Mutant epidermal growth factor receptor in benign, borderline, and malignant ovarian tumors

PURPOSE: Dysfunction of the epidermal growth factor (EGF) complex is essential to the growth and development of many human tumors. Overexpression of the EGF receptor (EGFR) is a characteristic finding in a considerable number of solid tumors and often signalizes poor prognosis. There is a major disagreement among researchers about both the frequency and possible clinical importance of EGFR overexpression in ovarian cancer. The type III variant of EGFR (EGFRvIII) is a mutant with a deletion. Contrary to the wild-type, it is constitutively active. EGFRvIII has not been found in normal tissue, and consequently, it is an attractive tumor-specific candidate for molecular targeted treatment. The literature dealing with this mutation in ovarian cancer has been very sparse. EXPERIMENTAL DESIGN: Tissue from 225 patients who underwent surgery for a pelvic mass was collected consecutively. The samples included 99 ovarian/peritoneal/tuba cancers, 17 ovarian borderline tumors, 66 benign ovarian tumors, 15 other cancer types, 24 normal ovarian biopsies, and 4 miscellaneous. The presence of EGFRvIII was investigated both by PCR analyses for EGFRvIII gene expression and with protein analysis by Western blots. RESULTS: None of the tissue samples was positive for the EGFRvIII mutation neither at the mRNA level nor at the protein level. CONCLUSIONS: The EGFRvIII mutation seems to be very rare in ovarian tissue. Our data indicate that EGFRvIII is not a part of the malignant phenotype in ovarian cancer and should not be pursued as a therapeutic target for treatment of this disease.     

Coregulation of epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) levels and locations: quantitative analysis of HER2 overexpression effects

Elevated expression of human epidermal growth factor receptor 2 (HER2) is known to alter cell signaling and behavioral responses implicated in tumor progression. However, multiple diverse mechanisms may be involved in these overall effects, including signaling by HER2 itself, modulation of signaling by epidermal growth factor receptor (EGFR), and modification of trafficking dynamics for both EGFR and HER2. Because these processes are so tightly interrelated, the net effect of HER2 overexpression is difficult to reliably attribute to any single particular mechanism. To take an important first step toward dissecting the effects of HER2 overexpression on cell responses in terms of the various specific underlying mechanisms, we have developed and validated a quantitative model of the relevant trafficking processes. We then use our model for successful prediction of EGFR and HER2 level and location changes attributable to HER2 overexpression in 184A1 human mammary epithelial cells expressing a series of HER2 levels by retroviral infection. Model predictions are based on our independent experimental measurement of key trafficking parameters for both EGFR and HER2. In terms of trafficking processes, HER2 overexpression reduces the EGFR internalization rate constant and increases the fraction of EGFR recycled. Consequently, our model successfully predicts that HER2 increases the overall level of activated EGFR by both enhancing its recycling and reducing its internalization, but it increases activated EGFR localization at the cell surface almost solely by its reduction of internalization. Furthermore, the model also successfully predicts the effects of monoclonal antibody 2C4, which interferes with HER2/EGFR heterodimerization, on EGFR and HER2 levels and compartmental locations. We anticipate that this model should ultimately be useful in parsing the relative contributions of direct effects of HER2 via signaling vis-a-vis indirect effects of HER2 via modification of EGFR signaling.     

Evaluation of RIP1K and RIP3K expressions in the malignant and benign breast tumors

Tumor Biology - Receptor-interacting protein kinase 1 (RIP1K) and RIP3K belong to RIPK family, which regulate cell survival and cell death. In the present investigation, the expression levels of...     

Expression of epidermal growth factor receptors in human lung tumors

Using the adjacent histologically normal tissues obtained from the same patients as controls, six human lung tumors were studied for the activities of epidermal growth factor (EGF) receptor binding, and receptor autophosphorylation. There was a 1.2- to 2.8-fold increase in EGF receptor activities in lung tumors due to an increase in the number of receptors without changes in their affinity. The increase had no direct correlation with the degree of differentiation or the type of lung tumors. The elevated expression of EGF receptor may be one of the characteristics in lung tumors. Epidermal growth factor and its receptor also may play a role in the regulatory mechanisms during tumorigenesis.     

Expression of epidermal growth factor receptors in human brain tumors

The expression of receptors for epidermal growth factor (EGF-R) was determined in 29 samples of brain tumors from 22 patients. Primary gliogenous tumors, of various degrees of cancer, five meningiomas, and two neuroblastomas were examined. Tissue samples were frozen in liquid nitrogen immediately after the operation and stored at -70 degrees until use. Cerebral tissue samples from 11 patients who died from diseases not related to the central nervous system served as controls. Immunoprecipitation of functional EGF-R-kinase complexes revealed high levels of EGF-R in all of the brain tumors of nonneuronal origin that were examined. The level of EGF-R varied between tumors from different patients and also between specimens prelevated from different areas of the same tumor. In contrast, the levels of EGF-R from control specimens were invariably low. The biochemical properties of EGF-R in brain tumor specimens were found to be indistinguishable from those of the well-characterized EGF-R from the A-431 cell line, derived from human epidermoid carcinomas. Human brain EGF-R displays a molecular weight of 170,000 by polyacrylamide-sodium dodecyl sulfate gel electrophoresis. It is phosphorylated mainly in tyrosine residues and shows a 2-dimensional phosphopeptide map similar to that obtained with the phosphorylated EGF-R from membranes of A-431 cells. Our observations suggest that induction of EGF-R expression may accompany the malignant transformation of human brain cells of nonneuronal origin.     

Expression of epidermal growth factor receptors on human cervical, ovarian, and vulval carcinomas

We describe the properties of two monoclonal antibodies produced to a synthetic peptide consisting of residues 985 to 996 from the cytoplasmic domain of the epidermal growth factor (EGF) receptor. We have examined a group of ten human tumors including cervical, ovarian, and vulval carcinomas for expression of EGF receptors by immunohistological staining using one of these antibodies and another monoclonal antibody to the extracellular domain of the molecule. The tumors were examined using a sensitive amplified enzyme system and a less sensitive indirect staining method. There was generally a good correlation in staining intensity with the two monoclonal antibody reagents. Both antibodies showed strong staining of squamous cell carcinomas and usually weak or heterogeneous patterns with the adenocarcinomas. Samples of each tumor were solubilized in detergent and analyzed for the presence of functional EGF receptors by immunoprecipitation and autophosphorylation. Three of the squamous cell tumors gave labeled bands, Mr 170,000, on sodium dodecyl sulfate:polyacrylamide gels. DNA was extracted from seven of the tumors and digested with two restriction endonucleases, and the fragments were analyzed on Southern blots using probes representing the extracellular and cytoplasmic domains of the molecule. The tumor DNA showed no apparent rearrangements or amplifications when compared to the EGF receptor gene in human placental DNA. These results suggest that there is a high level of EGF receptors on some squamous cell tumors.     

彩色多普勒对卵巢肿瘤诊断价值的探讨

为了探讨彩色多普勒超声对卵巢肿瘤良恶性的诊断价值,应用经阴道彩色多普勒超声观察56例卵巢良恶性肿瘤的声像图特征及血流情况。56例患者全部经手术及病理确诊为卵巢肿瘤,超声诊断符合率为94.64%;恶性肿瘤阻力指数(resistance index,RI)、搏动指数(pulse index,PI)明显低于良性肿瘤,差异有统计学意义,P<0.01。初步研究结果提示,彩色多普勒血流显像鉴别卵巢囊性肿瘤良恶性有可靠的诊断价值。     

Prostanoids and cyclic nucleotides in malignant and benign ovarian tumors

The concentrations of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, thromboxane B2(TxB2), cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in ovarian tumor tissue were measured in 38 post-menopausal women with malignant or benign ovarian tumor and in six women without ovarian neoplasm. PGE2 and TxB2 contents in ovarian cancer tissue were significantly (P less than 0.05) higher than in normal ovarian tissue. The prostanoids were also increased in the cyst fluid of epithelial malignant tumors compared to cyst fluids of benign ovarian tumors. Cyclic AMP concentrations in cancer tissue were lower than in non-malignant ovarian tissue, while the levels of cGMP were similar in all groups studied.     

良恶性大肠肿瘤组织血管内皮生长因子表达与意义

目的:研究血管内皮生长因子(VEGF)在大肠癌、大肠腺瘤和癌旁正常大肠黏膜标本中的表达,并探讨其表达与大肠癌发生、发展及转移的关系.方法:通过免疫组化SP法检测89例大肠癌、22倒大肠腺瘤、26例癌旁正常大肠黏膜标本中VEGF表达及与大肠癌临床病理特征的关系.结果:VEGF在大肠癌组织中的阳性率(71.9%,64/89)明显高于其在癌旁正常大肠黏膜组织(30.8%,8/26)、大肠腺瘤组织(40.9%,9/22)中的阳性率,差异有统计学意义(P<0.01);VEGF在大肠癌组织中的表达水平与肿瘤Dukes分期,有无淋巴结转移及患者年龄有关(P<0.05),与肿瘤组织学分级和患者性别无关.结论:VEGF表达升高与大肠癌的发生、发展、浸润及淋巴结转移有关,检测VEGF的表达情况有助于判断大肠癌的恶性程度及肿瘤预后.     

Protein expression and gene amplification of epidermal growth factor receptor in thymomas

BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression and amplification are important prognostic factors in many solid tumors and anti-EGFR antibody-based therapy is now available as a promising therapeutic modality. There is little information in the literature regarding the biologic role of EGFR in thymomas that are characterized by variable clinical presentations, histologic heterogeneity, and unpredictable behavior. METHODS: Protein expression and gene amplification of EGFR were investigated in 32 thymomas (9 World Health Organization [WHO] type A, 5 type AB, 7 type B2, 7 type B3, 4 type C) using immunohistochemistry and fluorescence in situ hybridization (FISH). FISH analysis included assessment of the average number of copies of the EGFR gene per cell, the average ratio of the EGFR gene to chromosome 7 copy numbers, and ploidy. RESULTS: The results of FISH analysis showed statistically significant correlation with WHO histologic type, invasion, advanced clinical stage, but not with tumor size and outcome. Thymomas associated with myasthenia gravis more frequently showed hyperploidy when compared with sporadic tumors, but there was no difference in EGFR gene amplification. EGFR protein expression assessed by immunohistochemistry did not correlate with any studied clinicopathologic variables. There was poor correlation between the protein expression and gene amplification, only 7 of 23 specimens (30%). CONCLUSIONS: The potential role of EGFR in the pathogenesis of advanced-stage thymomas indicated that evolving anti-EGFR antibody therapy may be considered as a treatment option.     

Immunohistochemical demonstration of epidermal growth-factor receptors in normal, benign and malignant thyroid tissues

Human epidermal growth factor receptor (EGF-receptor) has been detected immunohistochemically in normal, benign and malignant human thyroid tissues. With a monoclonal antibody for EGF-receptor and avidin-biotin-peroxidase complex (ABC), the expression of EGF-receptor was evaluated in paraffin-embedded sections. Carcinomas of the thyroid showed a moderate to intense staining for EGF-receptor in most cases. Apical cell surface and cytoplasmic staining was the most common pattern of immunoreactivity. Adenomas showed a variable positivity in the cytoplasm of th tumor cells, and their apical cell surface staining was generally negative to borderline. The follicular cells in Hashimoto's thyroiditis showed a weak to moderate cytoplasmic staining, but those in Graves' disease and normal thyroids showed an essentially negative cytoplasmic staining. Apical cell surface staining was essentially negative or borderline in these benign lesions. There were no significant correlations between EGF-receptor expression and tumor size, degree of invasion or cervical metastases in the thyroid carcinomas. The apical surface expression of EGF-receptor was characteristic to thyroid carcinomas and this feature may be useful in the differentiation of thyroid carcinomas from benign thyroid lesions.     

Inverse relationship of epidermal growth factor receptor and HER2/neu gene expression in human renal cell carcinoma

Expression of the oncogenes, epidermal growth factor (EGF) receptor, HER2/neu, c-myc, and c-fos, in renal cell carcinoma and corresponding nonneoplastic kidney tissue of 30 patients has been analyzed by Northern blot analysis. In renal cell carcinoma an inverse relationship of EGF receptor and HER2/neu gene expression was detected, with high expression of the EGF receptor gene in 22 of 30 (73%) cases and low expression of the HER2/neu gene in 28 of 30 (93%) cases. Furthermore, altered expression of the oncogenes c-myc and c-fos was detected in renal cell carcinoma, which appears to be related to the tumor grade of malignancy. Additional Southern blot analysis of six renal cell carcinomas gave no indication of chromosomal rearrangement events or gene amplification.     

HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells

Gefitinib (Iressa), an epidermal growth factor receptor targeting drug, has been clinically useful for the treatment of patients with non-small cell lung cancer (NSCLC). Gefitinib is currently being applied in clinical studies as either a monotherapy, or as part of a combination therapy against prostate, head and neck, gastric, breast, and colorectal tumors. However, success rates vary between different tumor types, and thus it is important to understand which molecular target(s) are responsible for limiting the therapeutic efficacy of the drug. In this study, we ask whether expression of HER2 affects sensitivity to gefitinib in human lung cancer cells. We established two clones, LK2/HER2-32 and LK2/HER2-57, by transfecting HER2 cDNA into LK2, a NSCLC line with a low expression level of HER2. We observed no mutations in exons 18, 19, and 21 of EGFR gene in LK2, LK2/mock- and two HER2-trasfectants when we observed in-frame deletion mutations (E746-A750) adjacent to K745 in a gefitinib-sensitive NSCLC cell line, PC9. These LK2/HER2-32 and LK2/HER2-57 were much more sensitive to the cytotoxic effects of gefitinib than the parental LK2 lines. Treatment with 0.5 to 1 micromol/L gefitinib specifically blocked Akt activation in both HER2-transfectant lines, but not in the parental LK2 cells. Extracellular signal-regulated kinase-1/2 activation, however, was not blocked by gefitinib up to 10 micromol/L in either the parent or transfectant lines. Gefitinib was also shown to induce cell cycle arrest in the G1-S phase, and an accompanying increase of p27Kip1 was observed. LK2/HER2 transfectants showed constitutive formation of HER2/HER3 heterodimer, which were seen to associate with a regulatory subunit of phosphoinositide-3-kinase, p85alpha, when active. Treatment of LK2/HER2 cells with gefitinib markedly decreased the formation of HER2/HER3 heterodimers, HER3 basal phosphorylation, and the association of p85alpha with HER3. This study is the first to show that under basal growth conditions, HER2 sensitizes low-EGFR NSCLC cell lines to growth inhibition by gefitinib.     

超声检查诊断卵巢良恶性肿瘤的临床价值分析

目的探究超声检查诊断卵巢良恶性肿瘤的临床价值。方法选取2013年3月至2016年3月间琼中黎族苗族自治县人民医院收治的90例卵巢肿瘤患者,按照检测方法不同分为观察组与对照组,每组45例。观察组采用超声检查,对照组采用X线检查,结合病理检查对照,观察分析两组患者卵巢肿瘤良恶性诊断符合率和良恶性病变类型。结果观察组患者超声检测出恶性肿瘤患者23例,符合率为100.0%(23/23),良性肿瘤患者22例,符合率为95.5%(21/22)。观察组中良性肿瘤病理诊断病变类型有卵巢囊肿4例,浆液性囊肿腺瘤3例,黏液性囊肿腺瘤2例,输卵管炎症3例,闭锁黄体3例,红体1例,黄体囊肿2例,副输卵管囊肿2例,子宫内膜异位症1例;恶性肿瘤病理诊断病变类型有腺癌2例,卵巢癌6例,透明细胞癌3例,子宫内膜样癌2例,成熟囊性畸胎瘤3例,乳头状癌2例,梭形细胞肿瘤3例,浆液性囊腺癌2例。对照组患者X线片检测出的恶性肿瘤符合率为80.0%(16/20),良性肿瘤符合率为76.0%(19/25),其良恶性肿瘤的病变类型未有明确辨别,两组患者的良恶性诊断符合率和病变类型差异均有统计学意义(均P<0.05)。结论采用超声检查对卵巢肿瘤患者进行诊断,可较好地提高卵巢肿瘤患者的诊断符合率,对临床诊断和治疗具有较大意义。