HER2／neu在胃癌中的研究进展

HER2/neu与多种肿瘤的发生、发展关系密切。它通过下游的信号转导途径参与肿瘤细胞的增殖、凋亡、浸润与侵袭等基因的调控。HER2/neu在胃癌中存在高表达或基因扩增现象,并可能影响胃癌患者的预后,也可能参与了胃癌肝转移过程。HER2/neu有望成为胃癌治疗的一个新靶点。     

Overexpression of Grb2/HER2 signaling in Chinese gastric cancer: their relationship with clinicopathological parameters and prognostic significance

Purpose  Growth factor receptor-bound 2 (Grb2)-mediated HER2 signaling is thought to play a critical role in gastric cancer development, progression and metastasis. However, little is known about their expression in gastric cancer. In this study, we try to explore their relationship with clinicopathological parameters and prognostic significance in gastric cancer patients. Materials and methods  We examined the expression of Grb2 and HER2 in normal gastric mucosa, primary gastric cancers, and lymph node metastases using immunohistochemical analysis of tissue microarrays containing specimens obtained from 1,143 patients with gastric cancer. Results  Grb2 was overexpressed in 48% (553/1,143) of primary tumors and 59% (155/262) of lymph node metastases. We observed significant differences in Grb2 expression between the primary tumors and the lymph node metastases (P < 0.01). Also, HER2 was overexpressed in 28% (321/1,143) of the primary tumors and 30% (79/262) of the lymph node metastases. Overexpression of Grb2 and Her2 was associated with age (>60 years), tumor location (cardia of stomach), adenocarcinoma, and high/moderate differentiation. A significant relationship was found between Grb2 and HER2 expression using Chi-Square Tests and Spearman Correlation. Overexpression of Grb2 correlated significantly with poor survival rates in both univariate and multivariate analysis. Conclusions  Our data demonstrated a progressive amplification of Grb2 and HER2 expression in gastric carcinogenesis, suggesting the importance of Grb2 and HER2 as positive biomarkers for gastric cancer development and progression.     

HER2 testing in gastric cancer: An update

Human epidermal growth factor receptor 2(HER2) overexpression is increasingly recognized as a frequent molecular abnormality in gastric and gastroesophageal cancer. With the recent introduction of HER2 molecular targeted therapy for patients with advanced gastric cancer, determination of HER2 status is crucial in order to select patients who may benefit from this treatment. This paper provides an update on our knowledge of HER2 in gastric and gastroesophageal cancer, including the prognostic relevance of HER2, the key differences between HER2 protein expression interpretation in breast and gastric cancer, the detection methods and the immunohistochemistry scoring system.     

HER2 aberrations and heterogeneity in cancers of the digestive system: Implications for pathologists and gastroenterologists

Management of cancers of the digestive system has progressed rapidly into the molecular era. Despite the significant recent achievements in the diagnosis and treatment of these patients, the number of deaths for these tumors has currently plateaued. Many investigations have assessed the role of HER2 in tumors of the digestive system in both prognostic and therapeutic settings, with heterogeneous results. Novel testing and treatment guidelines are emerging, in particular in gastric and colorectal cancers. However, further advances are needed. In this review we provide a comprehensive overview of the current state-ofknowledge of HER2 alterations in the most common tumors of the digestive system and discuss the operational implications of HER2 testing.     

RhoGDI2、PAK2在胃癌中的原位表达及与临床病理特征的相关性

目的 检测RhoGDI2、PAK2在胃癌患者中的表达状况,评价其与胃癌临床病理特征的相关性,评估RhoGDI2、PAK2在胃癌侵袭、转移中的临床意义.方法 采用免疫组织化学技术(EliviSionTM二步法)检测103例胃癌标本中RhoGDI2、PAK2的表达.结果 胃癌组织中RhoGDI2和PAK2蛋白表达阳性率分别为72.82％、60.19％;RhoGDI2和PAK2在胃癌中的表达与胃癌分化程度、肿瘤浸润深度、淋巴结转移个数、有无远处转移和TNM分期密切相关,RhoGDI2和PAK2的表达呈正相关.结论 胃癌组织中RhoGDI2、PAK2的表达与胃癌侵袭、转移病理特征密切相关.RhoGDI2与PAK2可能共同参与调节胃癌的侵袭、转移过程.     

HER2 in gastric cancer: Comparative analysis of three different antibodies using whole-tissue sections and tissue microarrays

AIM:To compare the performance of three commercially available anti-human epidermalgrowth factor receptor 2(HER2)antibodies in whole-tissue sections and tissue microarrays(TMAs)of a series of gastric tumors.METHODS:We present a comparative analysis of three anti-HER2 antibodies(HercepTest,4B5 and SP3)using TMA and whole-tissue sections prepared from the same paraffin blocks of 199 gastric adenocarcinomas operated upon between January 2004 and December2008 at a Brazilian cancer hospital.The data on the patients’age,sex,the anatomical location of the tumor and the Lauren’s histological classification were collected from clinical and pathological records.The immunohistochemical(IHC)results were examined by two pathologists and the cases were classified as positive(3+),equivocal(2+)and negative(0 or 1+),according to the criteria of the IHC scoring system of gastric cancer.TMAs and whole-tissue sections were evaluated separately and independently.All cases yielding discordant IHC results and/or scored as 2+were subjected to dual-color in situ hybridization in order to determine the final HER2 status.Besides determining the sensitivity and predictive value for HER2-positive status,we measured the accuracy of each antibody by calculating the area under the receiver operating characteristic(ROC)curve.The agreement between the results obtained using the TMAs and those obtained using the whole-tissue sections was assessed by means of Kappa coefficient.RESULTS:Intratumoral heterogeneity of HER2 expression was observed with all antibodies.HER2-positive expression(3+)in the whole-tissue sections was observed in 23 cases(11.6%)using the 4B5 antibody,in 18 cases(9.1%)using the SP3 antibody and in 10 cases(5.1%)using the HercepTest antibody.In the TMAs,11 positive cases(5.6%)were identified using SP3 antibody,9(4.6%)using the 4B5 antibody and 6(3%)using the HercepTest antibody.The sensitivity using whole-tissue sections and TMA,respectively,was 95.2%and 42.9%with 4B5,90.5%and 66.7%with SP3 and 47.6%and42.9%with HercepTest.T     

Dynamic changes in intrinsic subtype,immunity status,and risk score before and after neoadjuvant chemo- and HER2-targeted therapy without pCR in HER2-positive breast cancers: A cross-sectional analysis

Very few studies have been done in HER2 positive patients without complete pathological response (pCR) after combined neoadjuvant chemo- and HER2-target therapy to investigate changes in intrinsic subtype, risk of recurrence (ROR) score, and immunity status before and after treatment.Patients with nonmetastatic HER2-positive breast cancer failed to achieve pCR after neoadjuvant chemotherapy plus trastuzumab were included in current study. We examined the distribution of PAM50 subtypes, ROR score and immunity score in 25 paired baseline and surgical samples. The Miller–Payne grading system was used to evaluate the efficacy of the neoadjuvant therapy. It was observed that the distribution of intrinsic subtype, ROR category and immunity subgroup varied according to hormone receptor (HR) status. HER2-enriched and basal-like subtypes, median-high ROR categories and immunity-weak subgroup were dominant in baseline tumors. Compared to baseline samples, conversion of intrinsic subtype, ROR categories and immunity subgroups were found in 15 (60.0%), 13(52.0%), and 11(44.0%) surgical samples, respectively. The PAM50 subtype, ROR category, and immunity subgroup were concordant between baseline and surgical samples where nonluminal subtypes, median-high ROR categories and i-weak subgroup were still common.In conclusion, the HER2-positive breast cancer is highly heterogeneous with a distribution of 72-gene expression varying according to HR co-expression. The dynamics of the 72-gene expression pre- and posttreatment may become novel biomarker for guiding adjuvant therapy and hence warrant further investigation.     

TFF2在胃癌、癌旁及正常胃黏膜组织中的表达及其与血管生成的关系

目的:探讨三叶因子2(TFF2)、血管内皮生长因子(VEGF)和微血管密度(MVD)在胃癌发生、发展、浸润和转移中的作用.方法:选取广西医科大学第一附属医院2008-01/2009-06接受胃大部切除术的胃癌标本50例,采用SP免疫组织化学方法检测30例正常胃黏膜组织、50例癌旁组织和50例胃癌组织中TFF2、VEGF...     

EphB2在胃癌组织中的表达及意义

目的研究酪氨酸蛋白激酶受体EphB2在胃癌中的表达及意义。方法运用免疫组化法检测83例胃癌和10例正常胃组织中EphB2的表达。结果EphB2在大多数胃癌细胞质中表达,EphB2的表达和肿瘤的浸润深度及远处转移呈负相关,与肿瘤组织的分化程度呈正相关。结论EphB2对于肿瘤的生长起抑制作用,EphB2表达的减少促进了肿瘤的形成和演进。     

Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis

Purpose The clinicopathologic significance of the phenotype and Cdx2 expression has hitherto remained unclear in gastric cancers. In the present study, we therefore examined the correlation between prognosis, phenotype, and Cdx2 expression in advanced cases.Methods We evaluated 177 advanced gastric carcinomas histologically and phenotypically. The expression of Cdx2 was also assessed by immunohistochemistry.Results The lesions were phenotypically divided into 32 gastric (G type), 36 gastric and intestinal mixed (GI type), 53 intestinal (I type), and 56 null (N type) types, independent of the histological classification. Cdx2 nuclear staining demonstrated a close relation to intestinal phenotypic expression, not with the histological classification. Kaplan-Meier analysis of Cdx2 expression and the phenotype showed that the Cdx2 positive groups had a significantly better outcome than the negative ones (P =0.0013), and the patients with GI type cancers had significant better survival than those with N type (P =0.0052).Conclusions Our results suggest that Cdx2 is a useful prognostic marker. In addition, advanced gastric cancers with both intestinal and gastric phenotypic expression have a relatively good prognosis. Combined evaluation of gastric and intestinal epithelial cell markers, including Cdx2, is clinically useful to predict outcome in patients with advanced neoplasm of the stomach.     

E-钙粘蛋白-连接素复合体表达与胃癌临床病理学及生存期的关系

目的　E 钙粘蛋白 连接素复合体介导细胞 细胞间粘附 ,在维持上皮组织结构和功能方面起重要作用。检测胃癌组织E 钙粘蛋白和α 连接素、β 连接素的表达情况 ,分析它们与临床病理特征及病人生存期之间的关系。方法　采用免疫组化方法检测 14 8例胃癌E 钙粘蛋白和α 连接素、β 连接素的表达水平。结果　E 钙粘蛋白、α 连接素和 β 连接素在胃癌异常表达率分别为 4 4 .6 % ,73.6 %和4 3.2 %。14 8例胃癌中E 钙粘蛋白 连接素复合体总的异常表达率为 91.9%。E 钙粘蛋白和α 连接素、β 连接素表达下调与胃癌分化程度显著相关 (P <0 .0 0 5 )。伴有淋巴结转移或远处转移胃癌 ,其 β 连接素异常表达率显著高于无淋巴结转移或无远处转移者 (P <0 .0 0 5 )。β 连接素正常表达具有显著的生存优势 (P <0 .0 0 5 ) ,且独立于胃癌分期、分级和分型。结论　胃癌广泛存在E 钙粘蛋白复合体表达异常。β 连接素异常表达可能是对胃癌生存期具有预测价值的重要指标     

错配修复基因 hMLH1 和hMSH2 在胃癌组织中的表达及意义

目的探讨错配修复基因hMLH1 和hMSH2 在胃癌发生中的作用.方法采用免疫组化SP法,检测散发性胃癌、癌旁黏膜和胃炎黏膜组织中hMLH1 和 hMSH2基因的表达情况.结果 hMSH2在胃癌组织中的阳性表达率(67.1%)显著高于癌旁黏膜(41.4%)和胃炎黏膜组织(41.2%)(P<0.05),而后两者无显著差异(P>0.05).hMSH2在低分化腺癌中的阳性率(80.6% )显著高于高中分化腺癌(57.7%)和黏液癌(53.8%)(P<0.05),而后两者无显著差异(P>0.05).hMLH1在胃炎黏膜组织的阳性表达率(38.2%)显著低于胃癌(77.1%)和癌旁黏膜组织(74.3%)(P<0.05),后两者无显著差异(P>0.05). hMLH1在黏液癌中的阳性率(38.5%)显著低于高中分化腺癌(80.8%)和低分化腺癌(90.3%)(P<0.05),后两者无显著差异(P>0.05).结论 hMSH2高表达可能是胃癌发生的标志之一;hMSH2表达与肿瘤分化程度及患者预后有关;hMLH1有可能作为胃癌预警组织学标记物.     

c-ski在胃癌组织中的表达与临床因素相关性分析

目的探讨c-ski在胃癌组织中的表达与临床因素相关性分析。方法采用RT-PCR法和免疫组化法检测癌旁组织和胃癌组织中c-ski蛋白及mRNA表达情况。结果胃癌组织c-ski蛋白阳性率和c-skimRNA水平明显高于癌旁组织(P0.01);c-ski蛋白阳性率肠型胃癌明显高于弥漫型胃癌,差异具有统计学意义(P0.05)。c-ski蛋白阳性率与患者的性别、肿瘤的大小、浸润深度、是否有淋巴结及远处转移、1年的生存时间无关。结论 c-ski在胃癌组织中表达明显升高,且在弥漫型胃癌和肠型胃癌表达中存在差异。     

Ezrin和HER2在胃癌组织芯片中的表达及意义

目的:探讨Ezrin蛋白在胃癌组织中的表达,与肿瘤浸润、转移的关系及与HER2的相互作用.方法:485例原发性胃癌组织中高、中、低分化胃癌分别为19例、235例和231例;有淋巴结转移者353例;TNM分期Ⅰ、Ⅱ期166例,Ⅲ、Ⅳ期319例.另外取距肿瘤7cm的正常胃黏膜组织40例.制成8个组织芯片蜡块,用免疫组织化学方法检测石蜡包埋的胃及胃癌组织中的Ezrin和人类表皮生长因子受体2(hum an epidermal growth factor receptor 2,HER2)蛋白表达.所有患者均经外科手术治疗,病理诊断明确,术前未经放、化疗.结果:Ezrin和HER2在胃癌组织中高表达,二者均与肿瘤Lauren’s分型和肿瘤分化程度相关(χ2=17.625,χ2=20.386,均P=0.000;χ2=9.474,P=0.009,χ2=13.377,P=0.010);Ezrin同时还与组织学(日本分型)、TNM分期、浸润深度和淋巴结转移相关(χ2=37.542,P=0.000;χ2=12.237,P=0.002;χ2=21.194,P=0.002;χ2=9.868,P=0.007).Ezrin和HER2蛋白表达呈正相关(r=0.129,P=0.004).结论:Ezrin可能是预测胃癌组织浸润、转移有用的指标;联合检测Ezrin和HER2可作为判断胃癌预后、筛选高危转移患者的有效指标并有可能用于指导胃癌的个体化治疗.     

HER2与胃癌的研究进展

本文综述了HER2与胃癌相关的研究进展,介绍了HER2的结构、相关信号途径、在胃癌中的检测方法和检出率以及人源化抗HER2单克隆抗体曲妥珠单抗与胃癌治疗、HER2与胃癌预后的关系。研究显示HER2阳性是胃癌预后不良的重要因子,曲妥珠单抗与化疗药物联合应用是HER2阳性进展期胃和胃食管连接部癌以及伴肝转移患者治疗的新选择,可明显改善患者预后。