Effects of epidermal growth factor on the growth of human gastric cancer cell and the implanted tumor of nude mice

AIM：Epidermal growth factor(EGF)plays an important role in the regulation of gastrointestinal tissue growth and development,and it can stimulate epithelial proliferation,cell differentiation and growth,it has been established that the EGF can promote gastric cytoprotection and ulcer healing but the potential ability of EGF to reaulate the gastric cancer growth is unknown,This study is to investigate the influence of EGF on human gastric cancer cell and the implanted tumor growth of nude mice.METHODS:The cell growth rates of human gastric adenocarinome cell lines MKN-28,MKN-45,SGC-7901 and normal human gastric epithelial cells 3T3 were assessed when incubated with recombinant human EGF(rhEGF,0.05,0.1,0.5,1.0,10,50,100mg.L^-1)using MTT method ,The cells of MKN-28,MKN-45,SGC-7901(gastric cancer tissue 1.5mm^3)were implanted in the BALB/cA nude mice for 10 days,The EGF was given intraperitoneally(15,30,60μg.kg^-1)for 3 weeks.The body weights of the tumor bearing animals and their tumor mass were measured afterwards to assess the mitogenic effect of rhEGF in the nude mice.RESULTS:Within the concentration range of 0.05-100mg.L^-1 rhEGF could increase the cell growth of normal 3T3 cells (cell growth rate 100%vs 102.8%,P<0.05)but partially restrain the gastric cancer cell growth,The latter effect was related to cell differentiation ,In 15-60μg/kg rhEGF groups,the mean implanted tumor mass of MKN-28 cell were 1.75g,1.91g,2.08g/NS group 1.97g(P>0.05),the mean tumor mass of SGC-7901 cell were 1.53g,1.07g,1.20g/NS group 1.07g(P>0.05),and for MKN-45 cell,the tumor mass were respectively 1.92g,1.29g,1.77g/NS group 1.82g(P>0.05) So rhEGF had no obvious effect on implanted MKN-28,SGC-7901 and MKN-45 tumor growth.CONCLUSION:EGF has no stimulating effect on the human gastric cancer cell growth neither in vitro nor in vivo.     

VEGFR-3小干扰RNA对结肠癌裸鼠移植瘤生长的影响

目的:研究血管内皮生长因子受体3(vascularendothelial growth factor receptor 3,VEGFR-3)小干扰RNA对结肠癌细胞移植瘤模型生长的影响.方法:构建VEGFR-3小干扰RNA表达载体.将结肠癌LoVo细胞注射入裸鼠皮下建造裸鼠移植瘤模型.将15只裸鼠结肠癌模型随机分成3组:实验组(pG-siRNA/VEGFR-3重组质粒)、阴性对照组(pG-HK重组质粒)与空白对照组.分别瘤体内注射相应的siRNA混合物或转染剂混合液,每3 d注射1次,共注射3次,观察肿瘤体积的变化;6 wk后处死裸鼠,肿瘤称取质量,并进行qRT-PCR和Western blot测定VEGFR-3 mRNA和蛋白的变化,通过免疫组织化学进行微淋巴管计数.结果:实验组移植瘤体积和质量明显小于阴性对照组和空白对照组,有显著的统计学意义(P<0.001).实验组抑制率为52.75%,与对照组相比,差异有显著(P<0.001).qRT-PCR和Western blot测定VEGFR-3 mRNA和蛋白的变化比较,实验组有明显降低(P<0.001).实验组淋巴管计数较对照组差异显著(P<0.05).结论:VEGFR-3 siRNA可以抑制裸鼠结肠癌细胞移植瘤的生长,并减少裸鼠移植瘤淋巴管生成,能有效抑制结肠癌细胞的生长.     

Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.METHODS:One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study.HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization(FISH) and immunohistochemistry(IHC) analysis on formalin-fixed paraffinembedded gastric cancer samples from all patients.For scoring,Hofmann’s HER2 gastric cancer scoring system was adopted.All cases showing IHC3+ or FISH positiv-ity were defined as HER2 positive.Patient clinicopathological data and survival information were collected.Finally,χ 2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including;gender,age,tumor location,Lauren classification,differentiation,TNM staging,depth of invasion,lymph node metastases and distant metastasis.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.RESULTS:According to Hofmann’s HER2 gastric cancer scoring criteria,31 cases(15.74%) were identified as HER2 gene amplified and 19 cases(9.64%) were scored as strongly positive for HER2 membrane staining(3+),25 cases(12.69%) were moderately positive(2+) and 153 cases(77.66%) were HER2 negative(0/1+).The concordance rate between IHC and FISH analyses was 88.83%(175/197).Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression,with 24 of these cases being eligible for Herceptin treatment according to United States recommendations,and 29 of these cases eligible according to EU recommendations.Highly consistent results were detected between IHC3+,IHC0/1 and FISH(73.68% and 95.42%),but l     

Correlation of human epidermal growth factor receptor protein expression and colorectal cancer

AIM: To investigate the correlation between human epidermal growth factor receptor (HER-2) protein expression and colorectal cancer (CRC) using a case-control study and meta-analysis.METHODS: Tumor tissue specimens from 162 CRC patients were selected for the case group. Fifty cases were randomly selected, and normal CRC tissue at least 10 cm away from the tumor margins of these cases was used to generate the control group. The expression of the HER-2 protein in the 162 CRC tissue samples and the 50 adjacent normal mucosa tissue samples was detected via immunohistochemistry. The experimental data were analyzed using SPSS 18.0 software, and R software version 3.1.0 was utilized for further verification.RESULTS: The expression of HER-2 protein in the 162 CRC tissue samples was significantly higher than in the normal tissue specimens. The data showed that the expression of HER-2 in CRC was related to the Dukes’ stage, the depth of invasion and lymph node metastasis. The HER-2-positive patients had lower 3- and 5-year OS rates than the HER-2-negative patients, but there was no significant difference. However, there was a statistically significant difference in the 3- and 5-year disease-free survival (DFS) rates of HER-2-positive and HER-2-negative patients. The results of the meta-analysis showed that the expression of HER-2 in CRC patients was statistically significantly increased over that of healthy people. The 3-year DFS rate in HER-2-positive patients was markedly lower than that in HER-2-negative patients.CONCLUSION: Down-regulation of HER-2 expression might be a dependable strategy for CRC therapy.     

CIK细胞对裸鼠人胃癌移植瘤生长的抑制作用

目的: 探讨CIK细胞对裸鼠人胃癌移植瘤生长的抑制作用.方法: 用淋巴细胞分离液分离外周血单个核细胞, 给予多种细胞因子(rhIFN-γ、CD3mcAb、rhlL-2、rhlL-1), 诱导生成CIK细胞.培养人胃癌细胞株SGC-7901, 接种至40只裸鼠右腋皮下, 10 d后随机分2组, 每组20只, 分别为CIK组和对照组. 连续5 d在接种肿瘤细胞部位处给予CIK细胞和生理盐水注射治疗, 观察CIK细胞对胃癌移植瘤模型的抗肿瘤疗效.结果: CIK组胃癌肿块质量和生存期与对照组相比, 均具有显著性差异(1.21±0.34 g vs2.73±0.45 g, 65.8±6.2 d vs 44.3±4.8 d, 均P<0.01). 裸鼠体内实验表明, CIK细胞能够显著抑制胃癌细胞的生长, 其抑瘤率可达47.6%,明显高于对照组( P<0.01).结论: CIK细胞在裸鼠体内对人胃癌移植瘤有特异性抑瘤作用, 并可以延长裸鼠生存时间.     

Vascular endothelial growth factor monoclonal antibody inhibits growth of anaplastic thyroid cancer xenografts in nude mice.

BACKGROUND: Anaplastic thyroid cancer (ATC) does not respond well to any treatment and is one of the most aggressive of all human cancers. Based on the importance of angiogenesis in solid tumor growth, we hypothesized that angiogenic blockade might reduce the growth of ATC. METHODS: We tested the in vivo effect of vascular endothelial growth factor monoclonal antibody (VEGF-mAb) and thalidomide against ATC (ARO-81) xenografts in nude mice. Mice were injected subcutaneously with 1 x 10(6) ARO-81 cells, allowed to implant (1 week), and then given daily intraperitoneal injections of vehicle (control; n = 9), VEGF-mAb (200 microg/d; n = 9), or thalidomide (200 mg/kg per day; n = 9). Tumors were removed, sectioned, and stained for routine histology and immunohistochemistry. RESULTS: At 6 weeks, VEGF-mAb-treated tumors were smaller (1603 +/- 296 mm(3)) than either the thalidomide-treated (6007 +/- 1498 mm(3); p = 0.008) or the control groups (4040 +/- 831 mm(3); p = 0.014) and the VEGF-mAb-treated animals maintained greater weight (30.4 +/- 0.84 g at week 6 versus thalidomide-treated, 26.0 +/- 0.94 g, p = 0.003; and control, 25.8 +/- 0.78 g, p = 0.001 animals). Central necrosis was observed in 3 of 9 VEGF-mAb-treated confidence interval (33%; 95% [CI] = 0.12-0.65) but in none of the control or thalidomide-treated tumors (0/18 total; 95% CI = 0.0-0.30; p = 0.029). VEGF staining intensity for VEGF-mAb- (2.0 +/- 0.24; p = 0.012) and thalidomide- (2.1 +/- 0.05; p = 0.052) treated tumors was greater than control (0.89 +/- 0.31) as was p53 staining grade (VEGF-mAb [1.3 +/- 0.37; p = 0.012]; thalidomide [1.0 +/- 0.41; p = 0.05]; and controls [0.11 +/- 0.11]). CONCLUSION: We conclude that systemic VEGF-mAb significantly reduces growth of ATC xenografts and is associated with increased VEGF and p53 expression. Thalidomide has no effect on tumor growth, but is also associated with increased VEGF and p53 expression. These observations provide the first evidence that VEGF-mAb-induced angiogenesis blockade may be of use for the treatment of ATC.     

多希紫杉醇温敏纳米胶束对人胃癌裸鼠移植瘤的靶向治疗作用

目的:探讨多希紫杉醇温敏纳米胶束治疗人胃癌裸鼠移植瘤的疗效.方法:采用裸鼠BGC-823胃腺癌动物模型,每组6只,随机分配至设立的多希紫杉醇非热疗和热疗组,多希紫杉醇温敏纳米胶束非热疗和热疗组以及生理盐水对照组等共8组,采用尾静脉给药方式,并恒温43℃对热疗组肿瘤部位进行热导向化疗,动态观察并测定肿瘤的体积、瘤质量抑瘤率,评价治疗效果,并观察实验期间动物的全身情况及相对体质量变化,评价毒副作用.结果:多希紫杉醇温敏纳米胶束热疗组人胃癌移植瘤表现出明显抑制,体积和瘤质量抑瘤率分别为81.5%和85.4%,显著高于多希紫杉醇温敏纳米胶束非靶向组(32.2%,37.5%)和多希紫杉醇注射液组(49.2%,58.0%)(P<0.05),且多希紫杉醇温敏纳米胶束热疗组的小鼠体质量与其他各组比较相对平稳,且饮食、活动正常,对正常组织的毒副作用明显减轻.结论:温敏纳米胶束具有良好的高效低毒体内抗肿瘤作用,作为一种新型的药物载体显示了良好的应用前景.     

表皮生长因子受体及增殖细胞核抗原在胃癌中的表达及意义

为探讨表皮生长因子受体 ( EGFR)及增殖细胞核抗原 ( PCNA)在胃癌中的表达 ,应用免疫组织化学技术 ,对胃癌和胃良性肿瘤组织中 EGFR和 PCNA分别进行定性和半定量检测 ,分析其与临床病理参数的关系。结果显示 1在胃良性肿瘤组织中 EGFR的表达率为 2 3 .0 8% ,PCNA L I为 2 7.80± 12 .2 0 ,明显低于胃癌组织中的表达率 ( 49.0 9% ,PCNA L I5 2 .73± 12 .2 5 ,P<0 .0 1)。2胃癌组织中 EGFR和 PCNA的表达与患者性别、年龄、病变部位、分型、组织学类型及分化程度无关 ( P均 >0 .0 5 ) ,而与临床分期、浸润深度及淋巴结转移情况相关 ( P <0 .0 5 ) ,表明联合检测 EGFR和 PCNA可作为判断胃癌恶性程度、预测淋巴结转移、制定合理治疗方案及评估预后的重要指标     

表皮生长因子及其受体在糜烂胃黏膜中的表达

目的:观察胃窦黏膜糜烂区与糜烂旁胃黏膜、慢性萎缩性胃炎中表皮生长因子(epidermal growth factor,EGF)及其受体(epidermal growth factor receptor,EGFR)的表达,探讨其在胃黏膜损伤修复中的意义.方法:选择经胃镜及病理确诊的慢性萎缩性胃炎伴胃窦黏膜糜烂患者50例,距糜烂区3cm处40例,无糜烂慢性萎缩性胃炎40例,采用免疫组织化学染色法测EGF及EGFR的表达.结果:胃窦黏膜糜烂区EGF、EGFR阳性表达率分别为40%和30%,明显高于糜烂旁胃黏膜15%和10%及无糜烂慢性萎缩性胃炎20%和12.5%的阳性表达率(P<0.05),有统计学意义,无糜烂慢性萎缩性胃炎组略高于糜烂旁胃黏膜组,但无统计学差异.结论:EGF、EGFR在胃黏膜损伤后高表达,对促进胃黏膜修复有着重要意义.     

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

AIM: To investigate human epidermal growth factor receptor 2 (HER2)-phosphatidylinositol 3-kinase (PI3K)-v-Akt murine thymoma viral oncogene homolog signaling pathway.METHODS: We analyzed 231 formalin-fixed, paraffin-embedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment. The patients’ age, sex, tumor location, depth of invasion, pathological type, lymph node metastasis, and pathological stage were determined by a review of the medical records. Expression of HER2 was analyzed by immunohistochemistry (IHC) using the HercepTest^TM kit. Standard criteria for HER2 positivity (0, 1+, 2+, and 3+) were used. Tumors that scored 3+ were considered HER2-positive. Expression of phospho Akt (pAkt) was also analyzed by IHC. Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more. PI3K, catalytic, alpha polypeptide (PIK3CA) mutations in exons 1, 9 and 20 were analyzed by pyrosequencing. Epstein-Barr virus (EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA (EBER) with an EBER-RNA probe. Microsatellite instability (MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS: HER2 expression levels of 0, 1+, 2+ and 3+ were found in 167 (72%), 32 (14%), 12 (5%) and 20 (8.7%) samples, respectively. HER2 overexpression (IHC 3+) significantly correlated with intestinal histological type (15/20 vs 98 /205, P = 0.05). PIK3CA mutations were present in 20 cases (8.7%) and significantly correlated with MSI (10/20 vs 9/211, P < 0.01). The mutation frequency was high (21%) in T4 cancers and very low (6%) in T2 cancers. Mutations in exons 1, 9 and 20 were detected in 5 (2%), 9 (4%) and 7 (3%) cases, respectively. Two new types of PIK3CA mutation, R88Q and R108H, were found in exon1. All PIK3CA mutations were heterozygous missense single-base substitutions, the most common being H1047R (6/20, 30%) in exon20. Eighteen cancers (8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type (13/18 vs 93/198, P = 0.04). There were 7 cases of lymphoepithelioma-like carcinomas (LELC) and 6 of those cases were EBV-positive (percent/EBV: 6/18, 33%; percent/all LELC: 6/7, 86%). pAkt expression was positive in 119 (53%) cases but showed no correlation with clinicopathological characteristics. pAkt expression was significantly correlated with HER2 overexpression (16/20 vs 103/211, P < 0.01) but not with PIK3CA mutations (12/20 vs 107/211, P = 0.37) or EBV infection (8/18 vs 103/211, P = 0.69). The frequency of pAkt expression was higher in cancers with exon20 mutations (100%) than in those with exon1 (40%) or exon9 (56%) mutations. One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection. However, no cases showed both PIK3CA mutations and HER2 overexpression. One EBV-positive cancer with PIK3CA mutation (H1047R) was MSI-positive. Three of these 4 cases were positive for pAkt expression. In survival analysis, pAkt expression significantly correlated with a poor prognosis (hazard ratio 1.75; 95%CI: 1.12-2.80, P = 0.02).CONCLUSION: HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized. pAkt expression significantly correlates with HER2 expression and with a poor prognosis.     

Inhibition of human tumor growth in nude mice by a conjugate of doxorubicin with monoclonal antibodies to epidermal growth factor receptor.

Monoclonal antibodies that recognize the extracellular domain of the epidermal growth factor receptor (mAb108) were conjugated with doxorubicin through a dextran bridge. Several antibody-drug conjugates, containing different amounts of doxorubicin, retained binding capacity to human epidermoid carcinoma (KB) cells overexpressing epidermal growth factor receptors. Slight decrease in drug cytotoxicity was seen in in vitro tests, as determined either by inhibition of thymidine incorporation into cells or by reduction in number and size of KB-cell colonies. Yet, when tested in vivo against KB tumor xenografted into nude mice, the anti-epidermal growth factor-receptor drug conjugates with high drug-substitution levels were significantly more effective than free doxorubicin, antibody alone, mixture of dextran-doxorubicin and antibody, or drug conjugated with irrelevant antibody. When the labile covalent bonds linking antibody to dextran bridge were stabilized by reduction, the therapeutic efficacy of the conjugate was markedly decreased. These results show that antibodies against the extracellular domain of the epidermal growth factor can deliver doxorubicin specifically and efficiently to tumor sites that express high receptor levels exerting a specific antitumor effect.     

Expression of epidermal growth factor receptor in gastric carcinomas.

BACKGROUND & AIMS: Epidermal growth factor receptor belongs to the family of type I receptor tyrosine kinases. Overexpression of epidermal growth factor receptor has been observed in a variety of cancers with or without amplification of the gene. Novel chemotherapies targeting receptor tyrosine kinases might be effective for the treatment of cancers in which overexpression of this protein is a feature. The aim of this study was to assess the potential efficacy of epidermal growth factor receptor-targeted therapy in gastric cancer. This was achieved by determining the frequency of increased epidermal growth factor receptor expression in gastric cancers and investigating the relationship between protein overexpression and gene amplification. METHODS: Immunohistochemical evaluation of 413 gastric cancers was carried out by using a monoclonal antibody to the epidermal growth factor receptor. The intensity of reactivity was scored by using a 4-tier system (negative, 1+, 2+, and 3+). All positive staining (>1+) tumors overexpressing the protein were then analyzed for gene amplification by fluorescence in situ hybridization by using a gene-specific probe. RESULTS: High levels of overexpression (2+ or 3+ staining) were found in 9 of 413 (2.2%) patients, whereas low levels of overexpression (1+) were found in 34 (8.2%) of the study cohort. Fluorescence in situ hybridization analysis showed that more than 10 copies of the gene were recognized in all 5 cancers with 3+ staining and in 2 of the 4 tumors with 2+ staining. CONCLUSIONS: Although a high level of overexpression of epidermal growth factor receptor is uncommon in gastric carcinomas, it almost exclusively occurs by gene amplification.     

Role of human epidermal growth factor receptor 2 in gastric cancer:Biological and pharmacological aspects

Amplification of the human epidermal growth factor receptor 2(HER2)gene and overexpression of the HER2protein is found in 15%-20%of patients with gastric and gastroesophageal junction cancer.The degree of HER2 overexpression and amplification varies with the location of the carcinoma,with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach.Further,HER2 overexpression and amplification also seems to be related to the Lauren histological classification,with higher levels found in the intestinal phenotype compared to the diffuse and mixed types.The prognostic properties of HER2 overexpression and amplification are still under debate,but a large number of studies seem to indicate that HER2 is a negative prognostic factor.The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial,where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive5-FU/capecitabine and cisplatin,either alone or in combination with trastuzumab.A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy.Patients with a strong overexpression of the HER2 protein(IHC3+)specifically benefited from the treatment,with a median overall survival of 17.9 mo.As a consequence of the positive results of the ToGA trial,patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2.The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab,ado-trastuzumab emtansine,lapatinib,afatinib,and dacomitinib,which are currently undergoing phaseⅡandⅢclinical testing.Overall,this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.     

Insulin-like growth factor I receptor blockade enhances chemotherapy and radiation responses and inhibits tumour growth in human gastric cancer xenografts

BACKGROUND AND AIMS: Insulin-like growth factor (IGF) I receptor (IGF-Ir) signalling is required for carcinogenicity and proliferation of many tumours but this pathway has not been studied in detail in gastric cancer. We have previously shown successful therapy for colorectal, pancreatic, and lung cancer using recombinant adenoviruses expressing dominant negative (dn) IGF-Ir. In this study, we sought to better dissect the role of IGF-Ir on progression of gastric cancer and determine whether IGF-Ir targeted adenoviruses represent potentially effective therapeutics for human gastric cancer. METHODS: We assessed the effect of IGF-Ir ligands on proliferation and survival in gastric cancer cells in culture. Then, recombinant adenoviruses expressing truncated IGF-Ir (482 and 950 amino acids long, IGF-Ir/dn) that function as dn inhibitors were studied in the treatment of human gastric cancer xenografts. We characterised the effects of IGF-Ir/dn on signalling blockade, growth, apoptosis induction, and in vivo therapeutic efficacy. RESULTS: IGF-Ir signalling promoted tumour growth and survival in gastric cancer. IGF-Ir/dn expression suppressed tumorigenicity both in vitro and in vivo and upregulated stressor induced apoptosis. IGF-Ir/dn blocked Akt-1 activation induced by IGF-I, IGF-II, and des(1-3)IGF-I, but not by insulin. IGF-Ir/dn expression increased radiation and chemotherapy induced apoptosis and the combination of IGF-Ir/dn and chemotherapy was very effective against tumours in mice. In an intraperitoneal model, IGF-Ir/dn therapy also suppressed peritoneal dissemination. CONCLUSIONS: IGF-Ir is involved in the regulation of survival and cell growth in human gastric cancer and may be a good molecular therapeutic target. Adenovirus-IGF-Ir/dn may thus have therapeutic use in gastric cancer.     

胃癌组织中生长抑素与表皮生长因子受体表达的相关性及意义

目的观察胃癌组织中生长抑素（ＳＳ）表达与表皮生长因子受体（ＥＧＦＲ）表达的相互关系，探讨其抑癌的可能机制．方法应用免疫组化ＬＳＡＢ法及即用型ＳＰ法，对１４７例各种组织学类型胃癌中ＳＳ及ＥＧＦＲ的表达进行观察比较，并对其中１２７例患者进行预后随访．结果胃癌中ＳＳ阳性表达率为２５７％．ＥＧＦＲ阳性表达率５４３％．ＳＳ阳性及ＳＳ阴性两组胃癌ＥＧＦＲ的表达有明显差异（Ｐ＜００１）．ＳＳ阳性胃癌组ＥＧＦＲ的表达明显减少；ＳＳ阴性胃癌组ＥＧＦＲ的表达增多．ＳＳ阳性胃癌较ＳＳ阴性胃癌生存期长，预后好（Ｐ＜００１）．相反，ＥＧＦＲ阳性胃癌较ＥＧＦＲ阴性胃癌生存期短，预后差（Ｐ＜００１）．尤其是伴有ＳＳ阴性表达的ＥＧＦＲ阳性胃癌预后更差．结论ＳＳ及ＥＧＦＲ在人体胃癌组织中的表达有一定拮抗性．ＳＳ阴性的ＥＧＦＲ阳性胃癌预后更差．ＳＳ的抑癌机制之一可能是干扰了生长因子的合成，影响了细胞内调节细胞生长信号的传递，从而抑制肿瘤生长     

Reduced expression of epidermal growth factor receptor related protein in gastric cancer

OBJECTIVES: The recently cloned epidermal growth factor receptor related protein (ERRP) has been proposed to be a negative regulator of the epidermal growth factor receptor (EGFR). Because of the causal involvement of EGFR and its ligands in gastric cancer growth, we investigated expression of ERRP and cell proliferation in human gastric cancer. METHODS: We examined ERRP expression and localisation in surgical specimens of gastric cancers from 47 patients versus non-malignant gastric mucosa and determined their relationship to cell proliferation and differentiation. We also examined expression of ERRP by western blotting in three different gastric cancer cell lines. To further determine the functional properties of ERRP, we examined the effect of ERRP on epidermal growth factor (EGF) induced EGFR phosphorylation essential for its activation in MKN-28 gastric cancer cells. RESULTS: ERRP expression was dramatically reduced in gastric cancers (34% of all specimens positive) compared with non-malignant gastric mucosa (66% of specimens positive). Expression of ERRP in cancer cells inversely correlated with cell proliferation and grade of malignancy. Cell lines derived from metastatic gastric cancers had reduced ERRP expression compared with cell lines derived from a non-metastatic cancer. Exogenous ERRP protein markedly inhibited EGF induced EGFR phosphorylation in gastric cancer cells providing a novel molecular mechanism of its action. CONCLUSIONS: Our data indicate that downregulation of ERRP could play an important role in gastric cancer differentiation and progression. ERRP is a negative regulator of tumour cell proliferation and may exert its inhibitory effect, in part, by attenuating EGFR activation.     

Potential role of the epidermal growth factor receptor in human pancreatic cancer

The epidermal growth factor (EGF) receptor is a transmembrane protein that has tyrosine kinase activity. It is activated by both EGF and transforming growth factor-alpha (TGF-alpha). Human pancreatic cancer cells overexpress the EGF receptor and exhibit a parallel increase in EGF receptor mRNA without a detectable increase in the number of gene copies coding for the receptor. These cells also produce TGF-alpha and are capable of binding exogenous TGF-alpha. They often recycle EGF, but markedly and rapidly degrade TGF-alpha. However, TGF-alpha is 10-100-fold more potent than EGF in enhancing their anchorage-independent growth. Both growth factors induce EGF receptor down-regulation, but EGF is more efficient than TGF-alpha in this regard. The concomitant overexpression of the EGF receptor and production of TGF-alpha, the recycling of EGF, and the attenuated ability of TGF-alpha to down-regulate the EGF receptor may combine to provide a distinct growth advantage to human pancreatic cancer cells.     

斑蝥素抑制裸鼠胰腺癌移植瘤生长研究

目的 探讨斑蝥素对荷瘤裸鼠胰腺癌移植瘤生长的影响.方法 在培养人胰腺癌SW1990细胞的基础上建立荷瘤裸鼠胰腺癌模型,瘤内注射斑蝥素1 mg/kg体重作为斑蝥素组,瘤内注射等量生理盐水作为对照组,观测移植瘤大小改变及p53、Bcl-2和Bax蛋白表达的变化.结果 两组裸鼠移植瘤的体积随着时间的延长而明显增加,但斑蝥素组的增长幅度明显小于对照组(P＜0.05),移植后27 d瘤体缩小40%;斑蝥素组移植瘤Bcl-2无强阳性(+ +～+ + +)表达,p53强阳性表达6只(85.7%),Bax强阳性表达3只(42.9%),对照组强阳性表达分别为2只(33.3%)、3只(50%)和2只(33.3%).Bcl-2、p53表达两组差异显著(P＜0.05),而Bax表达无显著差异.结论 斑蝥素可明显抑制裸鼠胰腺癌移植瘤的生长,其机制可能与斑蝥素下调Bcl-2蛋白表达,上调p53蛋白表达有关.