TRAIL信号通路在胃癌的研究现状

目的介绍肿瘤坏死因子相关凋亡诱导配体（TRAIL）及其受体在胃癌的研究现状。方法检索PUB-MEDLINE和中国期刊全文数据库（CJFD），综述国内、外近年关于TRAII．及其受体在胃癌的相关研究文献。结果TRAIL在胃癌组织表达水平报道情况差异较大，但其与胃癌的分化程度和浸润、转移情况密切相关。其受体DR4及DR5在胃癌组织均表达阳性，而DcR1及DcR2在胃癌组织亦有表达阳性的报道。caspase-3、caspase-8和survivin对胃癌TRAIL信号通路有重要调节作用。5-氮2，-杂脱氧胞苷、阿霉素、5-氟尿嘧啶、α-生育酚及X射线照射可协同增强TRAIL对胃癌细胞的凋亡诱导作用。结论胃癌可能适合TRAIL靶向治疗，但其作用机理较为复杂并受到多因素影响。尚有如何有效增强和调控TRAIL凋亡诱导作用及TRAIL有何潜在毒性等诸多问题亟待研究。     

TRAIL受体在胰腺癌中的表达

目的 研究肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体在胰腺癌中的表达及意义。方法 应用半定量RT～PCR法检测TRAIL受体（死亡受体DR4、DR5和诱骗受体DcR1、DcR2）mRNA在胰腺癌组织及正常胰腺组织中的表达。结果 死亡受体DR4和DR5在所有胰腺癌组织和正常胰腺组织中均有表达，且在胰腺癌组织中的表达明显强于在正常胰腺组织中的表达（P〈0．01）。诱骗受体DcR1和DcR2在所有正常胰腺组织中均有表达，而在胰腺癌组织中仅有18例表达DcR1，有20例表达DcR2；诱骗受体DcR1和DcR2的表达水平在胰腺癌和正常胰腺组织中差异无统计学意义（P〉0．05）。胰腺癌组织中DR5的表达与肿瘤的分化程度和临床分期有关，分化程度越低，DR5的表达量越低，Ⅲ、Ⅳ期肿瘤DR5的表达显著低于Ⅰ、Ⅱ期（P〈0．05）。DR4、DcR1及DcR2在胰腺癌组织中的表达与肿瘤的分化程度和临床分期无关（P〉0．05）。结论 ①胰腺癌组织中普遍存在TRAIL受体的表达，并存在受体类型的表达差异，TRAIL基因受体在胰腺癌凋亡的调控机理中可能发挥重要作用。②胰腺癌组织中DR5的表达与肿瘤的分化程度及恶性程度相关；死亡受体DR4及诱骗受体DcR1和DcR2不能作为判断胰腺癌分化程度及恶性程度的指标。     

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。     

T3 对 MG63 细胞株 TRAIL，QPG，QPGL 表达的影响

目的观察在不同浓度T3环境下人成骨肉瘤MG63细胞株肿瘤坏死因子相关凋亡诱导配体(TRAIL)及其护骨素(OPG)、护骨素配体(OPGL)的表达,探讨甲亢性骨质疏松症的发病机制。方法用不同浓度T3(对照组,10-12、10-10、10-8mol/L组)分别刺激培养的MG63细胞24h,RT-PCR法检测TRAIL,OPG,OPGLmRNA的表达。结果T3对MG63细胞中TRAIL,OPGLmRNA的表达,均按照对照组、10-12mol/L组、10-10mol/L组、10-8mol/L组顺序递增(P<0.05),OPGmRNA的表达按照此顺序递减(P<0.05),10-8mol/L组TRAILmRNA的水平明显高于对照组(P<0.05)。同时,OPG/OPGL比率按照对照组、10-12mol/L组、10-10mol/L组、10-8mol/L组顺序递减。结论T3可能导致成骨细胞中TRAIL和OPGL表达增多,OPG的表达减少。这可能是甲亢性骨质疏松症的重要发病机制之一。     

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.     

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。     

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。     

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。     

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。     

Mutant Allele Tumor Heterogeneity (MATH) and Head and Neck Squamous Cell Carcinoma

Intra-tumor heterogeneity, variation between individual tumor cells within a patient’s tumor, is increasingly seen as a critical mechanism underlying treatment resistance and therapeutic failure. Despite this growing awareness, few methods to assess intra-tumor heterogeneity exist outside the research laboratory, especially in the absence of a known marker. Mutant allele tumor heterogeneity (MATH) is a novel, non-biased, quantitative method to assess genetic heterogeneity based on tumor next generation exome sequencing. The quantitative aspect of MATH has allowed it to be verified as an actionable biomarker in a retrospective HNSCC data set with available exome sequencing and clinical data. In addition, it was also capable of stratifying patient outcome after controlling for other high-risk features such as p53 mutation, HPV status, and advanced tumor stage. Future work will explore the predictive power of MATH in larger data sets such as The Cancer Genome Atlas and examine the underlying cellular mechanisms responsible for intra-tumor heterogeneity.     

Metastatic Squamous Cell Carcinoma Resembling Cellulitis and Osteomyelitis of the Fifth Toe

Statistically, metastasis of carcinomas to pedal phalanges is rare. However, true to all bone metastases of the body, its presence is associated with a very poor prognosis. A case of metastatic sinonasal squamous cell carcinoma to the fifth toe is presented followed by a review of the literature.     

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.     

定量RT-PCR测定食管鳞癌组织中人叉头样转录因子3基因的表达

目的测定食管鳞状细胞癌组织中人叉头样转录因子3（forkhead box P3,FOXP3）的基因表达水平,为食管癌的免疫治疗提供依据。方法基于TaqMan荧光探针技术,构建克隆载体pMD18-T—FOXP3,作为定量模板,建立检测FOXP3信使核糖核酸（mRNA）含量的实时荧光定量逆转录-聚合酶链反应（RT-PCR）方法,在GeneAmp7500型检测仪上测定42例食管鳞癌组织和30例正常对照组织中FOXP3 mRNA的含量。结果食管鳞癌组织FOXP3 mRNA表达高于正常对照组织[（72．20±23．10）×10^4拷贝／μg RNAvs．（0．68±0．34）×10^4拷贝μgRNA;P〈0．053。结论成功建立了人FOXP3基因mRNA表达含量的荧光定量检测方法,FOXP3在食管鳞癌组织中的表达较正常对照组织增高。     

CyclinD1蛋白在T2-3N0M0期食管癌中的表达及其与预后的关系

目的探讨CyclinDl蛋白在T2-3N0M0期食管鳞状细胞癌（食管鳞癌）组织中的表达及其与预后的关系。方法用免疫组织化学染色方法检测227例T2-3N0M0期食管癌组织中CyclinD1蛋白的表达,应用受试者工作（receiveroperatingcharacteristic,ROC）曲线确定CyclinD1免疫组织化学高表达和低表达的分界点,分析CyclinD1表达与食管癌临床病理因素和预后之间的关系。结果CyclinD1在食管癌组织中低表达90例（39．6％）,高表达137例（60．4％）。CyclinDl蛋白的表达与性别（P=-0．298）、年龄（P=O．525）、肿瘤位置（P=0．570）、肿瘤长度（P=-0．056）、分化程度（P=0．713）和浸润深度（P=0．557）无明显相关性,但CyclinD1低表达组与cyclinD1高表达组的预后差异有统计学意义（3年生存率：51．1％VS．43．8％;5年生存率：43．3％VS．30．7％;P=-0．047）。Cox风险比例模型分析显示CyclinD1不是T2-3N0M0期食管癌独立预后因素（艘值=1．378,95％CI：0．990—1．919,P=-0．057）。结论CyclinD1过表达可能是影响T2-3N0M0期食管癌不良预后的因素。     

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.     

Multivariate Analysis of the Pathologic Features of Esophageal Squamous Cell Cancer: Tumor Budding Is a Significant Independent Prognostic Factor

Absract Background  Tumor budding has been suggested to be a prognostic factor in various cancers but has never been studied in esophageal cancer. Methods  In this study, the microscopic finding of tumor budding in esophageal squamous cell carcinoma was correlated with outcome after esophagectomy. One hundred and thirty-six patients undergoing a curative esophagectomy were assigned to either a frequent (n = 82) or rare (n = 54) group according to the microscopically observed frequency of tumor budding in the tumor. Results  The 5-year survival rates after esophagectomy were 35.4% for the frequent group and 81.3% for the rare group. Multivariate analysis using the Cox proportional hazards model by a stepwise method identified this morphological variable as a significant independent prognostic factor. Conclusions  Tumor budding in esophageal squamous cell carcinoma reflects the biological activity of the tumor and may be a useful prognostic indicator.     

HPV-Related Nonkeratinizing Squamous Cell Carcinoma of the Oropharynx: Utility of Microscopic Features in Predicting Patient Outcome

Human papilloma virus (HPV) is an etiologic agent in a subset of oropharyngeal squamous cell carcinomas (SCCs). The aim of this study was to sub-classify SCC of the oropharynx based upon histologic features into nonkeratinizing (NK) SCC, keratinizing (K) SCC, and hybrid SCC, and determine the frequency of HPV and patient survival in each group. Patients with oropharyngeal SCC with a minimum of 2 years of clinical follow-up were identified from radiation oncology databases from 1997 to 2004. All patients received either up front surgery with postoperative radiation or definitive radiation based therapy. In situ hybridization (ISH) for high-risk HPV subtypes and immunohistochemistry for p16, a protein frequently up-regulated in HPV-associated carcinomas, were performed. Overall and disease-specific survival were assessed. Of 118 cases, 46.6% were NK SCC, 24.6% K SCC and 28.8% hybrid SCC. NK SCC occurred in slightly younger patients that were more often male. It more frequently presented with lymph node metastases and was surgically resected compared to K SCC. NK SCC was significantly more likely to be HPV and p16 positive than KSCC (P < 0.001) and to have better overall and disease-specific survival (P = 0.0002; P = 0.0142, respectively). Hybrid SCC was also more likely than K SCC to be HPV and p16 positive (P = 0.003; P = 0.002, respectively) and to have better overall survival (P = 0.0105). Sub-classification of oropharyngeal SCC by histologic type provides useful clinical information. NK SCC histology strongly predicts HPV-association and better patient survival compared to K SCC. Hybrid SCC appears to have an intermediate frequency of HPV-association and patient survival.