食管鳞状细胞癌EGFR 表达与放射治疗的关系研究进展

我国是全世界食管癌发病率和死亡率最高的国家之一。食管癌每年新增病例的一半发生在我国,但由于食管癌早期症状不明显及国内医疗技术水平等多种因素,目前的食管癌病人发现时多为中晚期,已失去了手术的机会,此时放疗成为其主要的治疗手段。然而,由于周围正常组织及食管本身因素的限制,导致放疗剂量无法继续提高,限制了放疗的效果,使得食管癌的5年生存率仍然较低。这就迫切的要求我们寻找可以指导我们选择最佳治疗方式的生物指标,以改善当前的治疗现状。伴随着EGFR研究的突破性进展及相关靶向药物在临床中的逐渐应用,近些年EGFR及相关靶向药物在食管癌中研究也在逐渐的开展,成为当前食管癌研究热点。本文将从食管鳞状细胞癌的EGFR表达情况及其与诊断、预后、放射治疗、放化疗综合治疗、放疗与靶向综合治疗的关系等方面的研究进展做简单的阐述。     

EGFR在晚期声门上型喉鳞癌组织中的表达及其临床意义

目的:研究表皮生长因子受体(epidermalgrowth factorreceptor,EGFR)在晚期声门上型喉鳞癌组织中的表达情况及其与临床各相关因素的关系,探讨EGFR能否作为判断晚期声门上喉鳞癌患者预后的预测性指标。方法:收集我院2004年1月~2008年4月共52例晚期(Ⅲ期、Ⅳ期)声门上型喉鳞癌患者手术后切除的肿瘤组织,应用免疫组化技术检测EGFR表达情况,运用统计学方法,结合临床资料分析其与肿瘤分期、淋巴结转移、病理分化程度、生存率及术后放疗对预后的影响等临床病理特征的关系。结果:EGFR在晚期声门上型喉鳞癌组织中存在阳性表达,阳性表达物质呈棕黄色,表达率为76.92%(40/52),其中过表达率为44.23%。EGFR的表达与晚期声门上型喉鳞癌患者的年龄、性别、吸烟无关,与浸润程度(P=0.005),淋巴结转移数目(P=0.018),TNM分期(P=0.003),病理分化程度(P=0.011)有关。单因素分析得出EGFR表达程度、T、N分期以及病理分化程度是影响无复发生存时间的危险因素(P0.05),T、N分期、病理分化程度是影响总生存时间的危险因素(P0.05)。多因素分析显示只有肿瘤浸润程度(T分期)和淋巴结转移(N分期)是影响无复发生存时间和总生存时间的独立预后因素。EGFR的阴性表达组与阳性表达组的3年、5年生存率不具有统计学差异(P0.05)。结论:EGFR在晚期声门上型喉鳞癌组织中存在过表达,证实了EGFR的过度表达与肿瘤的侵袭、转移相关,检测其表达水平对晚期喉癌的个体化治疗、靶向治疗有重要参考价值。但EGFR尚不能作为晚期声门上型喉鳞癌行手术及术后辅助放疗患者对无复发生存时间和总生存时间的预测指标。     

恶性胸腔积液中肺腺癌的EGFR、VEGF和P53的表达及分子生物学意义

目的探讨在恶性胸腔积液中肺腺癌细胞中EGFR、VEGF、P53表达的状态和关系及对临床治疗的分子生物学意义。方法利用液基薄层细胞学自动涂片技术方法和免疫化学方法筛查出恶性胸腔积液中肺腺癌77例和良性胸水10例,在用免疫细胞化学染色检测EGFR、VEGF、P53的表达情况。结果免疫细胞化学染色显示EGFR在肿瘤细胞中阳性表达55例,表达率为71.4%;VEGF和P53在恶性肿瘤细胞中阳性表达分别为57和31例,表达率分别为74%和40.3%,EGFR与VEGF表达具有相关性(r=0.609;P=0.000)。结论 EGFR、VEGF和P53在恶性胸腔积液的肺腺癌细胞中具有较高的表达率,且表达具有紧密联系,并可以对临床治疗有一定参考性。     

表皮生长因子受体与肺脏发育的关系

表皮生长因子受体(Epidermal growth factor receptor,EGFR)是一种跨膜蛋白受体,是ErbB家族成员之一,具有酪氨酸激酶活性。EGFR与相应的配体结合引起EGFR形成同源或异源二聚体启动胞内信号转导,激活下游多种信号转导途径,产生生物学效应,RAS/RAF/MEK/ERK通路与细胞增殖、分化和凋亡有关;PI3K/PDK1/AKT通路与细胞的迁移和粘附有关。EGFR能促进肺泡II型上皮细胞的成熟和肺表面活性物质的合成、分泌。EGFR对哺乳动物肺脏的作用呈现时空效应及剂量依赖效应,EGFR的下调表达则会引起肺脏发育不成熟;而EGFR过度表达促进肺肿瘤细胞的增殖、侵袭和转移。文章综述了EGFR及其调节信号通路的研究进展,以及EGFR与动物肺脏发育不成熟和肺癌之间的关系。     

以EGFR为靶点的肿瘤分子靶向药物研究进展

随着分子生物学研究的进展,分子靶向治疗已成为除手术、放疗、化疗之外的第4种治疗方法,越来越多的用于临床治疗恶性肿瘤。分子靶向药物进入体内能够特异地选择致癌位点,杀伤肿瘤细胞,而不会波及周围正常的组织细胞,因此分子靶向治疗又被称为"生物导弹"。与传统化疗药物相比,分子靶向药物具有特异性强、疗效明显、副作用少等优点。按照分子靶向药物的性质主要归为两大类:一类是单克隆抗体,如西妥昔单抗等;另一类是单靶点或多靶点的小分子抑制剂,如吉非替尼等。表皮生长因子受体(EGFR)对肿瘤的生长、发展以及肿瘤干细胞的维持都有着非常重要的作用,并且在多种实体瘤中存在过表达或异常表达,因此在肿瘤治疗中,EGFR成为一个非常重要的用药靶点。现主要对目前国内已上市的针对EGFR的分子靶向药物最新的临床研究进展作一简要综述。     

EGFR蛋白表达水平与结直肠癌放疗敏感性的相关性

为探讨表皮生长因子受体(EGFR)蛋白表达水平与结直肠癌放疗敏感性的相关性。选取我院2014年1月至2014年12月期间肛肠外科收治的50例局部进展期中低位结直肠癌患者,所有患者均接受放疗和直肠全系膜切除并达Ro切除治疗,均保留放疗前后的直肠癌组织病理标本,通过免疫组化SP法检测观察放疗前后病理表本中EGFR蛋白表达变化,根据肿瘤病理消退结果评估放疗敏感性,分析EGFR蛋白表达和放疗敏感性的的关系。50例患者放疗前后病理组织EGFR蛋白表达变化差异无统计学意义(p0.05),放疗后13例EGFR蛋白表达降低,21例表达无变化,16例表达升高;放疗后肿瘤病理消退42.00%(21/50),58.00%(29/50)患者病理消退并不明显;肿瘤病理消退单因素分析显示放疗方案、放疗总量、放疗前EGFR蛋白表达、放疗后EGFR蛋白表达变化是放疗敏感性的影响因素(x2=8.324,6.721,6.324,5.721,均p0.05);多因素Logistic回归分析显示放疗方案、放疗前后EGFR蛋白表达变化是放疗敏感性的独立影响因素(OR=2.547,19.824,均p0.05),放疗后EGFR蛋白表达升高提示结直肠癌患者放疗抵抗。结直肠癌患者放疗后病理组织EGFR蛋白表达变化不一,而放疗前后EGFR蛋白表达水平变化是放疗敏感性的独立影响因素。     

绵羊EGFR基因的克隆、表达及序列分析

表皮生长因子受体(epidermal growth factor receptor,EGFR)是酪氨酸激酶受体家族成员之一,不仅参与细胞增殖、生长和凋亡等多种生命活动,也可调节哺乳动物的乳腺发育及泌乳维持,但对绵羊EGFR基因的序列特征及组织表达情况鲜有报道.本试验以高泌乳量的小尾寒羊(泌乳高峰期和空怀期)及低泌乳量的甘肃高山细毛羊(泌乳高峰期)母羊为研究对象,利用RT-PCR、克隆及测序技术获得绵羊EGFR基因完整的CDS区,分析了 EGFR蛋白的结构特征及理化性质,利用RT-qPCR技术研究了基因的组织表达情况.结果表明,绵羊EGFR基因CDS区全长为3 627 bp,编码1 208个氨基酸.绵羊EGFR的氨基酸序列在各物种间较保守,与黄牛EGFR的氨基酸序列同源性最高.EGFR为跨膜蛋白,包含111个磷酸化位点,二级结构以α螺旋和无规则卷曲为主.网络互作分析表明EGFR蛋白与肝素结合表皮生长因子(HB-EGF)、表皮调节素(EREG)、双调蛋白(AREG)及生长因子受体结合蛋白2(GRB2)结合发挥作用.EGFR主要参与MAPK,PI3K/AKT,JAK/STAT及Wnt信号通路,从而参与了动物的乳腺发育及泌乳功能的调节.RT-qPCR结果表明,绵羊EGFR基因的表达具有组织特异性、时空特异性和品种特异性.该基因在所研究的8个组织中均表达,但在肾脏、卵巢、肝脏、乳腺和肺脏组织中的表达量较高;在小尾寒羊的乳腺组织中,该基因在空怀期的表达量显著高于泌乳高峰期的(P＜0.05);在泌乳高峰期的乳腺组织中,该基因在小尾寒羊中的表达量高于甘肃高山细毛羊的.本试验为深入研究绵羊EGFR基因的泌乳生物学功能提供了基础数据.     

EGFR Del 19 与JAK/STAT信号通路在NSCLC 中表达的相关性研究

目的:检测EGFR外显子19缺失突变(以下简称EGFR Del 19)和信号分子JAK/STAT在NSCLC组织中的表达,探讨EGFR Del 19表达与下游信号通路JAK/STAT表达之间的相关性,为进一步研究EGFR Del 19之NSCLC发生发展机制提供依据。方法:经ARMS法筛选出125例EGFR Del 19的NSCLC组织,应用免疫组织化学法检测该组织样本中EGFR Del 19、p-JAK1和p-STAT1的表达,统计分析三者在临床病理特点中的表达差异及EGFR Del 19与p-JAK1、p-STAT1表达之间的相关性。结果:EGFR Del 19阳性主要在细胞膜上表达,p-JAK1、p-STAT1阳性表达主要定位于细胞质和细胞核中。EGFR Del 19与NSCLC的病理分级、TNM分期、淋巴结转移与否显著相关(P值均0.05)。EGFR Del 19与p-JAK1、p-STAT1表达在不同病理分级、TNM分期及淋巴结转移与否组间具有显著相关性(P值均0.05,rs值均0.3)。结论:EGFR Del 19可能通过活化JAK1-STAT1途径促进NSCLC的发生发展。     

表皮生长因子受体信号通路在维吾尔族妇女宫颈癌中的表达研究

目的:随着表皮生长因子受体(epidermal growth factor receptor,EGFR)靶点治疗药物在其它肿瘤治疗中的应用,能否在妇科肿瘤中应用并取得疗效,已经得到学者们的重视。但在临床应用之前,必须明确EGFR与妇科肿瘤发生发展的关系及其机制。因此,我们来探讨表皮生长因子受体EGFR信号通路在维吾尔族不同级别宫颈病变组织中的差异表达及其临床意义。方法:应用免疫组织化学方法检测EGFR、P-EGFR、ERK 1/2、P-ERK1/2在108例子宫颈癌,47例CIN,79例正常宫颈组织中的表达,并分析其与临床病理参数的关系。结果:EGFR在子宫颈癌、CIN及正常宫颈组织中的阳性表达率分别是74.10%、66%、27.80%(P0.01);P-EGFR在三组间的阳性表达率分别是55.60%、74.50%、20.30%(P0.01);ERK1/2在三组间的阳性表达率分别是60.10%、76.60%、25.30%(P0.01);P-ERK1/2在三组间的阳性表达率分别是44.40%、66%、24.10%(P0.01),其在宫颈癌中EGFR与与浸润深度、淋巴结转移有关;ERK与肿瘤的临床分期、远处转移有关,而且在宫颈癌中EGFR与P-EGFR、ERK 1/2、P-ERK1/2的表达成正相关(P0.05)。结论:EGFR、P-EGFR、ERK1/2、P-ERK1/2的表达与宫颈癌的发生、发展相关,促进宫颈癌的浸润和转移,抑制EGFR信号通路可能为多靶点联合治疗宫颈癌提供新的方向。     

EGFR靶向的PET/SPECT分子成像研究进展

恶性肿瘤的发病率及死亡率逐年递增,分子靶向治疗为癌症治疗带来了新的革命,表皮生长因子受体(EGFR)在癌症发生、发展中发挥重要作用,针对EGFR的分子靶向治疗已成为近年研究热点。目前,已有多种EGFR分子靶向药物应用于临床,但总体有效率偏低。研究表明EGFR过表达和/或突变对治疗效果影响显著,因此治疗前准确评价肿瘤EGFR表达水平及突变状态显得尤为重要。分子成像能够实现活体细胞及分子水平生物学过程成像,并进行定性定量研究,使在体揭示EGFR表达状态成为可能。本文简述EGFR靶向分子成像的研究进展并对不同分子探针成像结果进行比较分析,对不同分子成像探针的功能进行评价,以期有益于EGFR靶向分子成像探针的研发及EGFR靶向分子成像研究。     

超声激活血卟啉对S180 肿瘤细胞表面EGFR 表达量的影响

目的：探讨超声激活血卟啉处理S180肿瘤细胞后膜表面EGFR表达量的变化。方法：将腹水瘤细胞随机分为四组,U组和UH组细胞分别于频率1．8MHz、2．0W／cm^2的超声装置中照射3min,并分别在1h3h5h后取材,应用免疫组化方法在光镜下观察EGFR的表达情况。结果：1h、3h取材,U组和UH组平均光密度值明显低于Cr组和H组,UH组最低。而5h取材时,UH组平均光密度值显著下降,其它组基本无变化。结论：提示在高频低强度处理下,随着时间的延长,超声激活HpD对EGFR的抑制作用增加,显示可能是基因调控使EGFR表达下调,从而使肿瘤细胞增殖减慢。     

表皮生长因子及受体在甲状腺肿瘤中的表达

目的:研究表皮生长因子(Epidermal Growth Factor,EGF)及受体(Epidermal Growth Factor Receptor,EGFR)及在甲状腺肿瘤中的表达。方法:应用免疫组织化学法检测91例甲状腺病变组织中EGFR和EGF的表达情况。结果:结节性甲状腺肿、甲状腺腺瘤、分化型甲状腺癌标本中EGFR表达的阳性率分别为15%、25%、68.62%,EGF表达的阳性率分别为10%、15%、68.62%,其中EGFR、EGF在分化型甲状腺癌与其余两组间差异均有统计学意义(P<0.05)。EGFR和EGF在甲状腺乳头状癌中的表达与性别、年龄、肿瘤大小、淋巴结转移、临床分期等临床因素无明显相关。结论:EGF和EGFR的表达可作为鉴别甲状腺肿瘤良恶性的一个指标。     

Epidermal Growth Factor (EGF)-enhanced Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression Promotes Macrophage and Glioblastoma Cell Interaction and Tumor Cell Invasion

Activated EGF receptor (EGFR) signaling plays an instrumental role in glioblastoma (GBM) progression. However, how EGFR activation regulates the tumor microenvironment to promote GBM cell invasion remains to be clarified. Here, we demonstrate that the levels of EGFR activation in tumor cells correlated with the levels of macrophage infiltration in human GBM specimens. This was supported by our observation that EGFR activation enhanced the interaction between macrophages and GBM cells. In addition, EGF treatment induced up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression in a PKCϵ- and NF-κB-dependent manner. Depletion of VCAM-1 interrupted the binding of macrophages to GBM cells and inhibited EGF-induced and macrophage-promoted GBM cell invasion. These results demonstrate an instrumental role for EGF-induced up-regulation of VCAM-1 expression in EGFR activation-promoted macrophage-tumor cell interaction and tumor cell invasion and indicate that VCAM-1 is a potential molecular target for improving cancer therapy.     

EGFR在胃癌中的研究进展

表皮生长因子受体（EGFR）通过下游的信号传导途径参与肿瘤细胞增殖、血管生成、侵袭、转移及凋亡抑制等的基因调控,在多种肿瘤组织中有高表达。近几年在胃癌的研究中显示：EGFR在胃癌中有高表达,与胃癌的发生、发展及生物学行为密切相关,被认为是胃癌等肿瘤治疗的理想靶点。当前以EGFR为靶点的生物治疗成为胃癌新的研究热点,本文就其近几年EGFR在胃癌的表达、预后及靶向治疗等研究现状作一综述。     

TGF-alpha-driven tumor growth is inhibited by an EGF receptor tyrosine kinase inhibitor.

The simultaneous presence of the EGFR and its ligand TGF-alpha in human tumor tissues suggests that autocrine TGF-alpha stimulation drives tumor growth. Here we show that autocrine TGF-alpha stimulation does cause increased tumor growth in vivo, an effect that was proven to be mediated via EGFR activation, and that this TGF-alpha/EGFR autocrine loop was accessible to an EGFR specific tyrosine kinase inhibitor. Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-alpha cDNA using a tetracycline-inhibitory system for gene expression. TGF-alpha expression was inhibited by the presence of tetracycline, and subcutaneous tumors forming from cell lines injected into nude mice could be inhibited by feeding mice tetracycline. We confirmed that TGF-alpha mRNA and protein were present in these tumors and that, subsequently, the endogenous EGFR was activated. Tumor growth could be inhibited by an EGFR specific tyrosine kinase inhibitor of the type 4-(3-chloroanilino)-6,7-dimethoxy-quinazoline, administered daily by intraperitoneal injection, thereby interrupting the autocrine loop.     

EGFR protein overexpression correlates with chromosome 7 polysomy and poor prognostic parameters in clear cell renal cell carcinoma

Background

The role of epidermal growth factor (EGF) and its receptor (EGFR) in the pathogenesis and progression of various malignant tumors has long been known, but there is still disagreement concerning prognostic significance of EGFR expression in clear cell renal cell carcinoma (CCRCC). The present study was designed to analyze more objectively the protein EGFR expression in CCRCC and to compare its value with EGFR gene copy number changes and clinicopathologic characteristics including patient survival.

Methods

The protein EGFR expression was analyzed immunohistochemically on 94 CCRCC, and gene copy number alterations of EGFR by FISH analysis on 41 CCRCC selected according to distinct membrane EGFR staining.

Results

Membrane EGFR expression in tumor cells was heterogeneous with respect to the proportion of positive cells and staining intensity. FISH analysis did not reveal EGFR gene amplification, while polysomy of chromosome 7 found in 41% was associated with higher EGFR membrane expression. Moreover, EGFR overexpression was associated with a higher nuclear grade, larger tumor size and shorter patient''s survival, while there was no connection with pathological stage.

Conclusion

In conclusion, the protein expression of EGFR had an impact on prognosis in patients with CCRCC, while an increased copy number of chromosome 7 could be the possible reason for EGFR protein overexpression in the absence of gene amplification.     

Ecto-5′-nucleotidase (CD73) is a potential target of hepatocellular carcinoma

High expression of ecto-5′-nucleotidase (CD73) has been reported in a number of epithelium origin malignancies. Here, we hypothesize that CD73 promotes hepatocellular carcinoma (HCC) growth and metastasis and that the effect is mediated by epithelial growth factor receptor (EGFR). HCC cells with different malignancies and Tissue microarrays of the tumor and peritumoral liver tissues from 30 independent patients were used to examine CD73 and EGFR expression. Then, MTT and Ki67 detection, together with cell adhesion, invasion, and migration assays were used to evaluate the effects of CD73 on cell growth and metastasis. The expression of EGFR in HCC cells was also tested after suppressing or overexpressing CD73. Lastly, tumor tissues from nude mice, which had been injected subcutaneously with HCC cells, were transplanted subcutaneously into CD73^−/− and wild-type (WT) C57 mice. CD73 expression was higher in HCC cells with greater metastatic potentials and tumor tissues compared with low metastatic cells and peritumor tissues. CD73 and EGFR were coexpressed and positively correlated in tumor and peritumor liver tissues in HCC tissue microarrays. Up-regulationof CD73 by plasmid transfection or by pharmacological agents promoted EGFR expression in HCC cells, whereas suppression of CD73 inhibited these effects. The growth of transplanted tumor tissues was dramatically slower in CD73^−/− mice than in WT type mice in the in vivo experiments. CD73 promotes HCC growth and metastasis and upregulated the expression of EGFR in HCC. Thus, CD73 and EGFR are potential targets in the treatment of HCC.     

Constitutive Activation of Epidermal Growth Factor Receptor Promotes Tumorigenesis of Cr(VI)-transformed Cells through Decreased Reactive Oxygen Species and Apoptosis Resistance Development

Hexavalent chromium (Cr(VI)) compounds are well-established lung carcinogens. Epidermal growth factor receptor (EGFR) is a tyrosine kinase transmembrane receptor that regulates cell survival, tumor invasion, and angiogenesis. Our results show that chronic exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) is able to cause malignant cell transformation. These transformed cells exhibit apoptosis resistance with reduced poly ADP-ribose polymerase cleavage (C-PARP) and Bax expression and enhanced expressions of Bcl-2 and Bcl-xL. These transformed cells also exhibit reduced capacity of reactive oxygen species (ROS) generation along with elevated expression of antioxidant manganese superoxide dismutase 2 (SOD2). The expression of this antioxidant was also elevated in lung tumor tissue from a worker exposed to Cr(VI) for 19 years. EGFR was activated in Cr(VI)-transformed BEAS-2B cells, lung tissue from animals exposed to Cr(VI) particles, and human lung tumor tissue. Further study indicates that constitutive activation of EGFR in Cr(VI)-transformed cells was due to increased binding to its ligand amphiregulin (AREG). Inhibition of EGFR or AREG increased Bax expression and reduced Bcl-2 expression, resulting in reduced apoptosis resistance. Furthermore, inhibition of AREG or EGFR restored capacity of ROS generation and decreased SOD2 expression. PI3K/AKT was activated, which depended on EGFR in Cr(VI)-transformed BEAS-2B cells. Inhibition of PI3K/AKT increased ROS generation and reduced SOD2 expression, resulting in reduced apoptosis resistance with commitment increase in Bax expression and reduction of Bcl-2 expression. Xenograft mouse tumor study further demonstrates the essential role of EGFR in tumorigenesis of Cr(VI)-transformed cells. In summary, the present study suggests that ligand-dependent constitutive activation of EGFR causes reduced ROS generation and increased antioxidant expression, leading to development of apoptosis resistance, contributing to Cr(VI)-induced tumorigenesis.