Activin A Causes Cancer Cell Aggressiveness in Esophageal Squamous Cell Carcinoma Cells

BACKGROUND: Expression of activin A is associated with lymph node metastasis and clinical stage in esophageal cancer. METHODS: To clarify the aggressive behavior of tumors with high activin A expression, we used the beta subunit of activin A to establish stable activin betaA (Act-betaA)-transfected carcinoma cells in two human esophageal carcinoma cell lines, KYSE110 and KYSE140. The biological behavior of these cells was compared with that in mock-transfected cells from the same cell lines. We focused our attention on cell growth and tumorigenesis, and proliferation and apoptosis. RESULTS: Both Act-betaA-transfected carcinoma cell lines showed a higher growth rate than the mock-transfected carcinoma cells. In an in vitro invasion assay and a xenograft analysis, the Act-betaA-transfected carcinoma cells showed far higher proliferation in vitro and a higher potency for tumorigenesis in vivo, respectively. Moreover, in an analysis of apoptosis via Fas stimulation, the Act-betaA-transfected carcinoma cells showed a higher tolerance to apoptosis compared with the mock-transfected carcinoma cells. Moreover, anti-activin-neutralizing antibody-treated squamous cell cancer cell lines inhibited their migration. CONCLUSIONS: Collectively, these data indicate that continuous high expression of activin A in esophageal carcinoma cells is not related to tumor suppression, but rather to tumor progression in vitro and in vivo. The inhibition of activin might be one of the methods to attenuate tumor aggressiveness.     

h-prune Is an Independent Prognostic Marker for Survival in Esophageal Squamous Cell Carcinoma

Background  The human homologue of Drosophila prune (PRUNE, which encodes h-prune) protein interacts with glycogen synthase kinase 3 and promotes cell motility. The aim of our study was to investigate the impact of immunohistochemically detected h-prune expression on the survival of patients with esophageal squamous cell carcinoma (ESCC). Methods  Immunohistochemical staining of h-prune was performed for 205 surgically resected specimens of ESCC. Results  In total, 43 (21%) of 205 ESCC cases were positive for h-prune. h-prune-positive ESCC cases showed a more-advanced T stage (P < 0.0001), N stage (P < 0.0001), and tumor stage (P < 0.0001) than h-prune-negative ESCC cases. In the group of 116 stage II and III ESCC cases, recurrence of ESCC was frequently found in h-prune-positive cases. In patients with lung recurrence, the tumors were more likely to be h-prune positive than h-prune negative. Univariate analysis revealed that T stage (P < 0.0001), N stage (P < 0.0001), tumor stage (P < 0.0001), and h-prune staining (P < 0.0001) were significant prognostic factors for survival. Multivariate analysis indicated that N stage (P = 0.0182) and h-prune staining (P < 0.0001) were independent predictors for survival. Conclusions  These results indicate that immunostaining of h-prune is useful to identify patients at high risk for recurrence or poor prognosis associated with ESCC.     

食管鳞状上皮细胞癌细胞凋亡表达及其临床意义

目的探讨食管鳞状上皮细胞癌（食管鳞癌）中细胞凋亡的表达及其临床意义。方法应用末端脱氧核苷酸转移酶介导的ｄＵＴＰ缺口末端标记（ＴＵＮＥＬ）法，研究人食管鳞癌细胞凋亡的表达水平。结果３８例手术切除的食管鳞癌组织平均细胞凋亡指数ＡｐｏＬＩ为１２．１０±５．１３‰。角化型ＡｐｏＬＩ高于非角化型（Ｐ＜０．０１）；肿瘤分化越好，细胞凋亡越多，低度、中度、高度分化ＡｐｏＬＩ有差异（Ｐ＜０．０５）；不同性别、年龄、肿瘤部位、长度、深度，其ＡｐｏＬＩ并无差异；以１０‰为界将ＡｐｏＬＩ分组绘制Ｋａｐｌａｎ－Ｍｅｉｅｒ生存曲线，ＡｐｏＬＩ≥１０‰组术后生存率高。结论细胞凋亡与原发食管鳞癌临床病理特征密切相关，并可用于食管鳞癌预后判断。     

T辅助细胞分泌的细胞因子在食管鳞癌组织中的表达及其临床意义

目的探讨T辅助细胞(Th)分泌的细胞因子在食管鳞癌组织中的表达及其临床意义,为食管癌患者寻求合理有效的治疗方案提供理论依据。方法将56例食管癌患者行食管癌切除术后的食管鳞癌标本分成两组,A组:28例,为级和级食管鳞癌标本;B组:28例,为级和级食管鳞癌标本;6例食管炎患者活检组织标本作为对照。检测肿瘤组织的肿瘤坏死因子α(TNF-α)、转化生长因子β(TGF-β)和白细胞介素10(IL-10)的阳性表达情况。结果A组和B组TNF-α、TGF-β和IL-10阳性表达率均较对照组高(P<0.01);A组TNF-α较B组高,TGF-β和IL-10较B组低(P<0.01)。TNF-α阳性表达率与TGF-β和IL-10的阳性表达率呈负相关(P<0.01),TGF-β阳性表达率与IL-10呈正相关(P<0.01)。生存期<3年患者的TNF-α阳性表达率较生存期>3年患者的阳性表达率低(F=36.25,P<0.01),生存期<3年患者TGF-β和IL-10阳性表达率较生存期>3年患者的阳性表达率高(F=29.29,26.69;P<0.01)。结论食管鳞癌组织通过改变肿瘤组织局部T辅助细胞因子的分泌,破坏了免疫系统的平衡状态,从而使肿瘤组织逃避机体的免疫攻击,并有利于其侵入周围组织。     

食管鳞状细胞癌患者预后危险因素的分析

目的通过对食管鳞状细胞癌(鳞癌)术后长期生存和短期生存患者临床病理特征的多因素分析,探讨影响食管鳞癌患者预后的危险因素。方法随机选取临床资料和随访资料完整的食管鳞癌手术患者126例,根据随访结果,将其分为长期生存组(≥5年,48例)和短期生存组(≤1年,78例),应用二项分类logistic回归对两组患者的临床病理特征进行多因素分析。结果单因素分析结果两组在肿瘤长度、肿瘤浸润深度、肿瘤病理分级和淋巴结转移方面差别有统计学意义(P<0.01),而在患者年龄、性别、肿瘤位置和食管残端鳞癌检查结果的阴阳性方面差别无统计学意义(P>0.05)。多因素分析显示肿瘤病理分级、淋巴结转移、肿瘤浸润深度和肿瘤长度与食管鳞癌患者预后有关(P<0.05),它们的危险系数分别为2.943,2.641,2.126和1.728。相关分析发现肿瘤长度与肿瘤浸润深度呈正相关(r=0.488,P<0.001),淋巴结转移与肿瘤浸润深度和肿瘤病理分级均呈正相关(r=0.216,P=0.014;r=0.238,P=0.007)。患者年龄、性别、肿瘤部位和食管残端癌残留阴阳性与食管鳞癌患者预后无关(P>0.05)。结论食管鳞癌患者预后的主要影响因素为肿瘤病理分级、淋巴结转移、肿瘤浸润深度和肿瘤长度;肿瘤病理分级为强危险因素,肿瘤长度为低危险因素;患者年龄、性别、肿瘤位置和食管残端癌残留阴阳性为非危险因素。     

CD105蛋白在食管鳞癌中的表达及其与P53蛋白表达的关系

目的探讨CD 105蛋白在食管鳞状细胞癌(鳞癌)组织中的表达,及其与P 53蛋白表达的关系。方法应用免疫组织化学链霉菌抗生物素蛋白-过氧化酶连接法(SP法)检测CD 105蛋白和P 53蛋白在10例正常食管组织及86例食管鳞癌组织中的表达。结果CD 105蛋白在正常食管组织中不表达,86例食管鳞癌组织中表达阳性率为74.4%(64/86)。早期食管鳞癌(Ⅰ~Ⅱ期)患者的CD 105蛋白表达阳性率为66.1%(37/56),晚期(Ⅲ~Ⅳ期)为90.0%(27/30),两者比较差别有统计学意义(P<0.05);食管鳞癌组织中P 53蛋白表达阳性、阴性者中,CD 105蛋白表达阳性率分别为87.1%(54/62)、41.7%(10/24),两者比较差别有统计学意义(P<0.05)。结论CD 105蛋白在食管鳞癌的发生中起重要作用,其表达与食管鳞癌的临床分期及组织中P 53蛋白的异常表达呈正相关。     

Cytokeratin 7 is a Predictive Marker for Survival in Patients with Esophageal Squamous Cell Carcinoma

Background

Patients diagnosed with stage II and III esophageal squamous cell carcinoma (ESCC) have variable prognosis. This group would benefit greatly from the discovery of prognostic markers that are capable of identifying individuals for whom adjuvant treatment would be advantageous. The aim of this study was to investigate the impact of immunohistochemically detected cytokeratin 7 (CK7) expression on disease-free survival, overall survival (OS), or therapeutic outcome in patients with ESCC.

Methods

Immunohistochemical analysis of CK7 was performed on 225 surgically resected specimens of stage 0?CIII ESCC.

Results

In total, 20 (9%) of 225 ESCC cases were positive for CK7. In stage 0?CIII ESCC patients, CK7 expression was statistically significantly associated with OS, independent of clinical covariates, including tumor, node, metastasis system stage. In stage II and III ESCC patients (n?=?124), CK7 expression was significantly associated with poorer OS (P?=?0.0377). Furthermore, in stage II and III ESCC patients who did not receive adjuvant chemotherapy (n?=?73), CK7 expression was significantly associated with poorer OS (P?=?0.0003). CK7 expression was not associated with therapeutic outcome in patients with stage II and III ESCC who received adjuvant chemotherapy. In patients with CK7-positive ESCC (n?=?16), receipt of adjuvant chemotherapy tended to be beneficial for patients with stage II and III ESCC (P?=?0.0654).

Conclusions

Immunohistochemical analysis of CK7 will help to identify high-risk patients.     

食管鳞癌DNA含量与临床病理及预后的关系

应用自动化图像分析仪对５０例食管鳞癌进行细胞ＤＮＡ定量分析，结合临床资料，发现肿瘤分化越差、外侵越严重，ＤＮＡ含量越高。淋巴结转移组ＤＮＡ含量高于非转移组。二倍体或近二倍体组１、３、５年生存率明显高于异倍体组（Ｐ＜０．０１）。表明ＤＮＡ含量的测定可从核酸代谢的分子水平揭示食管癌恶性生物学行为，同时可作为估计手术预后的客观定量指标。     

Overexpression of Claudin-1 is Associated with Advanced Clinical Stage and Invasive Pathologic Characteristics of Oral Squamous Cell Carcinoma

Claudins constitute a group of principal proteins forming the tight junctional complex. The altered expression of selected claudins has been reported in several human cancers. The purpose of this study was to investigate the expression of claudin-1 and claudin-4 in oral squamous cell carcinoma (OSCC) and examine its relationship with patient clinical-pathologic features. Forty-five OSCC cases were enrolled. Patient clinical, pathologic and follow-up data were reviewed and the claudin-1 and claudin-4 expression was analyzed immunohistochemically. Positive claudin-1 and claudin-4 immunoreactivities were noted in 86.7 and 80 % of cases, respectively. The majority of cases showed the staining in less than 25 % of cancer cells. The increased claudin-1 expression was significantly associated with the high pathologic grade, the presence of microscopic perineural invasion, vascular invasion, nodal metastasis, and advanced clinical stage. No relationship between various clinico-pathologic parameters and differential claudin-4 expression was observed. Claudin-1 may play a role in OSCC progression and could serve as a prognostic marker of advanced disease.     

食管鳞状细胞癌干细胞研究的现状及进展

摘要：越来越多的研究表明肿瘤细胞中存在肿瘤干细胞,它与肿瘤的起始、生长、转移及化疗抗性有密切关系。食管鳞癌细胞中也被发现具有干细胞特性的肿瘤细胞,这类细胞具有自我更新、分化潜能、裸鼠成瘤和化疗抗性,这类细胞将在肿瘤靶向治疗中发挥重要的作用。目前培养和分离食管鳞癌干细胞的方法主要有免疫荧光激活细胞分离法、免疫磁珠激活细胞分离法、悬浮培养法、侧群细胞分离法等。本文对当前食管鳞癌干细胞的研究方法、生物学特性及不足进行了综述,并认为食管鳞癌干细胞需要联合多个细胞标记进行研究。     

Altered E-Cadherin Expression and p120 Catenin Localization in Esophageal Squamous Cell Carcinoma

Background E-cadherin is a well-known tumor suppressor and its dysregulated expression correlates with tumor differentiation, metastasis and survival in esophageal squamous cell carcinoma (ESCC). p120 catenin is an Armadillo protein normally bound to E-cadherin in the cadherin–catenin complex at the adherens junction. Dysregulated expression and mislocalization of p120ctn affect the protective function of the complex. The objective of the present study was to evaluate the clinical significance of E-cadherin and p120ctn expression in ESCC. Methods Immunohistochemistry was performed to investigate the expression of E-cadherin and p120ctn proteins in 71 patients with ESCC. The relationships between protein expression and clinicopathological characteristics were analyzed. Results Reduced E-cadherin and p120ctn expressions were observed in 42.3% and 8.5% of ESCC cases, respectively. Reduction of membranous p120ctn was observed in 33.8% of cases. Membranous E-cadherin was preserved when p120ctn co-localized on the membrane of tumor cells (72.3%, P = 0.001). High level E-cadherin expression and membranous p120ctn preservation positively correlated with tumor differentiation (P = 0.001 and P = 0.008, respectively). p120ctn expression was also significantly related to lymph node metastasis (P = 0.003). Heterogeneous expression of both E-cadherin and p120ctn was observed in dysplasia. Conclusions Altered E-cadherin expression and p120ctn localization were related to tumor differentiation, indicating their important roles in the pathogenesis of ESCC.     

鳞状细胞癌抗原在食管癌临床的应用

采用微粒酶免疫荧光法测定了４０例食管癌和７例术后复发病人的血清鳞状细胞癌（ＳＣＣ）抗原含量，取２０例正常人，１５例食管良性病人和１５例腺癌病人作对照。结果表明，食管癌和术后复发病人的血清ＳＣＣ抗原含量显著高于正常人、良性病人和腺癌病人（Ｐ值分别＜０．００１、０．０１和０．０５），ＳＣＣ抗原与临床病期、细胞的分化程度有关。这提示血清ＳＣＣ抗原是食管癌理想的肿瘤标志物，对食管癌的诊断、预示术后复发和判断食管癌的恶性程度都有重要的临床价值。     

Prediction of Lymph Node Metastasis with Use of Artificial Neural Networks Based on Gene Expression Profiles in Esophageal Squamous Cell Carcinoma

Background: The aim of the study was (1) to detect candidate genes involved in lymph node metastasis in esophageal cancers and (2) to investigate whether we can estimate and predict occurrence of lymph node metastasis by analyzing artificial neural networks (ANNs) using these gene subsets.Methods: Twenty-eight primary esophageal squamous cell carcinomas were used. Gene expression profiles of all primary tumors were obtained by cDNA microarray. Lymph node metastasis–related genes were extracted with use of Significance Analysis of Microarrays (SAM). Predictive accuracy for lymph node metastasis was calculated by evaluation of 28 cases by ANNs with leave-one-out cross-n. The results were compared with those of other analyses such as clustering or predictive scoring (LMS).Results: Our ANN model could predict lymph node metastasis most accurately with 60 clones. The highest predictive accuracy for lymph node metastasis by ANN was 10 of 13 (77%) in newly added cases that were not used for gene selection by SAM and 24 of 28 (86%) in all cases (sensitivity: 15/17, 88%; specificity: 9/11, 82%). Predictive accuracy of LMS was 9 of 13 (69%) in newly added cases and 24 of 28 (86%) in all cases (sensitivity: 17/17, 100%; specificity: 7/11, 67%). It was difficult to extract useful information for the prediction of lymph node metastasis by clustering analysis.Conclusions: ANN had superior potential in comparison with other methods of analysis for the prediction of lymph node metastasis. This systematic analysis combining SAM with ANN was very useful for the prediction of lymph node metastasis in esophageal cancers and could be applied clinically in the near future.     

Expression and Prognostic Value of MG7-Ag in Patients With Surgically Resectable Esophageal Squamous Cell Carcinoma

Purpose MG7-Ag is a human gastric-carcinoma-associated antigen. The expression of MG7-Ag was found to increase gradually with the development and progression of gastric cancer. Moreover, a poorer prognosis was found in MG7-Ag positive gastric-carcinoma patients than in MG7-Ag negative patients. However, neither MG7-Ag expression nor its clinical significance has been previously examined in squamous cell carcinoma (SCC) of the esophagus. In this study, we examined the expression of MG7-Ag in esophageal squamous cell carcinomas to assess its value as a prognostic indicator. Methods The expression of MG7-Ag was detected in 112 cases of esophageal squamous cell carcinoma (SCC) by immunohistochemical analysis. The relation of MG7-Ag staining with various clinicopathological features was statistically analyzed. Results The staining of MG7-Ag was detected in SCC, while not in normal epithelial cells. In esophageal SCC, MG7-Ag was found significantly correlated with depth of invasion (P = .012), in T4, T3 carcinomas but not in T2, T1 carcinomas, lymph node metastases (P = .029), pathological stage (P = .005). Consistently, the survival rate tended to be statistically lower in patients with MG7-Ag positive SCCs than in MG7-Ag negative SCCs (P = .005). However, no significant difference was observed between MG7-expression and patient age, sex, tumor location, differentiation, distant metastasis, and lymphatic invasion. Conclusion MG7-Ag might play a positive role in the process of carcinogenesis and progression of esophageal SCC, and it could be considered as one valuable prognostic indicator in esophageal SCC.     

Primary Basaloid Carcinoma of the Nipple with Associated Squamous Cell Carcinoma in Situ

Abstract:  Basaloid carcinomas have been documented in various anatomic locations. We describe a primary invasive adenocarcinoma of the nipple with extensive basaloid features that was also associated with squamous cell carcinoma (SCC) in situ and an aggressive behavior. A 69-year-old woman without a history of breast neoplasia presented with right nipple pain. Biopsy of the nipple revealed SCC in situ. One year later, she returned with nipple ulceration. An excisional specimen showed a 1.7 cm nodule composed of invasive sheets and ribbons of basaloid cells with numerous mitoses, extensive tumor necrosis and evidence of glandular differentiation. SCC in situ was present in the overlying epidermis. The differential diagnosis included a primary basaloid adenocarcinoma of the nipple, basal cell carcinoma of the nipple, neuroendocrine carcinoma, melanoma, basaloid variant of adenoid cystic carcinoma and metastatic disease. Immunohistochemical profile of this tumor supported a primary basaloid adenocarcinoma of the nipple. Although the initial sentinel lymph node biopsy was negative, within a year of diagnosis, the patient developed ipsilateral axillary node and pulmonary metastases. To the best of our knowledge, this is the first case of basaloid carcinoma to be documented in this anatomic site.