Human epidermal growth factor receptor 3 in head and neck squamous cell carcinomas

Human epidermal growth factor receptor 3 (HER3) is a member of the human epidermal growth factor receptor (HER) family. The main characteristic of HER3 is that it does not possess tyrosine kinase activity, unlike other HERs. The role of HER3 in tumorigenesis has now been recognized, particularly in head and neck squamous cell carcinomas (HNSCCs). Despite conflicting studies, HER3 was found to be overexpressed in HNSCC samples, and correlates with disease progression and poor survival, especially when it is coexpressed with other HERs. HER3 is a significant factor in HNSCC treatment resistance. Indeed, HER3 is a major mechanism described for cetuximab resistance because of modification of epidermal growth factor receptor (EGFR) internalization and by phosphotidylinositol‐3‐kinase (PI3K)/AKT signaling pathway activation. HER3 also affects resistance to tyrosine kinase inhibitors (TKIs) and thereby promotes treatment escape and radiotherapy resistance by activation of the survival signaling pathway. To counteract this, pharmacologic inhibitors of HER3 are currently in development and could significantly improve HNSCC treatment. © 2016 Wiley Periodicals, Inc. Head Neck 38 : E2412–E2418, 2016     

Urine human epidermal growth factor (hEGF) levels following surgery

In order to investigate the contribution of growth factors in conditions of postoperative stress, we measured the blood and urine hEGF levels in patients with various surgical disorders. While the levels of serum and plasma hEGF did not change significantly after surgery, urine hEGF (u-hEGF) stayed at the base-level followed by a single peak within a postoperative period of two weeks. The peak day of u-hEGF in patients with more than 1000 ml of intraoperative bleeding was later than that in patients with bleeding of less than 1000 ml. In patients with postoperative renal failure or dysfunction, u-hEGF levels dropped and did not rise until the recovery of renal function. The changing pattern of u-hEGF levels was an indicator of operative bleeding volume and renal function.     

Urine human epidermal growth factor (hEGF) levels following surgery

In order to investigate the contribution of growth factors in conditions of postoperative stress, we measured the blood and urine hEGF levels in patients with various surgical disorders. While the levels of serum and plasma hEGF did not change significantly after surgery, urine hEGF (u-hEGF) stayed at the base-level followed by a single peak within a postoperative period of two weeks. The peak day of u-hEGF in patients with more than 1000 ml of intraoperative bleeding was later than that in patients with bleeding of less than 1000 ml. In patients with postoperative renal failure or dysfunction, u-hEGF levels dropped and did not rise until the recovery of renal function. The changing pattern of u-hEGF levels was an indicator of operative bleeding volume and renal function.     

Correlation of epidermal growth factor receptor status and clinical outcome in gastric carcinoma

Analysis of epidermal growth factor receptor (EGFR) was performed on 242 primary gastric carcinomas and the results correlated with histologic findings and S-phase fractions measured by bromodeoxyuridine (BrdU) labeling. They were stained for EGFR by means of an indirect immunoperoxidase technique using a monoclonal antibody against the receptor. Seventy-six of these cancer tissues exhibited EGFR reactivities. All the cancer cell membranes were stained and sometimes the stroma were stained. These EGFR status were then compared on the basis of pathologic findings including macroscopic type, depth of invasion, differentiation type, vascular invasion and lymph node metastasis. Staining for EGFR in Borrmann's 3 or 4 type was significantly stronger than those in other macroscopic types. The staining for EGFR was closely related to the poorly differentiated type and frequent serosal involvement. BrdU labeling index was studied in 25 cases. These values were from 2.3% to 18.6%, with a mean of 10.4%. The mean BrdU labeling index of EGFR positive cases was 12.2%, of negative cases 7.6%, respectively. There was a good correlation between BrdU labeling index and EGFR status. In addition, There was a signifiCANT 8P less than 0.05) correlation between the presence of the EGFR and poor prognosis. However, EGFR status was not significantly correlated with the lymph node metastasis, vessel invasion and size of the tumors. These results indicate that demonstration of EGFR status may be useful in prognosis and this receptor may be a suitable target for therapy.     

Expression of human epidermal growth factor and DNA ploidy pattern in gastric carcinoma

Expression of human epidermal growth factor (EGF) was examined immunohistologically in 93 surgically resected gastric carcinomas, using Biotin-StreptAvidin method pretreated by protease, and its relation with cancer progression and DNA ploidy pattern was studied. DNA ploidy pattern was determined by cytofluorometric measurement. The gastric cancers were divided into two basic ploidy patterns; a diploid mode and an aneuploid mode. EGF expressions were found in 5 out of 20 cases (25%) in intramucosal carcinomas and, the more deeply the carcinomas invaded into the gastric wall, the greater the frequency of EGF expressions did not always become. In the carcinomas with the aneuploid pattern, EGF expression was found only in 2 out of 12 cases (17%) in early cancers and significantly increased in advanced cancers, 15 out of 22 cases (68%). On the other hand, in the carcinomas with the diploid pattern, EGF was expressed in 9 out of 31 cases (29%) in advanced cancers, not significantly different in early cancers, 11 out of 28 cases (39%). Consequently, in advanced cancers, EGF was found more frequently in the aneuploid tumors than in the diploid tumors. These results suggested that EGF expression in the gastric carcinomas is closely correlated with the progression to the advanced cancer with DNA aneuploidy.     

Effect of epidermal growth factor (EGF) on experimental granulation tissue

Subcutaneously implanted cylindrical hollow viscose cellulose sponges were used to study the effects of locally applied epidermal growth factor (EGF) on developing granulation tissue in rats. In the first set of experiments the test implants were treated with a single injection of a solution containing 5 micrograms of EGF in 0.5% albumin while the control implants were treated correspondingly with the carrier solution only. In the second set of experiments the injections of both test and control implants were repeated daily. Analyses of wound fluid and granulation tissue in the sponge cylinders were carried out 10 days after implantation. After single application of EGF no essential differences were detected in wound fluid prostaglandin E2 levels or various components of granulation tissue between the groups. After daily application, however, a stimulatory effect of EGF on granulation tissue formation was observed: cellularity increased, as evidenced by the elevated amounts of nucleic acids, and accumulation of collagen and glycosaminoglycans was enhanced.     

Human epidermal growth factor receptor 2 (Her-2) and S-1 adjuvant chemotherapy in stage 2/3 gastric cancer patients who underwent D2 gastrectomy

Purposes

The trastuzumab for Gastric Cancer study newly defined tumors that were positive for human epidermal receptor-2 (Her-2) and created a Her-2-oriented treatment strategy that is also applicable in the adjuvant setting for stage 2/3 cancers. However, there is currently no information available on the rate of Her-2 positivity and the relapse-free survival (RFS) stratified by Her-2 status in stage 2/3 patients.

Methods

The Her-2 status, defined by the current standard method, was examined in 100 gastric cancer patients who underwent curative D2 surgery, who were pathologically diagnosed with stage 2/3 cancer, and received adjuvant S-1 chemotherapy between June 2002 and December 2011.

Results

Ten of the 100 patients were Her-2 positive. Her-2-positive status was more frequently seen in tumors with a differentiated histology. The 5-year RFS rate was 56.3 % in Her-2-positive cases, and 48.8 % in Her-2 negative cases, which was not significantly different (P = 0.786).

Conclusions

The Her-2-positive rate for stage 2/3 gastric cancer patients was low, at only 10 %. Although the RFS was not significantly different based on the Her-2 status, the low positive rate made interpretation difficult. A multi-center study with a large sample size is necessary to clarify the prognostic impact of Her-2 in stage 2/3 gastric cancer patients.     

The correlation of epidermal growth factor with invasion and metastasis in human gastric cancer

We examined the localization of epidermal growth factor (EGF) in 185 specimens of primary human gastric cancer using the avidin-biotin peroxidase complex immunohistochemical method on formalin-fixed paraffin-embedded sections. Thirty-four per cent of the gastric cancer specimens were positive for EGF, which was mainly located in the cytoplasm of the cancer cells and occasionally in the stromal cells, but was not detected in non-cancerous gastric epithelium. Moreover, the presence of EGF in gastric cancer was correlated with gastric wall invasion and lymph node metastasis. EGF was found more often in advanced cancers than in early ones (p less than 0.01), and also more often in cancers with lymph node metastasis than in those without (p less than 0.05). The five-year survival of patients with EGF-positive tumors was worse than that of patients with EGF-negative tumors (p less than 0.05). The presence of EGF in human gastric cancer may thus represent higher malignant potential.     

Human epidermal growth factor receptor 2 as a prognostic indicator in osteogenic sarcoma

Prognostic biologic factors that can be assessed at the time of diagnosis for patients with osteogenic sarcoma have not been identified. The current study was designed to evaluate the prognostic significance of the human epidermal growth factor receptor 2 as it relates to histologic response to preoperative chemotherapy and event-free survival. A retrospective immunohistochemical study was performed on material from patients who were newly diagnosed with osteogenic sarcoma who were treated according to the T12 protocol from the authors' institution between 1986 to 1993. Staining for HER2/erbB-2 was accomplished using standard monoclonal antibodies and methods. At the time of initial biopsy, 42.6% of the samples showed HER2/erbB-2 overexpression. Higher levels of expression were observed in samples from patients with clinically detectable metastases at initial presentation and at relapse. Expression of HER2/erbB-2 correlated with inferior event-free survival in patients with nonmetastatic disease (47% versus 79% at 5 years). In addition, HER2/erbB-2 expression was associated with significantly less tumor necrosis after preoperative chemotherapy as determined by the Huvos grading system. These data suggest that HER2/erbB-2 should be evaluated prospectively as a prognostic indicator and clinical trials using antibodies that target this receptor should be considered for the treatment of patients with osteogenic sarcoma.     

The correlation of epidermal growth factor with invasion and metastasis in human gastric cancer

We examined the localization of epidermal growth factor (EGF) in 185 specimens of primary human gastric cancer using the avidinbiotin peroxidase complex immunohistochemical method on formalin-fixed paraffin-embedded sections. Thirty-four per cent of the gastric cancer specimens were positive for EGF, which was mainly located in the cytoplasm of the cancer cells and occasionally in the stromal cells, but was not detected in non-cancerous gastric epithelium. Moreover, the presence of EGF in gastric cancer was correlated with gastric wall invasion and lymph node metastasis. EGF was found more often in advanced cancers than in early ones (p<0.01), and also more often in cancers with lymph node metastasis than in those without (p<0.05). The five-year survival of patients with EGF-positive tumors was worse than that of patients with EGF-negative tumors (p<0.05). The presence of EGF in human gastric cancer may thus represent higher malignant potential.     

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。     

Role of membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF) in renal epithelial cell branching

Role of membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF) in renal epithelial cell branching.BACKGROUND: The developing metanephros is characterized by growth and differentiation of the ureteric bud and the surrounding mesenchymal tissue. These processes can be influenced by several growth factors, including epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). We examined whether another member of the EGF family of growth factors, heparin-binding epidermal growth factor (HB-EGF), might act as a morphogen in renal epithelial tubulogenesis.METHODS: Expression of HB-EGF mRNA and immunoreactive protein were examined in fetal, neonatal and adult rat kidneys. For in vitro studies of tubulogenesis, a rat renal epithelial cell line (NRK52E) stably transfected with proHB-EGF (NRKproHB-EGF) was treated with TPA for 30 minutes, washed with 2 mol/L NaCl to remove soluble HB-EGF trapped by cell surface heparan sulfate proteoglycan and replated onto plastic dishes in the absence of fetal calf serum. In further experiments, NRKproHB-EGF were suspended in a type I collagen gel in serum-free media.RESULTS: Northern blot analysis indicated that HB-EGF was strongly expressed in embryonic rat kidney (embryonic days 18-20) and was still increased in the neonatal kidney (day 10), compared to the low basal levels in adult kidney. Immunohistochemical analysis confirmed that immunoreactive HB-EGF expression in the fetal rat kidney was localized predominantly to the ureteric bud. When NRKproHB-EGF were plated onto plastic substrata, they became progressively flattened and enlarged and exhibited filopoidia. By 10 hours after plating, NRKproHB-EGF began to migrate and subsequently developed cell-cell contact and fully established tubular-like structures. Immunoelectron microscopy revealed that the initial recovery of cellular proHB-EGF was localized predominantly to areas of cell-cell attachment. No tubule-like structures were observed in similarly treated NRK52E cells transfected with the vector alone. In collagen gels, NRKproHB-EGF developed short tubule-like structures in the absence of TPA treatment, but with simultaneous TPA treatment, longer and more arborized structures developed. MMP-1 mRNA and immunoreactive protein increased in the TPA-treated cells, suggesting that protein kinase C-mediated collagenase activity was important for the observed tubulogenesis. However, inhibition of EGF receptor tyrosine kinase with AG 1478 significantly blunted the TPA-induced tubulogenesis by NRKproHB-EGF grown in collagen gels.CONCLUSIONS: These results indicate that membrane-bound HB-EGF can mediate both epithelial cell branching and cell motility. Localization of proHB-EGF to the site of cell-cell contact and development of tubule-like structures in collagen gels suggests that proHB-EGF may be an important morphogen for renal epithelial cells.     

肾移植前后表皮生长因子含量研究

为了探讨细胞生长调节因子之一的表皮生长因子（ＥＧＦ）在肾脏损害修复中的作用及ＥＧＦ与肾功能及缺血性肾损伤修复之间的关系，观察了１３８例慢性肾功能衰竭（尿毒症期）患者血ＥＧＦ含量和肾移植术前后血和尿中ＥＧＦ含量。结果显示，肾功能衰竭、肾脏损伤期血ＥＧＦ水平极低，移植后肾功能恢复早期，血ＥＧＦ即明显回升。恢复后期，血ＥＧＦ水平稍降，但仍比移植前增高。血ＥＧＦ含量持续不升高者与急性排斥反应和急性肾小管坏死的发生有关。ＥＧＦ的存在，在肾损伤修复时具有重要的作用。检测血清ＥＧＦ含量可作为判断移植肾损伤修复状态的指标之一。     

Detection of P-glycoprotein in human urogenital carcinomas and its relationship to epidermal growth factor receptor expression.

P-glycoprotein and epidermal growth factor (EGF) receptor expression were surveyed immunohistochemically in the tissue of urogenital carcinomas including 12 renal cell carcinomas, 9 bladder transitional cell carcinomas, 2 prostate adenocarcinomas and 1 penile squamous cell carcinoma. Three bladder carcinomas and the penile carcinoma were following initial chemotherapy at the time of relapse. P-glycoprotein expression was detected in 3 of 12 renal cell carcinomas and in all recurrent carcinomas. EGF receptor was not detected in any of the specimens.     

大鼠血清表皮生长因子和睾丸表皮生长因子受体与精子生成的相关性

目的　探讨血清表皮生长因子 ( EGF)和睾丸组织表皮生长因子受体 ( EGF-R)与大鼠精子生成的关系。　方法　 40只性成熟期雄性 SD大鼠 ,随机分为假手术组( SOG)、去颌下腺组 ( SG)、去颌下腺加腹腔注射 EGF I组 ( SG-EGF I)和 II组 ( SG-EGFII) ,每组 1 0只。SG-EGF I和 SG-EGF II分别腹腔内注射 EGF0 .2 5和 0 .50 μg·kg- 1·d- 1。大鼠常规喂养 48d,断头取血和睾丸。放射免疫法检测血清 EGF水平 ,病理检查睾丸生精功能和免疫组织化学检测睾丸组织 EGF-R的表达。　结果　大鼠血清 EGF水平SG-EGF I组明显下降 ( P<0 .0 5) ,SG组有非常显著下降 ( P<0 .0 1 ) ;睾丸生精功能中、重度障碍 ;间质细胞 EGF-R表达明显减少 ( P<0 .0 5)。补充不同剂量的 EGF对睾丸生精功能有不同影响。 SOG、SG-EGF I和 SG-EGF II大鼠睾丸生精细胞、支持细胞及间质细胞 EGF-R表达无显著性差异 ( P>0 .0 5)。　结论　EGF对精子发生具重要的调控作用 ,血清 EGF水平和睾丸间质细胞 EGF-R高表达与睾丸生精功能呈正相关     

Chronic cystitis: Excretion of epidermal growth factor (EGF)/urogastrone (URO)

Summary To investigate the role of epidermal growth factor (EGF)/urogastrone (URO) in the cytoprotection of the urothelium in the urinary bladder we measured the concentration of EGF/URO by radioimmunoassay in urine from patients with chronic cystitis. The series comprised 12 patients with classical interstitial cystitis, 10 young females with recurrent bacterial cystitis and 12 children with recurrent cystitis together with sex- and age-matched controls. The results showed no variation in the substance concentration of EGF/URO in urine from cystitis patients and control groups. A negative correlation was found between 1) the urinary concentration of EGF/URO and increasing age, and 2) the excretion of EGF/URO per mol creatinine. The present study did not show a decreased output of EGF/URO in patients with chronic cystitis. Further studies are necessary in the evaluation of the physiological role of EGF/URO in the urinary tract.     

Expression of epidermal growth factor and epidermal growth factor receptor genes in healing colonic anastomoses in rats.

This study uses complementary DNA probes to find out if epidermal growth factor (EGF) and EGF receptor genes are activated in healing colonic anastomoses in rats. 35 rats had a colocolonic anastomosis which was removed for study 1, 2, 3, 5, 7, or 14 days after operation. Six animals without surgery served as controls. The specimens were examined by northern blotting, in situ hybridisation, and conventional microscopy. Microscopic healing progressed normally. The expression of the EGF gene was minimal and surgery did not activate it. However, surgical trauma did increase the expression of the EGF receptor gene by 2.2 times when compared to day one. In situ hybridisations localised a strong EGF receptor expression in mucosal epithelial cells in all specimens, and a moderate reaction in fibroblasts in the repair tissue in the anastomotic line. The enhanced EGF receptor gene expression suggests that anastomotic healing is associated with the presence of EGF or an EGF-like substance and its activity increases during the first postoperative week.     

The correlation between serum epidermal growth factor/testicular epidermal growth factor receptor and spermatogenesis in rat

<正>Objective: To investigate the correlation between epidermal growth factor (EGF)/testicular epidermal growth factor receptor (EGF-R) and spermatogenesis in rat. Methods: Forty mature male Spraque-Dauley (SD) rats were randomly assigned to four groups, ten rats in each: sham operation group (SOG), sialoadenectomy group(SG), sialoade-nectomy group with injection of EGF (0. 25 μg·kg-1·d-1, SG-EGF Ⅰ) and sialoadenectomy group with injection of EGF (0. 50 μg·kg-1·d-1 , SG-EGF Ⅱ). The rats were routinely feed, and blood and testes were obtained on the 48th day after the operation. Serum EGF concentrations were determined by radioimmunoassay (RIA) , expression of EGF-R in testes was examined by the immunohistochemical method, and the spermatogenesis was pathologically checked. Results: Serum EGF levels in SG-EGFIand SG decreased significantly when compared with those of SOG (P<0. 05 and P< 0. 01, respectively). The testicular function of spermatogenesis showed a moderate to severe impairment in SG. The expression of EGF-R in Leydig cells decreased in SG(P<0. 05). The two dosage groups of EGF replacement had different effects. There were no significant differences of EGF-R expression in testicular germ cells, Sertoli cells and Leydig cells in SOG, SG-EGFⅠand SG-EGFⅡ(P>0. 05). Conclusion: EGF may play an important role in the regulation of spermatogenesis. Serum EGF concentration and high expression of EGF-R in Leydig cells have a positive correlation with spermatogenic function of the testes.     

前列腺癌细胞中表皮生长因子受体的表达和激活

目的：探讨前列腺癌（ＰＣａ）细胞中表皮生长因子受体（ＥＧＦＲ）表达和激活及其与雄激之间的相互作用。方法：采用免疫沉淀和Ｗｅｓｔｅｒｎ ｂｌｏｔ方法,检测雄激素依赖人ＰＣａ细胞株ＬＮＣａＰ及雄激素非依赖人ＰＣａ细胞株ＤＵ－１４５、ＰＣ－３中ＥＧＦＲ的表达和磷酸化激活,测定雄激素对ＬＮＣａＰ ＥＧＦＲ表达和激活的影响。结果：在ＤＵ－１４５和ＰＣ－３中,ＥＧＦＲ表达和激活的基础与表皮生长因子（ＥＧＦ）处