表皮生长因子调节水通道蛋白3表达对结肠癌细胞迁移能力的影响

目的:探讨EGF调节AQP3表达对结肠癌细胞迁移能力的影响。方法:Western blot检测EGF不同条件作用下结肠癌细胞株HCT116 AQP3的表达情况;划痕实验检测不同AQP3表达程度下结肠癌细胞迁移能力的变化。结果:Western blot检测显示EGF上调AQP3表达并且呈时间和剂量依赖,在不同剂量EGF刺激下和不同作用时间下,AQP3的表达强度具有统计学差异(P<0.05);划痕实验示不同AQP3表达各组结肠癌细胞株HCT116迁移能力具有统计学差异(P<0.05),AQP3高表达可以促进结肠癌细胞迁移能力增强并且这一作用可以被AQP3抑制剂CuSO4阻断。结论:AQP3在EGF结合EGFR后上调表达并增强结肠癌细胞的迁移能力。     

人表皮生长因子受体-2及雌激素受体与乳腺癌的关系

乳腺癌与人表皮生长因子受体-2及雌激素受体关系密切,这两种受体也是乳腺癌的分类标准和治疗靶点。在大多数乳腺癌患者中,人表皮生长因子受体-2信号途径和雌激素受体信号途径参与了细胞的增生存活过程。而且在乳腺癌病例中,人表皮生长因子受体-2和雌激素受体呈现出一定程度的负相关。这说明这两种受体活化后有一些联系。本文简要综述了人表皮生长因子受体-2和雌激素受体的联系以及这种联系在乳腺癌治疗中的意义。     

表皮生长因子、雄激素受体和表皮生长因子受体在肝癌组织中的表达及影响因素分析

目的探讨肝癌患者肝癌组织中的表皮生长因子(EGF)、雄激素受体(AR)、表皮生长因子受体(EGFR)的表达情况及临床意义。方法采用免疫组织化学染色法检测EGF、AR、EGFR在90例肝癌患者的肝癌组织和90例非肝癌患者的非肝癌组织中的表达情况,比较不同临床特征肝癌患者肝癌组织中EGF、AR、EGFR的表达情况,分析肝癌患者肝癌组织中EGF、AR、EGFR表达的影响因素。结果肝癌组织中的EGF、AR、EGFR的阳性表达率均明显高于非肝癌组织,差异均有统计学意义(P﹤0.01)。有肝炎史、Ⅲ+Ⅳ期、中低分化、有淋巴结转移的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率均高于无肝炎史、Ⅰ+Ⅱ期、高分化、无淋巴结转移的肝癌患者,差异均有统计学意义(P﹤0.05);不同年龄、性别、肿瘤直径的肝癌患者肝癌组织中EGF、AR、EGFR的阳性表达率比较,差异均无统计学意义(P﹥0.05)。Logistic回归分析结果显示,有淋巴结转移、TNM分期为Ⅲ+Ⅳ期是肝癌患者肝癌组织中EGF、AR、EGFR表达的独立危险因素。结论EGF、AR、EGFR在肝癌患者的肝癌组织中呈高表达,且其表达与肝癌患者的淋巴结转移情况和TNM分期密切相关。     

RNA干扰下调不同肿瘤细胞表皮生长因子受体表达及其意义

背景与目的：表皮生长因子受体在多种上皮源性肿瘤中过表达，与肿瘤的发生、发展密切相关，是肿瘤治疗的重要靶点。本研究采用针对EGFR的小干扰RNA（siRNA），探讨其在不同类型肿瘤细胞A431、HeLa、SPC-A-1中的RNA干扰效应。方法：化学合成针对EGFR的siRNA，转染A431、HeLa、SPC—A-1细胞，通过定量RT-PCR、免疫荧光染色和流式细胞仪检测EGFR表达；通过集落形成实验观察细胞集落形成能力，分析不同类型肿瘤细胞的RNA干扰效应。结果：转染siRNA-EGFR后，3种肿瘤细胞的EGFR表达均明显下调。在A431细胞，其mRNA水平下调73．9％，蛋白水平下调77．0％。在HeLa和SPC-A-1细胞，mRNA水平的下调分别为44．6％和57．7％。蛋白水平下调61．3％和65．2％。EGFR下调后细胞集落形成能力均出现抑制，A431、HeLa和SPC-A-1的集落形成抑制率分别为27．2％、53．9％和59．1％。结论：siRNA-EGFR可在不同类型肿瘤细胞中产生RNA干扰效应。抑制细胞集落形成能力。RNA干扰技术在开发广谱抗肿瘤靶向治疗药物中具有应用价值。     

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Preclinical antitumor activity of S‐222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER2 inhibitor, S‐222611, that selectively inhibited both kinases with IC₅₀s below 10 nmol/L. S‐222611 also inhibited intracellular kinase activity and the growth of EGFR‐expressing and HER2‐expressing cancer cells. In addition, S‐222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. In evaluations with two patient‐oriented models, the intrafemoral implantation model and the intracranial implantation model, S‐222611 exhibited excellent activity and could be effective against bone and brain metastasis. Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S‐222611 showed equivalent or slightly weaker antitumor activity but a safer profile. These results indicated that S‐222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses. Considering the safer profile than for irreversible inhibitors, S‐222611 could be an important option in future cancer therapy.     

Impact of clinicopathological characteristics on the efficacy of neoadjuvant therapy in patients with human epidermal growth factor receptor‐2‐positive breast cancer

Neoadjuvant therapy has become increasingly common in human epidermal growth factor receptor‐2 (HER2)‐positive breast cancer. In this study, we examined the impact of different clinicopathological characteristics on pathological complete response (pCR) in patients treated with anti‐HER2 agents. The PubMed and Embase databases were searched from inception through April 2017 to identify studies that met pre‐specified criteria. The odds ratios (ORs) and 95% confidence intervals (CIs) were extracted directly or were calculated with other available information. Eleven randomized controlled trials (RCTs) that involved 3,269 HER2‐positive women were included in this meta‐analysis. Patients with hormone receptor (HR)‐negative breast cancer benefited more from anti‐HER2 therapy than did patients with HR‐positive tumours (OR, 2.25; 95% CI, 1.93‐2.62). Furthermore, this improvement in pCR was independent of anti‐HER2 agents, phase, combined chemotherapy, neoadjuvant duration, year the trials started and region where the trials were conducted. Patients with small tumours achieved greater benefits than patients with large tumours (OR, 1.25; 95% CI, 1.00‐1.55). Age did not predict an additional benefit from anti‐HER2 neoadjuvant treatment (OR, 1.02; 95% CI, 0.73‐1.45). The impact of nodal status on pCR was dependent on the anti‐HER2 agents. In conclusion, for HER2‐targeted neoadjuvant treatment in breast cancer, greater benefits were achieved in patients with small HR‐negative tumours compared with patients with large HR‐positive tumours. These results may improve drug development and treatment strategies, economic analyses and the design and interpretation of clinical trials.     

Prognostic value of epidermal growth factor receptor in node-positive breast cancer

Summary The prognostic significance of EGFR (epidermal growth factor receptor) was studied in a cohort of 68 node-positive patients with breast cancer, who entered a controlled protocol of adjuvant therapy between February 1980 and June 1984. EGFR radioligand binding assay was carried out on frozen stored samples. Twenty five (37%) of 68 primary sites and 9 (41%) of 19 lymph node metastases assayed were EGFR-positive with a cut off value of 5 fmol/mg membrane protein; there is no statistical difference between the two distributions. EGFR was significantly correlated to ER and histological grade. EGFR-positive tumors and high levels of EGFR were mainly found in the ER-negative group of tumors (p = 0.008) and in histological grade III (p = 0.007). Fifty five patients could be followed for 40 to 92 months. EGFR was an independent prognostic factor for survival after 40 months (p = 0.05). EGFR⁺/ER^– patients had the lowest survival probability, but statistical significance was not reached (p = 0.06). The EGFR phenotype appeared as a prognostic parameter in node-positive patients, individualizing subgroups of patients with different early outcome, with potential therapeutic implication especially in the group of ER-negative patients. These results emphasize the need for a standardized assay methodology and for further clinical studies, particularly in protocols where adjuvant hormonal therapy is prescribed on the basis of steroid hormone receptor status, in order to assess the respective prognostic worth of EGFR and ER (or PR).     

Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells

The epidermal growth factor receptor (EGF-R) pathway plays a pivotal role in the progression of human gastric cancer. The angiogenic factor vascular endothelial growth factor (VEGF) has been shown to be induced by EGF in various cancer cell lines. Neuropilin-1 (NRP-1) acts as a coreceptor for VEGF-165 and increases its affinity for VEGF receptor 2 (VEGFR-2) in endothelial cells. Furthermore, NRP-1 has been found to be expressed by tumour cells and has been shown to enhance tumour angiogenesis and growth in preclinical models. We examined the expression of NRP-1 mRNA and EGF-R protein in seven human gastric cancer cell lines. NRP-1 expression was expressed in five of seven cell lines, and EGF-R expression closely mirrored NRP-1 expression. Moreover, in EGF-R-positive NCI-N87 and ST-2 cells, EGF induced both NRP-1 and VEGF mRNA expression. C225, a monoclonal antibody to EGF-R, blocked EGF-induced NRP-1 and VEGF expression in NCI-N87 cells in a dose-dependent manner. The treatment of NCI-N87 cells with EGF resulted in increases in phosphorylation of Erk1/2, Akt, and P38. Blockade of the Erk, phosphatidylinositol-3 kinase/Akt, or P38 pathways in this cell line prevented EGF induction of NRP-1 and VEGF. These results suggest that regulation of NRP-1 expression in human gastric cancer is intimately associated with the EGF/EGF-R system. Activation of EGF-R might contribute to gastric cancer angiogenesis by a mechanism that involves upregulation of VEGF and NRP-1 expression via multiple signalling pathways.     

人绒毛膜促性腺激素对小鼠睾丸间质细胞的表皮生长因子及其受体的影响

目的　探讨HCG 与EGF、EGFR 共同调节生精过程机制, 为HCG 及EGF的临床应用提供一定依据。方法　应用免疫组化、体视学、图像分析方法对切除颌下腺和给予HCG 前后的ICR系小鼠睾丸间质细胞的EGF、EGFR 变化进行观察比较。结果　颌下腺切除后, 小鼠睾丸EGF阳性间质细胞体密度不变, 而光密度下降; 睾丸EGFR 阳性间质细胞体密度、光密度下降;EGF及EGFR阳性间质细胞体积减小。切除颌下腺后给予HCG, EGF 及EGFR 阳性间质细胞体密度、光密度增高, 比表面减小, 体积增大; EGF 及EGFR 阳性间质细胞的细胞核体积增大。结论　间质细胞EGF合成减少及EGFR 表达减弱是切除颌下腺引起小鼠少精症的重要原因之一;HCG 能增强睾丸间质细胞EGF合成及EGFR 的表达     

Clinical value of enzyme immunoassay of epidermal growth factor receptor in human breast cancer

Summary Epidermal growth factor receptor (EGFr) levels were analyzed in 140 primary breast cancer specimens by immunohistochemical assay (ICA), competitive binding assay (BA), or enzyme immunoassay (EIA). Thirtynine of 118 specimens (33.1%) were scored as positive by ICA, 30 of 116 (25.9%: cut-off level 10 fmol/mg protein) by BA, and 31 of 80 (38.9%: cut-off level 5 fmol/mg protein) by EIA. Agreement on EGFr status was 72.3% (68/94) between ICA and BA, 77.0% (57/74) between BA and EIA, and 73.8% (59/80) between EIA and ICA. These discrepancies are based on assay differences and the heterogeneous distribution of cancer cells within specimens. Regardless of the assay method used, EGFr status had a significantly negative correlation with estrogen receptor status. Although EGFr-ICA and BA status had no relationship with prognosis, patients with medium and high EGFr-EIA level tumors (over 5 fmol/mg protein) had shorter relapse-free periods than those with low level tumors. However, the prognostic value of positive EGFr-EIA status was weaker than that ofc-erbB-2 overexpression.     

Heparin-binding epidermal growth factor-like growth factor isoforms and epidermal growth factor receptor/ErbB1 expression in bladder cancer and their relation to clinical outcome

BACKGROUND: Cleavage of membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields a soluble HB-EGF isoform (sHB-EGF), which is an activating epidermal growth factor receptor (EGFR) ligand and a C-terminal fragment HB-EGF-C acting directly in the nucleus. In bladder cancer, overexpression of both HB-EGF and EGFR have been observed, but to the authors' knowledge the prognostic significance of different modes of HB-EGF signaling have remained unclear. METHODS: Expression and intracellular localization of HB-EGF and EGFR were examined by immunohistochemistry in paraffin-embedded specimens from 121 patients who underwent cystectomy for bladder cancer. Tumor stage was pTis/pT1 in 7 patients, pT2 in 41 patients, pT3 in 55 patients, and pT4 in 18 patients. Lymph node metastases were present in 32 patients. RESULTS: Using an antibody directed against the C-terminal domain, HB-EGF expression was detected in the cytoplasm or in the nucleus of tumor cells. EGFR staining was uniform at the plasma membrane. The actuarial 5-year cancer-specific survival of patients with tumors with predominant nuclear HB-EGF staining was 28% compared with 57% if HB-EGF staining was predominantly cytoplasmic (P = .027). Disease outcome of patients with a 'mixed' HB-EGF staining pattern was found to be between that of the 2 former groups. In agreement with previous studies, strong EGFR expression was associated with poor prognosis. Despite strong EGFR expression, predominant cytoplasmic HB-EGF staining was associated with a more favorable outcome, whereas a predominant nuclear pattern defined a subgroup with extremely poor prognosis (5-year tumor-specific survival of 55% vs 13%, respectively; P = .026). CONCLUSIONS: The current study results confirm that EGFR expression is significantly correlated with disease-specific mortality but that the outcome is also influenced by the mode of HB-EGF signaling. Additional nuclear HB-EGF signaling, indicative of increased cleavage of proHB-EGF, appears to enhance the adverse activities. Cytoplasmic HB-EGF staining likely reflects proHB-EGF, which may also exert antiproliferative effects.     

人表皮生长因子受体2模拟表位的筛选

目的:从噬菌体12肽库中筛选出人表皮生长因子受体2（Her2）的抗原模拟表位。方法:以曲妥珠单抗为靶分子,在噬菌体12肽库中进行3轮淘选,以ELISA方法及竞争抑制实验鉴定阳性克隆,并对阳性克隆株进行测序。结果:经过3轮淘选,与曲妥珠单抗结合的噬菌体得到了有效富集,回收率从（2.00×10-8）%增加到（2.87×10-5）%,ELISA显示20个克隆中筛选获得了18个与曲妥珠单抗具有较高亲和性的阳性噬菌体,对阳性克隆测序获得两种氨基酸序列:HTSSLWHLFRST、VHWDFRQWWQPS。结论:噬菌体展示技术可成功筛选到表皮生长因子2模拟表位,为探索乳腺癌的防治研究创造了条件。     

Efficacy of epidermal growth factor receptor-targeted molecular therapy in anaplastic thyroid cancer cell lines

Anaplastic thyroid cancer is one of the most aggressive human malignancies and the outcomes of conventional therapy have been far from satisfactory. Recently, epidermal growth factor receptor (EGFR)-targeted therapy has been introduced as an alternative therapeutic strategy for highly malignant cancers. This study was undertaken to investigate the expression of EGFR in anaplastic thyroid cancer cell lines, and to explore the potential of therapies targeting EGFR as a new therapeutic approach. EGFR was universally expressed in anaplastic cancer cell lines at a variety of levels. Specific EGFR stimulation with epidermal growth factor showed significant phosphorylation of ERK1/2 and Akt, and resulted in marked growth stimulation in an anaplastic thyroid cancer cell line, which highly expressed EGFR. This EGFR-transmitted proliferation effect of the cancer cell line was completely inhibited by gefitinib, an EGFR tyrosine kinase inhibitor. Moreover, growth of xenografts inoculated in mice was inhibited in a dose-dependent manner with 25-50 mg kg(-1) of gefitinib administrated orally. Inhibition of EGFR-transmitted growth stimulation by gefitinib was clearly observed in anaplastic thyroid cancer cell lines. Our results suggested that EGFR-targeted therapy, such as gefitinib, might be worth further investigation for the treatment of anaplastic thyroid cancer.     

229例人表皮生长因子受体2阳性Ⅳ期乳腺癌患者曲妥珠单抗的治疗分析

目的 探讨曲妥珠单抗对人表皮生长因子受体2(HER2)阳性Ⅳ期乳腺癌的治疗效果及患者预后的影响因素.方法 收集229例应用曲妥珠单抗治疗的HER2阳性Ⅳ期乳腺癌患者的临床资料,采用Cox比例风险回归模型分析HER2阳性Ⅳ期乳腺癌患者无进展生存时间(PFS)和总生存时间(OS)的影响因素.结果 229例HER2阳性Ⅳ期乳...     

Limited human epidermal growth factor receptor 2 discordance in metastatic breast cancer patients treated with trastuzumab,a population based study

BackgroundAccurate assessment of the human epidermal growth factor receptor 2 (HER2) in breast cancer is essential for proper treatment decisions. HER2 positivity confirmation rates in breast cancer trials by central testing pathology laboratories were reported to be approximately 85%. The aim of our study was to assess in a population based sample concordance of HER2 status in metastatic breast cancer (MBC) patients locally tested HER2 positive and treated with trastuzumab. Moreover cost-effectiveness of in situ hybridisation (ISH) in patients with an immunohistochemical score 3+ (IHC3+) was explored.MethodsMBC patients treated between 2005 and 2009 with trastuzumab-based therapy in North East Netherlands were identified by a survey of hospital pharmacies. Primary tumour samples were retested centrally for HER2 status using 1 immunohistochemical (IHC) method and two methods using ISH on tissue micro-arrays. Potential discordant patients were retested on whole tumour slides. HER2 positivity was defined as: (1) ISH amplification (according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice Guideline Update) and (2) when ISH failed an IHC score of 3+. Cost-effectiveness was estimated using potential ISH and treatment costs.ResultsHER2 status could be retested in 174 of 194 (90%) patients. The HER2 concordance rate was 87%. The 21 discordant patients were in the 67% due to primary HER2 testing with only IHC. Overall survival of HER2 discordant and concordant patients was not significantly different (18 versus 25 months, p = 0.131). Structural ISH in the case of IHC3+ has an estimated potential saving of €87,710 per 100 patients.ConclusionHER2 concordance in a population based study is comparable to those described in selected populations. Discordance is mostly due to testing with only IHC. ISH in the case of IHC3+ is cost-effective.     

曲妥珠单抗耐药后HER 2阳性转移性乳腺癌靶向治疗策略

人表皮生长因子受体2（human epidermal growth factor receptor 2,HER 2）是一种跨膜酪氨酸激酶受体,可以激活下游一系列信号通路,导致肿瘤细胞增殖和存活。HER 2阳性乳腺癌是乳腺癌的特殊类型,恶性程度高,预后差。抗HER 2单克隆抗体曲妥珠单抗能够改善该类乳腺癌治疗效果,但最终仍难逃耐药的结局。近年来,针对曲妥珠单抗耐药机制的研究、新型靶向药物的研发以及治疗策略的探索,在克服曲妥珠单抗耐药性方面取得了重大进展,本文将对其耐药后治疗策略及临床试验数据进行综述。     

Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin-resistant human epidermal growth factor receptor 2-positive breast cancer

Chemotherapy-resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial-mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem-like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple-negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial-to-mesenchymal transition, as well as the stem-like phenotype in cisplatin-resistant HER2-positive breast cancer. Alamar Blue and Annexin V/7-AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem-like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2-positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial-mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl-2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2-positive breast cancer.     

人类表皮生长因子受体2阳性肿瘤靶向药物研究进展

人类表皮生长因子受体2(HER-2)是目前研究最为透彻的人类原癌基因之一.研究表明在人类乳腺癌、胃癌、卵巢癌及其它肿瘤中均存在HER-2过表达的现象,这种过表达使其成为药物研发中的理想靶点.与传统的化疗药物相比,靶向药物和抑制剂类药物,能更好地改善患者的预后,提高患者的生存率,安全性和有效性也更加明显.本文综述了HER-2阳性肿瘤靶向药物的研究现状及治疗进展,为HER-2相关药物开发和临床治疗提供有价值的参考.