Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients

BACKGROUND: Unlike other human tumors, gastric cancer remains a great therapeutic challenge since no standardized postoperative treatment exists. Knowledge of molecular pathways determining the behavior of individual gastric tumors seems to be crucial for therapeutic decisions, and evaluation of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression might be critical for prognosis, assessment, and identification of patients that could be treated with tailored therapies. METHODS: VEGF and EGFR determination was performed in 88 gastric cancer samples as well as 25 normal gastric mucosa specimens from non-cancer patients using a commercially available immunohistochemistry kit. In all samples, the correlation of VEGF and EGFR expression was investigated with each other, and with other prognostic indicators in all samples, and, finally, with survival rates in 69 patients undergoing potentially curative surgery. RESULTS: Forty-eight per cent (42 cases) of gastric cancers expressed VEGF, and 44% (39 cases) stained for EGFR. In curatively treated patients, VEGF and EGFR expression was demonstrated to correlate with worse survival in both univariate and multivariate analyses. Molecular profiling was shown to more accurately estimate the risk of cancer-related death than TNM stage, and, of most interest, to allow sorting out high-risk patients within the same stage. CONCLUSIONS: These findings provide evidence that contemporary evaluation of VEGF and EGFR expression may be crucial to select gastric cancer patients with poor prognosis who may benefit of tailored treatments.     

表皮生长因子受体,多胺与肺癌的关系

探讨表皮生长因子受体（ＥＧＦＲ）和多胺（ＰＡ）对人肺癌及正常肺组织生长、分化的影响。方法放射性配体结合法检测ＥＧＦＲ含量；高效液相色谱分析法测ＰＡ含量。结果肺癌组织中ＥＧＦＲ的含量（５．６２±４．２６ｆｍｏｌ／ｍｇ膜蛋白）高于非癌肺组织（３．９０５±２．２７９ｆｍｏｌ／ｍｇ膜蛋白），有显著性差异（Ｐ＜０．０１）；肺癌组织ＰＡ的含量亦高于正常肺组织（Ｐ＜０．０１）。结论ＥＧＦＲ和ＰＡ可促使肺癌发展，可作为肺癌的肿瘤标记物     

Clinical Significance of the Epidermal Growth Factor Receptor and HER2 Receptor in Resectable Gastric Cancer

Background: Epidermal growth factor receptor (EGFR or HER1) and its homolog c-erbB-2 (HER2) are membrane receptors. Both EGFR and HER2 genes are overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients. The objective of this work was to evaluate the EGFR and HER2 contents in resectable gastric cancer, their possible relationship with clinicopathologic parameters of tumors, and their prognostic significance.Methods: This was a prospective analysis of 63 patients with resectable gastric carcinomas, with a mean follow-up period of 40.7 months. Membranous EGFR levels were examined by radioligand binding assays, and cytosolic HER2 levels were examined by means of an immunoenzymatic assay.Results: There was a wide variability of EGFR (1–1,239 fmol/mg of protein) and HER2 (7–20,863 NHU/mg of protein) levels in tumors. There was no significant correlation between these levels and patient or tumor characteristics. However, high levels of EGFR and HER2 were significantly associated with a shorter overall survival period (P = .03 and P = .02, respectively).Conclusions: There is a wide variability in membranous EGFR levels and in cytosolic HER2 levels in gastric cancer, which seems to be related to the biological heterogeneity of these tumors. In addition, high tumor EGFR and HER2 levels were associated with an unfavorable outcome in patients with resectable gastric cancer.     

Elevated Serum Epidermal Growth Factor Receptor Level in Stage IV Thymoma

Using the enzyme immunoassay for epidermal growth factor receptor (EGFR), we investigated whether serum EGFR levels could be used as a predictor of the development and extension of thymoma. Serum samples were collected from 31 patients with thymoma and 16 patients with nonmalignant thoracic disease before clinical treatment. There was no difference between the serum EGFR levels of the patients with thymoma and the nonmalignant controls, being 49.1 ± 136.3 and 22.6 ± 7.3fm/ml, respectively (P = 0.11). However, patients with stage IV thymoma had significantly higher EGFR levels than those with stage I or stage II thymoma, the respective values being 127.8 ± 243.9, 10.9 ± 9.2 (P = 0.02), and 19.7 ± 10.6 (P = 0.0433) fm/ml. The serum EGFR levels were similar in the pathological subtypes. These findings suggest that serum EGFR levels may serve as a marker that could be used as a diagnostic indicator of the invasion of thymoma.     

Epidermal Growth Factor Receptor Expression in Spindle Cell Carcinomas of the Head and Neck

Spindle cell carcinoma (SpCC) is an uncommon head and neck squamous cell carcinoma (SCC) variant consisting of spindled and/or pleomorphic cells with epithelial differentiation. Epidermal growth factor receptor (EGFR) is expressed by >90 % of conventional SCC, and high level expression is associated with a poorer prognosis. Anti-EGFR therapies are commonly used to treat head and neck SCC. However, no studies have evaluated EGFR expression in SpCC. Cases of SpCC were retrieved from department files. The diagnosis required either a biphasic lesion with a squamous neoplastic component, or a purely spindle cell or pleomorphic tumor with immunohistochemical positivity for epithelial markers. EGFR immunohistochemistry was performed and was quantified in quartiles. Medical records were reviewed for clinical follow up information. EGFR was expressed in 21/30 (70 %) cases, including in the squamous component in 18/19 (95 %) and the spindle cell component in only 12/30 (40 %). Where the spindle cell component was positive, the intensity and distribution were lower than for the squamous component. Recurrent tumors were predominantly (80–90 %) of the spindle cell component, and had low (or absent) EGFR expression. Kaplan–Meier survival analysis showed no statistically significant differences in overall or disease free survival between the EGFR expressing and non-expressing groups (p = 0.414 and 0.19, respectively). SpCCs of the head and neck have a poor prognosis, and markedly reduced EGFR expression. EGFR-specific therapies may not be ideal for SpCC patients, which may lack EGFR expression, but further studies are needed.

Electronic supplementary material

The online version of this article (doi:10.1007/s12105-014-0604-y) contains supplementary material, which is available to authorized users.     

Epidermal Growth Factor Receptor (EGFR) Expression is Associated With a Worse Prognosis in Gastric Cancer Patients Undergoing Curative Surgery

Background In gastric cancer, the recurrence rate is high even after curative surgery. A relevant issue is the identification of independent prognostic factors to select high-risk patients; such features can be used as predictive factors for tailored therapies. In this study we have investigated the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for predicting cancer behavior and clinical outcome in gastric cancer patients undergoing potentially curative surgery. Methods Epidermal growth factor receptor determination using a commercially available immunohistochemistry (IHC) kit was performed in tissues from 82 gastric cancer patients receiving primary surgical treatment and in 25 normal gastric mucosa specimens from noncancer patients. The EGFR positivity was correlated with disease recurrence and survival in univariate and multivariate analyses. Results Forty-four percent (36 cases) of gastric cancers were EGFR positive. In 66 curatively treated patients, EGFR expression correlated with disease recurrence and poorer survival in both univariate and multivariate analyses. In a multivariate model for predicting recurrence and survival, advanced tumor extension (T₃ or T₄), nodal metastases, and EGFR expression were the only independent covariates. In particular, EGFR expression was shown to be a significant predictor of poor prognosis among gastric cancer patients having the same stage according to the current TNM staging system. Conclusions These findings suggest that EGFR expression may be useful in identifying high-risk gastric cancer patients undergoing potentially curative surgery. Multimodal treatments should be considered in the adjuvant treatment of these patients.     

吉非替尼对表皮生长因子受体在胆管上皮细胞中表达的影响及意义

目的通过观察吉非替尼对肝内病变胆管上皮细胞中表皮生长因子受体(EGFR)表达的影响,探讨抑制胆管上皮细胞过度增殖的可行性。方法选择双流县第一人民医院2006年8月至2008年8月期间住院需要手术的肝内胆管结石患者共61例,年龄25～65岁(平均46.92岁),随机分为治疗组和对照组。治疗组30例,术中在病变胆管内留置细导管,术后灌注吉非替尼溶液;对照组31例只作T管引流。分别于术中、术后6周和12周行胆道镜碎石及取石的同时,活检灌注处的病变胆管壁组织,行HE染色、免疫组化和RT-PCR检测,观察组织学变化和EGFR的表达。结果术中,2组胆管壁病理组织学改变及EGFR蛋白和mRNA表达无明显差异。术后6周和12周,治疗组的胆管黏膜上皮和黏膜下腺体增殖程度均较对照组明显减弱,EGFR蛋白表达较对照组明显减弱,EGFR mRNA表达明显低于对照组(P0.05)。结论 EGFR在慢性增生性胆管炎中呈过表达状态,术后局部持续给予吉非替尼治疗能够特异性地阻断EGFR的激活和表达,能有效地抑制术后胆管上皮细胞的过度增殖。     

膜表面核仁素参与表皮生长因子受体信号启动的研究

目的探讨膜表面核仁素（nucleiolin,NCL）在表皮生长因子受体（epidermal growth factor receptor,EGFR）信号启动中的作用。方法采用免疫组化法检测NCL及EGFR在甲状腺乳头状癌组织中的表达;Western blot法检测甲状腺乳头状癌细胞TPC-1中磷酸化EGFR（phosphorylation EGFR,p-EGFR）的表达水平;Transwell小室试验检测TPC-1细胞的迁移能力。结果免疫组化染色结果显示,甲状腺乳头状癌组织中NCL及EGFR的表达阳性率分别为100％（56／56）和80.4％（45／56）;NCL及EGFR的表达与淋巴结转移有关（P〈0.05）,且NCL的表达与EGFR的表达呈正相关关系（r=0.635,P〈0.01）。Western blot法检测结果显示,拮抗甲状腺乳头状癌TPC-1细胞的NCL或EGFR后,其p-EGFR表达水平均明显下调（P〈0.01）。Transwell小室试验发现,拮抗NCL和EGFR后,可明显减少TPC-1细胞的穿膜细胞数（P〈0.01）。结论膜表面NCL可能是EGFR受体信号启动的必要成分,可能通过EGFR参与肿瘤的生长与转移。以NCL为靶点将开拓肿瘤新的治疗领域。     

胸腺瘤表皮生长因子受体、增殖细胞核抗原、Bcl-2和Bax表达及临床意义

目的　探讨胸腺瘤表皮生长因子受体 ( EGFR)、增殖细胞核抗原 ( PCNA)、Bcl- 2和 Bax的表达与胸腺瘤临床病理特征的关系及临床意义。　方法　应用免疫组织化学链霉素亲生物蛋白 -过氧化酶 ( S- P)法检测 4 6例胸腺瘤患者EGFR、PCNA、Bcl- 2和 Bax的表达。　结果　胸腺瘤 EGFR阳性表达率为 71.7% ,PCNA标记指数为 4 .0 0 %± 1.87% ,Bcl- 2、Bax阳性率分别为 4 1.3 %、15 .2 %。EGFR表达与胸腺瘤 Masaoka分期、肿瘤性质有明显关系 ,EGFR阴性者术后生存率显著高于阳性者 ( P=0 .0 0 5 )。 PCNA标记指数和 Bcl- 2与胸腺瘤肿瘤性质有明显关系 ,Bcl- 2阴性者术后生存率显著高于阳性者 ( P=0 .0 0 2 )。EGFR、PCNA、Bcl- 2和 Bax表达均与胸腺瘤组织学类型、是否合并重症肌无力无明显关系。　结论　EGFR与胸腺瘤的发生、发展有关 ,可作为 Masaoka分期的补充推测预后。Bcl- 2与胸腺癌发生有关 ,可作为胸腺癌的标记物用于鉴别诊断。     

过敏性紫癜患儿尿表皮生长因子水平变化及意义探讨

目的:探讨过敏性紫癜(HSP)患儿尿表皮生长因子(EGF)水平变化在早期肾损害中的意义.方法:采用双抗体夹心ELISA方法检测91例过敏性紫癜患儿和30例正常对照组儿童的尿表皮生长因子.结果:(1)HSP患儿尿EGF水平为(78.59±18.09)μg/L,明显高于正常对照组(29.30±13.92)μg/L,有统计学差异(t值为13.64,P＜0.01).(2)HSP各临床分型间比较发现紫癜肾型尿EGF水平(98.31±17.68)μg/L,分别高于其他临床型:皮肤型(78.76±12.66)μg/L,腹型(77.16±11.77)μg/L,关节型(76.49±17.45)μg/L,混合型(77.71±13.49)μg/L,均有统计学差异(P均＜0.05),而其余各临床分型间比较无统计学意义(P均＞0.05).结论:HSP患儿尿EGF水平明显增高,EGF在HSP伴有肾损害者早期升高尤为明显,考虑EGF增高可能与HSP病理改变程度有关,因此,EGF在过敏性紫癜肾损害的发生中具有重要意义.     

Prognostic Significance of the Combination of Biological Parameters in Breast Cancer

To evaluate whether the combination of biological parameters increases their prognostic value, the expression of epidermal growth factor receptor (EGFR), DNA ploidy, and estrogen receptor (ER) status were analyzed on 998 patients with breast cancer. Poor findings for each biological parameter were positive for EGFR, aneuploid for DNA ploidy, and negative for ER. According to the number of poor findings in these three parameters, the groups with none (309 cases), one (377 cases), two (161 cases), and three (151 cases) poor findings were classified. A significant ( P < 0.0001) difference was found in the disease-free survival (DFS) among the four groups. A multivariate analysis indicated the combination of three biological parameters to be an independently significant factor for DFS, while the relative risk gradually increased as the number of poor findings increased. In conclusion, the present study indicated a gradual increase in the prognostic significance as the number of combined biological parameters increased.     

法尼酯X受体的激活抑制结肠癌细胞生长

目的 探讨法尼酯X受体（FXR）的激活是否抑制结肠癌细胞的生长。方法 对人结肠癌HCT-116细胞进行体外培养,用四唑氮蓝还原法（MTT）和流式细胞仪测定FXR特异性激动剂GW4064对结肠癌HCT-116细胞生长的抑制作用,同时应用RT-PCR方法检测其FXR mRNA及VEGF mRNA的表达。结果 FXR特异性激动剂GW4064可上调结肠癌HCT-116细胞的FXR mRNA表达,下调VEGF mRNA的表达; 对结肠癌HCT-116细胞的生长具有明显的抑制作用,并促进结肠癌HCT116细胞的凋亡,且均呈剂量及时间依赖关系。结论 FXR特异性激动剂GW4064可以显著抑制结肠癌HCT116细胞的生长,激活FXR受体可能为结肠癌的治疗提供一种潜在的靶点。     

表皮生长因子及其受体在睾丸中的分布与功能

睾丸Sertoli细胞和早期生精细胞不仅存在表皮生长因子 (EGF)而且存在EGF受体 (EGFR) ,睾丸Leydig细胞也含有EGFR。EGF通过和EGFR结合 ,发挥特定的生物学效应 ,能刺激睾丸雄激素的合成和生精细胞的成熟。但是高浓度的EGF反而会抑制生精细胞的成熟。     

Down-Regulation of Osteoblastic Cell Differentiation by Epidermal Growth Factor Receptor

The role of epidermal growth factor receptors (EGF-R) in osteogenic cell differentiation was investigated using preosteoblastic MC3T3-E1 (MC3T3) cells and osteoblast-like ROS 17/2.8 (ROS) cells. When cultured in the presence of β-glycerophosphate (GP) and ascorbic acid (AA), MC3T3 cells underwent spontaneous differentiation into osteoblasts which was confirmed as they expressed osteoblast markers such as alkaline phosphatase (ALP), bone sialoprotein (BSP) and osteocalcin (OC). Interestingly, the number of EGF-binding sites decreased during their differentiation into osteoblasts, and the osteogenic protein-1 (OP-1) treatment, which accelerated their differentiation, lowered the number of EGF-binding sites even further. On the other hand, ROS cells with high expression levels of osteoblast markers and no EGF-R, after being transfected with human EGF-R cDNA (EROS cells), expressed numerous EGF-binding sites as well as EGF-R mRNA and protein; in the process, they ceased to express osteoblast markers, indicating their dedifferentiation into osteoprogenitor cells. Both MC3T3 and EROS cells showed increased cell growth in response to EGF, whereas ROS cells did not. These results imply that the EGF/EGF-R system in osteogenic cells has a crucial function in osteoblast phenotype suppression and osteogenic cell proliferation.     

PTEN，表皮生长因子受体和Ki-67在胸腺瘤中的表达及其临床意义

目的探讨张力蛋白同源、10号染色体缺失的磷酸酶基因（phosphatase and tensin homolog deleted on chromosome ten，PTEN）、表皮生长因子受体（epidermal growth factor receptor，EGFR）及增殖性核抗原Ki-67在人胸腺瘤发生、浸润和转移中表达的生物学意义及其相互关系。方法采用免疫组织化学SP法，检测45例胸腺瘤患者中PTEN、EGFR和Ki-67的表达，用5例先天性心脏病手术患者的正常胸腺组织作对照。结果5例正常胸腺组织中，PTEN全部为阳性表达，EGFR仅微量阳性表达，Ki-67无1例阳性表达。45例胸腺瘤组织中，从良性胸腺瘤、侵袭性胸腺瘤到胸腺癌，PTEN阳性表达率逐渐下降，差异有统计学意义（x^2=7．808，P=0．020）；EGFR、Ki-67表达率逐渐增高，差异有统计学意义（x^2=8．032，0．018，7．006，P=0．030）；PTEN、EGFR和Ki-67的阳性表达率与胸腺瘤的肿瘤性质、Masaoka分期及淋巴结转移等参数有关（P〈0．05）；PTEN与EGFR、Ki-67的表达呈负相关（r=0．632，-0．653；P〈O．01），EGFR与Ki-67的表达呈正相关（r-0．807，P〈O．01）。结论胸腺瘤的发病分子机制中存在多种基因变异，PTEN的失表达和EGFR、Ki-67的过度表达在其发生、浸润和转移中起一定的作用；PTEN、EGFR和Ki-67的异常表达密切相关，共同影响着胸腺瘤的发生、发展，三者的检测有助于对胸腺瘤的早期诊断，并判断其恶性程度、侵袭和转移能力及预后。     

表皮生长因子及其受体对雄性生殖系统的影响

表皮生长因子 (EGF)是首先从小鼠颌下腺分离出来的含 5 3个氨基酸残基的单链多肽 ,通过与其受体(EGFR)相结合发挥多种生物学效应。近年来发现 ,在人类和其他动物的雄性生殖系统有EGF与EGFR表达 ,对雄性生殖器官的发育、维持及变异起着重要的作用 ,同时 ,对雄性激素的分泌和精子发生也有很大的影响。EGFR在睾丸的支持细胞和间质细胞上均有表达 ,可影响睾酮的分泌 ;能维持正常前列腺组织的生长发育 ,刺激前列腺增生组织和前列腺癌组织的生长和分化 ;EGF参与精子发生 ,其作用点主要在减数分裂过程 ;可影响性分化 ,在雄激素诱导下使胚胎向雄性方向发育。     

Prognostic Significance of Vascular Endothelial Growth Factor,Basic Fibroblast Growth Factor,and Angiogenin in Patients With Resectable Hepatocellular Carcinoma After Surgery

Background: Hepatocellular carcinoma (HCC) is a hypervascular malignancy. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiogenin (ANG) are important angiogenic factors of neoangiogenesis. This study investigated the predictive value of serum VEGF, bFGF, and ANG in tumor recurrence, disease-free survival (DFS), and overall survival (OS) in HCC patients.Methods: Preoperative serum VEGF, bFGF, and ANG were measured in 98 patients with resectable HCC and in 15 healthy controls. The median follow-up time was 43 months.Results: Preoperative serum VEGF was increased in patients with resectable HCC compared with healthy controls (P < .05). Increased serum VEGF was correlated with tumor recurrence (P = .001). Univariate analysis showed that serum VEGF, tumor-node-metastasis stage, tumor size and number, macroscopic portal vein invasion, and microscopic vascular invasion were correlated with OS and DFS. Serum bFGF and ANG were not associated with survival. Multivariate analysis showed that serum VEGF was the most significant predictor of DFS (relative risk, 2.35; 95% confidence interval, 1.26–4.39; P = .007) and OS (relative risk, 3.44; 95% confidence interval, 1.81–6.57; P < .001) in HCC patients after surgical resection.Conclusions:Preoperative serum VEGF is a significant independent predictor of tumor recurrence, DFS, and OS in patients with resectable HCC.     

阉割对大鼠颌下腺雄激素受体及表皮生长因子的影响

目的:观察阉割对大鼠颌下腺雄激素受体(AR)及表皮生长因子的影响。方法:60只30~60日龄的W istar雄性大鼠,随机分为阉割组、假手术组和正常对照组,每组20只。1周后摘除各组大鼠颌下腺。颌下腺匀浆后用于W estern印迹分析。结果:与其他两组相比,阉割组颌下腺中的AR含量明显降低(P<0.05),而且,颌下腺分泌的表皮生长因子亦低于其他两组(P<0.05)。结论:阉割影响了颌下腺中AR的产生,并进一步影响了颌下腺分泌表皮生长因子的功能。