role in promoting disease progression and resistance to neoadjuvant therapy

BackgroundEpithelial mesenchymal transition (EMT) may be physiological as part of embryological development, or pathological as part of cancer development. It is one of the key initiating events in the metastatic cascade. EMT has profound effects on tumour cell invasiveness, proliferation and motility. In the present article we aimed to review the potential role of EMT as a process to explain colorectal cancer progression and resistance to neoadjuvant therapy.MethodsExtensive literature searches were performed in Pubmed, EMBASE and Google Scholar databases to identify relevant articles published before March 2012.ResultsThere is adequate evidence to support the complex upstream signalling alterations needed for EMT to occur in colorectal cancers. Changes of EMT are likely to be found at the tumour invasive front: the deepest, growing tumour margin. Loss of E-cadherin at the cell membrane causes loss of cellular integrity, with subsequent migration of malignant cells and tumour budding. These processes are associated with metastases and recurrence of colorectal cancer. There is early evidence from a limited number of studies that resistance to neoadjuvant therapy in colorectal cancer is associated with changes of EMT. However, there is a lack of supporting evidence originating from human colorectal cancer tissues.ConclusionsEmerging evidence demonstrates that development of EMT in colorectal cancer leads to an aggressive phenotype that may promote metastatic spread, and augment treatment resistance during neoadjuvant therapy. A clearer understanding of the processes and role of EMT in colorectal cancer may also highlight novel therapeutic strategies.     

Epithelial mesenchymal transition during development in fibrosis and in the progression of carcinoma

Epithelial mesenchymal transition (EMT) is a fundamental mechanism controlling multiple events during embryonic development. Mesenchymal cells appear transiently in some diploblasts, the most primitive species characterized by two epithelial layers. Since almost 800 million years, EMT has been conserved throughout evolution to control morphogenetic events, such as the formation of the three primary germ layers during gastrulation. Most interestingly, specific molecular pathways have been conserved in many different species to drive EMT. In the animal kingdom, a recurrent theme is that EMT controls the intercellular adhesion machinery and the dynamics of its associated cytoskeleton. EMT pathways are also tightly connected to determination and differentiation programs, and are reactivated in adult tissues following injury or exposure to toxic agents. EMT is now shown to operate during the early stages of carcinoma invasion leading to blood or lymph vessel intravasation of malignant cells. The converse mechanism - mesenchymal-epithelial transition (MET) - then operates at distant sites from the primary tumor to form macrometastases from isolated micrometastatic cells. The mesenchymal-like state of carcinoma confers stemness, protection from cell death, escape from immune response and, most importantly, resistance to conventional and targeted therapies. Our laboratory has designed an EMT high-throughput screen of small molecular weight compounds and biologics in order to establish new therapeutic approaches that interfere with the plasticity of carcinoma cells. New therapeutic interventions are envisioned to delay tumor recurrence.