Androgenic and antiandrogenic control on epidermal growth factor,epidermal growth factor receptor,and androgen receptor expression in human prostate cancer cell line LNCaP

Both androgen and antiandrogen treatments enhance the proliferation rate of the hormone-dependent prostate cancer cell line LNCaP, expressing a mutated androgen receptor (AR). We studied the modification of the expression of epidermal growth factor (EGF), of its receptor (EGF-R), and of androgen receptor (AR) in the LNCaP cell line, under basal conditions and during androgen (R1881) and antiandrogen hydroxy-flutamide (OH-FLU) treatment. After prolonged R1881 administration, a marked increase of EGF release was observed, completely blocked by the addition of OH-FLU. The Scatchard plot analysis of EGF-R binding revealed two classes of binding sites with high and low affinity. The administration of OH-FLU alone or combined with R1881 did not modify the affinity constants, while the low-affinity component disappeared after androgen administration. Both androgen and antiandrogen administration led to a significant increase of the EGF-R high-affinity component. AR mRNA and protein levels were downregulated by R1881 treatment. Following OH-FLU administration, AR mRNA was slightly downregulated, and there was not a strict parallelism between AR mRNA levels and AR binding capacity. When combined with R1881, OH-FLU partially counteracted the androgen-induced AR downregulation. Our data show that EGF-R binding capacity is the only parameter constantly raised in cell proliferation with respect to quiescent cells, and highlights the nonunivocal action of OH-FLU on androgen-induced effects.     

Human epidermal growth factor receptor type 2 protein expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after exposure to hormonal therapy

Aim： To investigate human epidermal growth factor receptor type 2 （HER2） protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods： Immunohistochemistry （IHC） was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transurethral resection of the prostate （TURP）. HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2＋ were investigated for HER2 gene amplification status by fluorescent in situ hybridization （FISH）. Results： Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1＋, 2＋ and 3＋ in 49 （47.1%）, 45 （43.3%）, 8 （7.7%） and 2 （1.9%） cases, respectively. There was a significant association between HER2 expression and Gleason score （P = 0.026）. HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores 〉 2＋ showed HER2 gene amplification. Patients with HER2 scores 〉 2＋ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 （P = 0.004） and 1＋ （P = 0.034）. Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death （P = 0.039）. Conclusion： An HER2 IHC score 〉 2＋ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.     

人表皮生长因子受体家族在胃癌中表达的临床意义

目的探讨人表皮生长因子受体（HER）家族成员[HERl（EGFR）、HER2、HER3和HER4]在胃癌患者中的表达情况及其与预后的关系。方法回顾性分析2006年1月至2006年12月江苏省肿瘤医院胃肿瘤诊疗中心收治的161例胃癌患者的临床资料,应用免疫组织化学方法判断HER家族成员的表达情况,并对其表达与患者预后情况进行分析。结果161例患者中,HERl高表达者74例（46．0％）;HER2高表达者17例（10．6％）;HER3高表达者90例（55．9％）,HER4高表达者110例（68．3％）。单因素分析显示：HER2高表达与肿瘤Lauren分型有关（P〈0．05）;HER3高表达与肿瘤浸润深度、淋巴结转移、肿瘤分期和神经脉管侵犯及预后有关（P〈O．05）;HER4高表达与肿瘤浸润深度和远处转移及肿瘤分期有关（P〈O．05）。HER2-HER3协同高表达与患者预后有关（P=0．023）。多因素分析显示：肿瘤分期和HER3高表达是影响胃癌预后的因素（P〈0．05）。结论HER3有可能成为评价胃癌预后的独立因素。     

不同结果判定标准下胃食管结合部癌人表皮生长因子受体2的表达及其与临床病理特征的关系

目的对比在不同的结果判定标准下胃食管结合部癌中人表皮生长因子受体2（HER2）的表达情况及其与临床病理学因素的关系。方法回顾性分析2009年1—12月间北京大学肿瘤医院外科收治的127例胃食管结合部癌患者的临床资料．并对手术标本进行免疫组织化学（免疫组化）染色。结果采用新的和传统的HER2免疫组化判定标准、HER2阳性表达率均为15．0％（19／127）,强阳性率则分别为10．2％（13／127）和6．3％（8／127）（P=0．26）。单因素分析显示．HER2表达与胃食管结合部癌肿瘤分化程度和Lauren分型有关：多因素分析则显示,肿瘤分化程度和TNM分期是影响HER2在胃食管结合部癌表达的独立因素（均P〈0．05）。结论新旧两种免疫组化判定标准下HER2的阳性率并无差异;HER2在胃食管结合部癌中的表达与临床病理特征关系密切。     

表皮生长因子受体在乳腺癌中的研究进展

近几十年,在分子肿瘤的研究中发现一些能够促进肿瘤生长、存活的分子,为肿瘤的治疗带来了新的希望.表皮生长因子受体是最早发现的对抑制肿瘤具有重要意义的分子之一,大约50％的三阴性乳腺癌和炎性乳腺癌都过度表达表皮生长因子受体.表皮生长因子受体及其下游通路可以促进上皮问质转化、肿瘤细胞迁移以及肿瘤浸润.此外,由于凋亡信号转导的发生针对表皮生长因子受体治疗可以提高三阴性乳腺癌细胞化疗的敏感性.研究表明,表皮生长因子受体靶向治疗可能对三阴性乳腺癌和炎性乳腺癌的治疗具有重要作用.     

表皮生长因子受体在前列腺癌雄激素非依赖型细胞系中表达的意义

目的探讨转化生长因子(TGF)-α和表皮生长因子(EGF)对前列腺癌雄激素非依赖型细胞系中表皮生长因子受体(EGFR)表达的调控作用.方法采用逆转录-多聚酶链式反应和免疫印迹法分别对TGF-α和EGF刺激前列腺癌雄激素非依赖型细胞系PC3、ARCaP后EGFR mRNA表达及其蛋白水平进行定量分析.结果EGF引起PC3、ARCaP的EGFR mRNA升高,分别为5.01±0.45和2.41±0.26,差异无显著性(P＞0.05);TGF-α引起各细胞系EGFR mRNA升高,分别为9.05±0.63和3.54±0.33,差异无显著性(P＞0.05).各细胞系EGFR蛋白水平TGF-α组明显高于EGF组(P＜0.05).结论TGF/EGF-EGFR通路在发生发展中起重要作用;TGFα-EGFR自分泌环在非依赖型前列腺癌中的作用强于EGF-EGFR自分泌环.     

Epidermal growth factor receptor (ErbB1) expression in prostate cancer progression: correlation with androgen independence

BACKGROUND: The role of the epidermal growth factor receptor (ErbB1) in the progression of prostate cancer is incompletely understood. METHODS: Tissue microarrays from hormone-naive and advanced androgen-independent tumors were used to investigate the role of ErbB1 in prostate cancer progression. RESULTS: ErbB1 expression in tumor tissues was strongly associated with hormone-refractory status (odds ratio = 6.67, 95% CI = (2.6, 17.4), P = 0.0001). However, ErbB1 overexpression was not a statistically significant covariate in a multivariate proportional hazards model for biochemical failure of hormone-na?ve prostate cancer. Moreover, ErbB1 overexpression was not associated with tumor differentiation (P = 0.44), positive margins (P = 0.53), seminal vesicle invasion (P = 0.69), extraprostatic extension (P = 0.10), or preoperative PSA (P = 0.18) in the hormone-na?ve group. CONCLUSIONS: These findings are consistent with a model in which ErbB1 expression increases during the development of the androgen-independent state, and suggest that drugs targeted toward ErbB signaling could be of therapeutic relevance in the management of advanced prostatic carcinoma.     

The prognostic significance of epidermal growth factor receptor expression in breast cancer

The association between epidermal growth factor receptor (EGFR) expression, clinicopathological variables, silver-stained nuclear organizer region (Ag-NOR) counts, and patient survival was determined in 93 patients with operable breast cancer. The EGFR expression was found to be significantly associated with the presence and number of axillary lymph node metastases (P = 0.0429), but not with age, menopausal status, tumor size, histologic type or grade, or Ag-NOR counts. In a univariate analysis, a significant difference was also observed in the survival of patients stratified by tumor size (P = 0.0091), histologic grade (P = 0.0352), axillarly lymph node metastases (P = 0.0001), and EGFR expression (P = 0.0263). However, a multivariate analysis revealed that axillarly lymph node metastases was the only strong independent predictor ol'survival (P < 0.0001). When axillary lymph node metastases were excluded from the Cox model, the EGFR expression tended to be an independent prognostic factor (P = 0.0558). The results of this study thus indicate that the prognostic value of EGFR expression is limited because the EGFR expression is significantly associated with axillary lymph node metastases.     

人类表皮生长因子受体2表达与胃癌组织学的相关性研究

目的 分析内镜下不同活检部位胃癌组织中人类表皮生长因子受体2（HER2）表达阳性率及与胃癌组织学特点相关性。方法 收集本院2017年1月至2020年1月收治的胃癌患者87例列入胃癌组,选取同期住院治疗的慢性浅表型胃炎患者21例列入正常胃黏膜组,入院后将内镜或手术获得的标本行病理检查,比较内镜标本中不同活检部位组织的HER2阳性率和胃癌病理学特征与人类表皮生长因子受体2表达水平的关系。结果 胃癌组HER2阳性率较胃黏膜正常组更高（17.2%和0.0%,P<0.05）,内镜下肿瘤浅表弥漫部、溃疡隆起部、溃疡床及肿块突起部组织HER2阳性率分别是100%、90%、44%、100%,病理类型为管状腺癌及镜下不含印戒细胞较其他组织类型癌和镜下含印戒细胞HER2阳性率高（分别是23.0%、23.6%和3.8%、6.3%,P<0.05）。结论 胃癌HER2表达水平与其病理组织学特点具有相关性,镜下不含印戒细胞的胃癌组织HER2阳性率可能更高,在评估内镜活检标本HER2表达时应着重选择肿瘤浅表弥漫部和肿块突起部,可以为胃癌靶向治疗提供参考。     

Expression of human epidermal growth factor and its receptor in esophageal cancer

The expression of human epidermal growth factor (hEGF) was examined immunohistochemically in 86 esophageal cancer lesions, comprising 67 primary tumors and 19 metastatic lymph nodes. In the normal esophagus, the parabasal and intermediate cell layers showed a weak expression of hEGF, however, hEGF-positive tumor cells were detected in 62 (92.5 per cent) of the 67 primary esophageal carcinomas and in 18 (94.7 per cent) of the 19 metastatic lymph nodes. In this study, the immunoreactivity of hEGF was classified into 4 grades according to the number of stained tumor cells. A significant correlation was observed between the histologic type and the grade of hEGF immunoreactivity (Chisquare test, p<0.01). hEGF immunoreactivity in well differentiated squamous cell carcinomas was significantly higher than in other squamous cell carcinomas, although there were no correlations between other pathological findings and hEGF immunoreactivity. Patients with hEGF immunoreactivities of grades II or III had much worse prognoses than those with grades 0 or I (p<0.05). In 22 esophageal carcinomas and 10 normal esophageal mucosae, EGF receptor (EGFR) contents were measured by the competitive binding assay. The average EGFR content (101.3±35.7 fmol/mg protein, mean±SE) of the esophageal carcinomas was significantly higher than that (5.3±1.2) of the normal esophageal mucosae (p<0.05). Moreover, in hEGF negative tumors, EGFR contents were lower than in hEGF positive tumors. These results suggest that hEGF and EGFR show increased production in squamous cell carcinomas and could to be useful prognostic factors in patients with esophageal cancer.     

肝细胞生长因子受体和表皮生长因子受体在胰腺癌中的表达及临床意义

目的 探讨肝细胞生长因子受体(Met)及表皮生长因子受体(EGFR)在胰腺癌临床病理和生存预后中的意义.方法 回顾性分析1995至2005年间收治的70例胰腺癌患者的临床病理数据及随访资料,以免疫组织化学染色法(EnVision法)检测Met和EGFR在胰腺癌病理石蜡组织中的表达水平,分析其与临床病理指标的关系,并探讨两种受体表达水平之间的相关性;对总生存时间进行Kaplan-Meier生存分析及相关风险因素的Cox回归检验.结果 Met和EGFR与胰腺癌TNM临床分期、肿瘤大小、血管侵犯相关(P＜0.05).Met和EGFR的表达水平呈正相关(rp=0.658,P＜0.05),两者的表达水平与患者生存时间相关(P＜0.05).Met为影响预后的独立危险因素.结论 Met和EGFR与胰腺癌的生物学行为及临床预后相关;两种受体存在相关性.胰腺癌的靶向治疗策略应兼顾Met及EGFR.     

Changes in epidermal growth factor receptor expression in human bladder cancer cell lines following interferon-alpha treatment

PURPOSE: We examined the regulation of epidermal growth factor (EGF) receptor (EGFR) expression in human bladder cancer cell lines by interferon-alpha (IFN-alpha), the ability of IFN-alpha to inhibit cell proliferation and the sensitivity of IFN-alpha pretreated cells to EGF. MATERIALS AND METHODS: Cell proliferation was determined using crystal violet colorimetric and clonogenic assays. EGFR expression was measured by flow cytometry using specific antibody or ligand binding approaches. RESULTS: After IFN-alpha (100 IU/ml) treatment cell surface EGFR expression was upregulated in 6 of 11 and down-regulated in 2 of 11 bladder cancer cell lines. The over expression of cell surface EGFR peaked within 48 to 96 hours and increased by 35% to 241% in individual cell lines. High level cell surface EGFR correlated with intracellular EGFR expression. Cell growth inhibition by IFN-alpha coexisted with EGFR over expression in the 6 lines. IFN-alpha treated cells remained sensitive to EGF treatment. CONCLUSIONS: IFN-alpha transiently up-regulates EGFR expression and inhibits in vitro growth in some human bladder cancer cells. IFN-alpha does not prevent EGFR from binding EGF or signal transduction via the EGF-EGFR pathway. This may have clinical implications for improving treatment based on EGFR targeting in select patients with bladder cancer.     

乳腺癌细胞中表皮生长因子对雌激素受体表达的影响及机制

目的研究表皮生长因子（EGF）在雌激素受体（ER）阳性及阴性乳腺癌细胞株中对ER表达的影响及其可能的机制。方法以逆转录-聚合酶链反应（RT—PCR）技术分别研究EGF途径以及抑制该途径的信号传导后，对乳腺癌细胞株中ERcxmRNA的影响。结果在ER阳性乳腺癌细胞株中，EGF能显著抑制ERα mRNA的表达（P〈0．05），而通过抑制表皮生长因子受体（EG-FR）、磷脂酰肌醇3激酶（P13K）阻断EGF信号传导可减弱上述抑制作用（P〈0．05）；在ER阴性乳腺癌细胞株中，ERα mRNA无显著变化。结论EGF能够明显抑制ER阳性乳腺癌细胞株中ER的表达，这种抑制作用可能通过EGFR、蛋白激酶B（PKB，又称AKt）信号传导途径完成；这种作用在ER阴性乳腺癌细胞株中并不明显。     

Prostate cancer cells generated during intermittent androgen ablation acquire a growth advantage and exhibit changes in epidermal growth factor receptor expression

BACKGROUND: Intermittent androgen ablation is a palliative treatment option for advanced prostate cancer which is associated with less side effects, improved quality of life of patients, and reduced costs. Regulation of growth and survival of prostate cancer cells during intermittent androgen withdrawal has not been studied in appropriate models yet. METHODS: Two cycles of androgen withdrawal and supplementation were performed in human prostate cancer cells LNCaP in vitro. Proliferation of prostate cancer cell sublines established after intermittent androgen withdrawal was assessed in the absence or presence of epidermal growth factor (EGF) by protein determination. Cell cycle was analyzed with a flow cytometer. EGF was measured in the supernatants of LNCaP sublines with a commercial ELISA. EGF receptor mRNA and protein were determined by real-time PCR and Western blot, respectively. RESULTS: Basal proliferation rate of all newly generated LNCaP sublines increased over that of the parental LNCaP cell line. The highest stimulation of proliferation by exogenous EGF was observed in parental LNCaP cells. In each LNCaP derivative established during intermittent androgen withdrawal, the percentage of cells in the S phase of cell cycle was higher than that in parental LNCaP cells. EGF levels did not increase during intermittent androgen ablation. The expression of EGF receptor protein decreased following each cycle of androgen ablation and increased subsequently after androgen supplementation. EGF receptor (EGFR) mRNA was regulated in a similar manner in LNCaP derivatives established during the second cycle of intermittent withdrawal. CONCLUSIONS: Changes in the expression of the EGF receptor occur during intermittent androgen ablation but they cannot be solely responsible for increased basal proliferation. Alternatively, other ligands and receptors of the EGF system may become overexpressed during prolonged withdrawal and supplementation of androgenic hormones in prostate cancer therapy.     

Protease activated receptor 2 and epidermal growth factor receptor are involved in the regulation of human sperm motility

Aim： To investigate mechanisms of tryptase-induced reduction of sperm motility and explore whether epidermal growth factor receptor （EGF-R） and protease activated receptor 2 （PAR-2）- associated pathways are involved. Methods： Fresh semen was collected from healthy donors （n = 15）. Semen parameters and quality were assessed in accordance with the World Health Organization （WHO） criteria. Swim-up sperm were fixed and subjected to immunocytochemistry and immunoelectronmicroscopy with specific antibodies directed against PAR-2 and EGF-R. Protein extractions from swim-up spermatozoa were analyzed by Western blotting with antibodies for both receptors. Motility of spermatozoa was evaluated by computer-assisted semen analysis. Results： Immunocytochemistry found PAR-2 and EGF-R in approximately 30% of examined human ejaculated spermatozoa. Both receptors were localized in the plasma membrane. Like tryptase, the PAR-2 synthetic agonist SLIGKV reduced sperm motility, and this effect was inhibited by application of two specific EGF-R pathway blockers （AG1478 and PD168393）. Conclusion： The observed reduction of sperm motility by tryptase through the PAR-2 receptor involves EGF-R pathways.     

Serum levels of shed Her2/neu protein in men with prostate cancer correlate with disease progression

PURPOSE: We determined the association between serum levels of shed Her-2/neu protein and disease progression in men with prostate cancer. MATERIALS AND METHODS: Serum from 279 patients enrolled in a prospective serum bank and database at New York University Medical Center was analyzed using the Food and Drug Administration approved Immuno-1 Her-2/neu assay. Patients were classified by the Prostate-Specific Antigen Working Group model into 5 groups, namely group 1-no evidence of cancer in 60, group 2-clinically localized disease in 67, group 3-prostate specific antigen increasing after therapy and no clinical metastases in 77, group 4-clinical metastases and castration sensitivity in 42, and group 5-clinical metastases and castration resistance in 33. A cutoff of 14 ng/ml for normal serum Her-2/neu was established based on the 95th order statistic in group 1. RESULTS: Of 279 patients 37 (13.3%) had increased serum Her-2/neu, that is 5%, 11.9%, 10.4%, 16.7% and 33.3% in groups 1 to 5, respectively. There was a significant difference between patients with (groups 4 and 5) and without (groups 2 and 3) clinical metastases (p = 0.006). In group 5 patients serum Her-2/neu was significantly higher than in group 2 patients (p <0.02). The risk of cause specific death increased significantly with each unit increase in serum Her-2/neu (p <0.001). CONCLUSIONS: Increased serum Her-2/neu correlates with the presence of metastatic disease and it may indicate an increased risk of death in patients with castrate, metastatic prostate cancer. The detection of serum Her-2/neu is a minimally invasive alternative to tumor sampling for identifying potential candidates for anti-Her-2/neu treatment strategies. Further studies are needed to optimize this assay for application in the clinical setting.     

不同结果判定标准下胃癌人表皮生长因子受体-2的表达及其与临床病理特征的关系

目的对比在不同的结果判定标准下胃癌人表皮生长因子受体-2(HER-2)的表达情况及其与临床病理学因素的关系。方法回顾分析2009年1月至12月北京大学肿瘤医院外科收治胃癌患者的资料,对手术标本进行切片、免疫组织化学染色。结果采用新的和传统的HER-2免疫组织化学判定标准,HER-2强阳性率(3+)分别为6.7%和3.3%(P=0.076);采用新的免疫组织化学判定标准,HER-2的阳性率(2+和3+)为8.5%。单因素分析显示,HER-2表达与肿瘤分化程度、Lauren分型和肿瘤大小有关;多因素分析发现,肿瘤大小是影响HER-2表达的独立影响因素。结论新旧两种免疫组织化学判定标准下HER-2的阳性率其差异没有统计学意义;HER-2在胃癌中的表达与临床病理特征有密切关系。