IGF-I和IGF-IR在高氧致新生鼠慢性肺疾病中的动态表达及其作用

目的研究IGF-I、IGF-IR在高氧致新生鼠慢性肺疾病（CLD）中的表达及作用。方法将足月新生大鼠144只随机分为高氧组和空气组,分别于实验1d,3d,7d,10d,14d,21d应用免疫组化和RT-PCR技术检测IGF-I、IGF-IR的动态表达。结果CLD时IGF-I和IGF-IR呈动态变化,高氧组和空气组比较,在实验3d～10d IGF-I和IGF-IR表达明显降低（P〈0.05）,14d和21d表达明显增强（P〈0.05）。结论IGF-I和IGF-IR是肺泡发育的正向调节因子,与CLD时肺泡分隔受阻、肺泡成熟障碍和肺纤维化有关。     

Oestrogen receptor and epidermal growth factor receptor expression in male breast carcinoma.

Male breast carcinomas are probably hormone-dependent, but receptor studies are few because this is a relatively rare tumour. We have studied 21 cases of male breast carcinoma immunohistochemically for oestrogen receptor (ER) and epidermal growth factor receptor (EGFR) expression employing the antibodies ER-ICA and 12E on formalin-fixed, paraffin-embedded material. In our series, 86 per cent of male breast cancers were ER-positive and 76 per cent were EGFR-positive. Male breast carcinomas do not exhibit the inverse correlation between ER and EGFR expression that characterizes female breast carcinomas. Owing to the limitations of a small series, we were unable to comment on the relationship between ER and EGFR expression and patient survival. However, the relatively high incidence of ER expression may provide a growth advantage for this tumour in a male environment characterized by low levels of oestrogen. In addition, high EGFR expression may also contribute to a poor prognosis independent of ER status.     

人胰岛素样生长因子-1的真核表达及其生物学功能研究

目的：构建人胰岛素样生长因子1（IGF-1）分泌型真核表达载体，并检测表达产物的生物活性。 方法：用RT-PCR法从人肝细胞克隆IGF-1基因，并将其连入Psec Tag/FRT/V5-His载体，用脂质体法转染CHO细胞，将转染细胞上清培养骨髓基质干细胞，用MTT法测定骨髓基质干细胞的增殖情况。 结果：成功扩增210 bp的IGF-1基因，表达产物经SDS-PAGE分析及Western blotting检测具有7.7 kD特异性条带。骨髓基质干细胞的增殖随转染细胞上清的浓度、转染细胞上清培养时间的增加而增加。 结论：成功构建分泌型IGF-1真核表达载体，其表达产物对骨髓基质干细胞具有促增殖作用。     

Expression of PC-cell-derived growth factor in benign and malignant human breast epithelium

PC-cell-derived growth factor (PCDGF, progranulin) is a novel autocrine growth factor that is overexpressed in human breast cancer cell lines. We have examined immunohistochemical PCDGF expression in 206 paraffin-embedded human breast lesions and investigated its association with clinicopathological variables. PCDGF staining was observed in breast carcinoma, whereas it was almost always negative in benign breast epithelium. PCDGF expression was more common in invasive ductal carcinoma (80% cases positive) than in invasive lobular carcinoma (53% positive). PCDGF staining was almost never observed in lobular carcinoma in situ. Ductal carcinoma in situ expressed PCDGF in 66% of the cases, and this expression correlated strongly with nuclear grade. Similar correlation was observed between PCDGF expression and histologic grade of invasive ductal carcinoma. Average Ki-67 index of PCDGF-negative/weakly positive invasive carcinomas (30.3) was significantly lower than that of strongly PCDGF-positive tumors (48.8, P=0.01). A larger percentage of tumors that expressed PCDGF with a staining intensity of 2+ or 3+ were p53 positive (44%) than were PCDGF-negative tumors (25%), P=0.02. PCDGF expression was independent of c-erbB-2 overexpression and of ER and PR status. Our study provides the first evidence of high incidence of PCDGF expression in human breast cancer in which it correlates with clinicopathological variables such as tumor grade, proliferation index, and p53 expression. These characteristics, as well as the virtual absence of expression in benign breast tissue, suggest an important role of PCDGF in breast cancer pathogenesis and make it a potential novel target for the treatment of breast cancer.     

Oestrogen receptor in breast cancer: prognostic studies using a new immunohistochemical assay

A recently developed and validated histochemical method--immunogold-streptavidin enhancement--was used to determine oestrogen receptor content in paraffin sections of breast cancers. The selection of the best cut-off point to define oestrogen receptor status as rich or poor was made on the basis of survival data, using the following indices: survival to term; disease-free interval; survival at 5 years; and disease-free interval at 5 years. Oestrogen receptor status was examined in relation to histological grade, lymph node status, menopausal status and tumour size and these four indices were considered as independent prognostic factors. Semi-quantitative assay of receptor content showed that increasing content was related to better prognosis. Adjuvant therapy alone had no effect on patient outcome. Independently, histological grade and lymph node status, but not menopausal status or tumour size, were prognostic indicators. Oestrogen receptor rich status, as measured by immunogold-streptavidin, in conjunction with certain of these factors indicated a better prognosis. This was comparable with results in reports using other methods of receptor assay. We found the oestrogen receptor status and menopausal status more significant at 5 years than at term. The advantage of immunogold-streptavidin enhancement, which we found as reliable as other methods for oestrogen receptor assay, is that it can be used on archival, routinely paraffin-processed material.     

胰岛素样生长因子在口腔黏膜下纤维性变组织中的表达

目的：探讨胰岛索样生长因子-1在口腔黏膜下纤维性变发病中的作用。方法：应用原位杂交的方法，对27例口腔黏膜下纤维性变（OSF）组织和9例正常组织进行了IGF-1mRNA的检测。结果：8例OSF早期患者角朊细胞中IGF-1mR-NA表达均为阳性，19例OSF中晚期组织有7例表达阳性，9例正常组织均为阴性，三组之间均有显著差异；所有组织中成纤维细胞IGF-1mRNA表达均为阳性，但强度无明显差异；中晚期组织有5例毛细血管内皮细胞表达阳性。结论：OSF病人角朊细胞可合成IGF-1，IGF-1可能在OSF发病中起重要作用。     

The insulin-like growth factor type 1 receptor and colorectal neoplasia: insights into invasion

This study examines the expression of the insulin-like growth factor type 1 receptor (IGF-1R) in colorectal neoplasia. Previous studies have shown that the IGF-1R is expressed at high levels in normal embryonic stem cells and in many cancer phenotypes. However, lower IGF-1R levels are expressed in some advanced cancer phenotypes. The timing of and the reasons for these changes in expression during the evolution of a cancer are not understood. Here, we examine IGF-1R expression in the evolution of colorectal cancer by means of Northern blotting and immunohistochemistry validated by tissue and reagent controls and Western blotting. We show for the first time that (1) in normal colorectal crypts, epithelial stem cells in the basal crypt region express high IGF-1R levels, which decrease to low levels when these cells migrate to and differentiate in the mid and upper crypt regions; (2) in tumor initiation in aberrant crypt foci, all of the transformed cells express high levels of the IGF-1R at stem cell levels throughout the crypt axis; (3) in tumor progression in adenomatous and cancerous crypts, tumor cells of an epithelial type morphology express high levels of the IGF-1R; (4) in advanced cancers, low levels of the IGF-1R are expressed in invasive foci where cancer cells dedifferentiate to a mesenchymal-type morphology and show a loss of cell adhesion. Interestingly, these cells can form an alternating pattern with mesenchymal type cells that show cell adhesion and high levels of IGF-1R expression. In summary, this study shows that high-level IGF-1R expression in colorectal neoplasia is initiated by an abnormality of stem cell programmed differentiation in the aberrant crypt focus. However, low-level IGF-1R expression is found in some invasive cancers where it is consequent to cancer cell dedifferentiation to a mesenchymal type morphology with loss of cell adhesion.     

Prognostic factors in breast cancer: immunohistochemical staining for SP1 and NCRC 11 related to survival, tumour epidermal growth factor receptor and oestrogen receptor status

It has been proposed that intense immunohistochemical staining using the monoclonal antibody NCRC 11 is indicative of a better prognosis in breast cancer, and that expression of pregnancy specific glycoprotein (SP1) and epidermal growth factor receptors (EGFR) are poor prognosis indicators. In order to evaluate the significance of staining for NCRC 11 to prognosis and to these other variables, we studied two series of breast cancer patients. In one series (n = 93), staining with NCRC 11 and for SP1 was correlated with prognosis: in neither case was there any overall relationship between staining and survival. However, when the patients were stratified by tumour histological (Bloom's) grade, SP1 expression was associated with a poorer prognosis in grade II tumours (p less than 0.025). In a further series (n = 94), NCRC 11 staining was carried out and fresh tumour samples were assayed biochemically for oestrogen receptor (OER) and EGFR. NCRC 11 showed a negative correlation with EGFR status (p = less than 0.05) but no significant association with OER status. Thus despite our demonstration of a negative correlation with an indicator of poorer prognosis, we were unable to demonstrate any direct relationship between staining with NCRC 11 and survival.     

Expression of amphiregulin and epidermal growth factor receptor in human breast cancer: analysis of autocriny and stromal-epithelial interactions

Amphiregulin (AR) and its receptor, epidermal growth factor receptor (EGFR), were evaluated by dual immunostaining in a series of 84 invasive ductal breast carcinoma specimens, 33 of which were from locally advanced inflammatory (T4d) cancer. Co-expression of AR and EGFR was always found in non-malignant breast tissues adjacent to tumours (24/24). Alternatively, expression of AR and EGFR was found in invasive epithelial tumour cells in 50% and 17.8% of specimens, respectively. In tumour stroma, 59.5% and 30.9% of specimens, respectively, were positively stained. By univariate analysis, AR and EGFR expression in invasive carcinomas was correlated with large tumour size, inflammatory carcinoma, node involvement, Bloom-Richardson (SBR) grade III, and absence of oestrogen receptor. EGFR expression in stromal cells was correlated with non-inflammatory carcinoma. A putative autocrine loop with AR and EGFR expression in invasive carcinoma was detected in 14.3% of cases. Stromal expression of AR and EGFR expression in invasive tumour cells was detected in 11.9% of cases and related to poor prognostic parameters. By multivariate analysis, AR expression in invasive tumour was strongly related to inflammatory carcinoma (p=0.005) and marginally related to SBR grade III (p=0.07). EGFR expression in invasive tumour and stromal cells was correlated with absence of oestrogen receptor and non-inflammatory carcinoma (p=0.002 and p=0.015, respectively).     

The epidermal growth factor receptor in human pancreatic cancer.

The epidermal growth factor receptor (EGFR) and its ligands are thought to be important in the control of proliferation of many epithelial systems, including the exocrine pancreas. Abnormalities in expression of two of the known ligands of the EGFR, transforming growth factor alpha and epidermal growth factor, occur frequently in ductal adenocarcinoma of the human pancreas. We have examined an archival series of cases of pancreatic pathology for expression of the EGFR using the anti-EGFR antiserum 12E and found that there is almost ubiquitous overexpression of EGFR in pancreatic cancer and in chronic pancreatitis. Southern blot analysis showed no evidence of amplification or rearrangement of the EGFR gene. We conclude that an autocrine loop involving the EGFR system may be involved in the genesis of both neoplasia and reactive hyperplasia of pancreatic ductal epithelium.     

血管内皮细胞生长因子在肥胖乳腺癌患者乳腺癌组织中的表达及临床意义

 摘要：　目的 探讨肥胖乳腺癌患者乳腺癌组织中血管内皮细胞生长因子（vascular endothelial growth factor,VEGF）的表达及临床意义。方法 采集45例肥胖乳腺癌患者,37例正常体重乳腺癌患者,用RT-PCR和免疫组织化学检测肥胖组和正常体重组乳腺癌组织VEGF的mRNA和蛋白表达。结果 肥胖组乳腺癌组织VEGF的mRNA和蛋白表达均高于正常体重组 (P<0.05),并且VEGF mRNA和蛋白表达之间呈正相关(r=0.785,P<0.05);VEGF在肥胖乳腺癌组织中的表达与组织学分级、5年复发转移有关,与患者年龄无关。结论 VEGF在肥胖乳腺癌患者中具有高表达趋势,提示VEGF可能在肥胖相关性乳腺癌的发生、演变及预后中起重要作用。     

p53 expression in human breast cancer related to survival and prognostic factors: an immunohistochemical study

In a study of 90 breast cancer patients, tumour p53 protein expression was determined by immunohistochemistry using the monoclonal antibody PAb1801. Patient lymph node status and Bloom's grade were determined, and both oestrogen and progesterone status assessed, also by immunohistochemistry. Lymph node status, tumour grade, and progesterone receptor status all had a significant influence on survival. Patients with p53-positive tumours showed poorer survival but this did not achieve significance. p53 protein expression showed a significant relationship to high tumour grade and a weak correlation with negative oestrogen receptor status. The data suggest that p53 protein expression may be a marker of more aggressive carcinomas but that the prognostic power of expression is likely to be weak and unlikely, therefore, to be of clinical value. The results do not resolve whether detectable p53 protein expression represents a random product of dedifferentiation, or an important feature of the malignant phenotype, playing a key role in tumour behaviour. The number of patients in our study is small, however, and investigation of a larger series is clearly indicated.     

干扰表皮生长因子受体磷酸化过程对乳腺癌的抑制效应

目的 探讨干扰表皮生长因子受体(EGFR)的磷酸化过程对裸鼠乳腺癌移植瘤生长的影响及其作用机制.方法 建立裸鼠乳腺癌移植瘤模型,成型后随机分为Ad5-hSulf1组、Ad5-EGFP组和对照组,干预治疗后,测量计算移植瘤生长率,采用免疫组化法检测各组裸鼠移植瘤hSulf-1、EGFR和p-EGFR阳性表达,采用Western blot法检测各组裸鼠移植瘤hSulf-1、EGFR和p-EGFR蛋白表达.结果 Ad5-hSulf1组裸鼠注射治疗后第14天、21天和28天的肿瘤生长率[(165.9±23.8)％,(172.6±25.9)％,(377.3±30.5)％]明显小于同期的对照组,差异均具有统计学意义(t=12.153,21.247,14.587;P =0.000).Ad5-hSulf1组裸鼠移植瘤p-EGFR阳性表达率(46.7％)和蛋白表达[(52.7±7.4)％]明显低于Ad5-EGFR组和对照组,差异均有统计学意义(x2=8.146,t=7.384,7.587;P =0.004、0.000、0.000).结论 使用hSulf1基因抑制乳腺癌细胞的EGFR磷酸化过程,可产生明显的肿瘤抑制效应,对寻求肿瘤基因治疗的一个很有潜力的靶点具有很好的借鉴参考意义.     

The relation between anti‐TGBFR1 immunohistochemical reaction and low Ki67, small tumor size and high estrogen receptor expression in invasive breast cancer

Most breast cancers are derived from the luminal epithelium, which composes the inside of the breast ductal structure. Ductal carcinoma in situ (DCIS) leads to invasive ductal carcinoma, but noncancerous intraductal proliferative lesions are also a risk factor for ductal carcinoma. The transforming growth factor beta (TGFB) signaling pathway behaves as a tumor suppressor in the early stage of cancer, and conversely as a tumor growth factor in invasive stages in several cancers. In this study, we performed immunohistochemistry with an antibody that detects the cytoplasmic region of TGFB receptor 1 (TGFBR1) and elucidated TGFBR1 protein expression in luminal epithelial cells of noncancerous breast ducts and in several cases of DCIS and invasive carcinoma. TGFBR1 expression was higher in noncancerous breast tissue than in cancerous tissue, and a difference in expression was also seen among histological subtypes. Comparing the expression level of TGFBR1 in cancer cells and clinico‐pathological parameters, cases expressing low TGFBR1 tended to show low estrogen receptor expression, large tumor size (≥10 mm), and a high Ki67 labeling index. These data suggested that TGFBR1 protein expression may be related to the suppression of breast cancer cell growth.     

宫内发育迟缓大鼠血清胰岛素样生长因子Ⅰ、Ⅱ、BP3的变化及L-精氨酸的保护作用

目的通过L-精氨酸孕期干预后大鼠血清胰岛素样生长因子-Ⅰ、Ⅱ及结合蛋白3水平的变化,探讨L-精氨酸的保护作用及其机制。方法采用被动吸烟法造大鼠IUGR模型,孕鼠随机分为4组:对照组、模型组、L-精氨酸小剂量和大剂量防治组,每组9只。孕21d剖宫取胎,测量胎鼠体重。应用酶联免疫吸附法检测各组大鼠血清IGF-Ⅰ、IGF-Ⅱ及IG-FBP-3水平。结果对照组、模型组与小、大剂量L-精氨酸防治组IUGR发生率分别为3.92%,54.95%,5.55%和9.09%。模型组大鼠血清IGF-Ⅰ、IGF-Ⅱ水平较对照组明显降低(P<0.01),小剂量和大剂量L-精氨酸防治组与模型组相比,IGF-Ⅰ、IGF-Ⅱ水平明显增高(P<0.01)。模型组大鼠血清IGFBP-3水平较对照组明显增高(P<0.01),小剂量和大剂量L-精氨酸防治组与模型组相比,IGFBP-3水平明显降低(P<0.01),与对照组亦有明显差异(P<0.01)。结论L-精氨酸可增高被动吸烟致宫内发育迟缓大鼠血清胰岛素样生长因子-Ⅰ、Ⅱ的水平,降低胰岛素样生长因子结合蛋白3的水平,从而促进胎鼠发育,防治IUGR的发生。     

胰岛素、胰岛素样生长因子Ⅰ及其受体在PCOS患者子宫内膜的表达

目的探讨胰岛素及其受体、胰岛素样生长因子I及其受体在多囊卵巢综合征患者子宫内膜的表达特点。方法利用免疫组化实验技术分析INS、INS-R、IGF-I和IGF-IR在多囊卵巢综合征和非多囊卵巢综合征不孕症患者子宫内膜中的表达情况,对结果进行图像分析,并利用SPSS10.0软件进行统计学分析,比较各组间的差异。结果1.多囊卵巢综合征患者子宫内膜IGF-I和INS-R表达水平明显高于对照组,差异有显著性(P<0.01)。其中多囊卵巢综合征中子宫内膜增生症患者的IGF-I和INS-R表达水平高于多囊卵巢综合征组增殖期患者,差异有显著性(P<0.05)。2.IGF-IR和INS在多囊卵巢综合征患者与对照组子宫内膜的表达水平无明显差异(P>0.05)。结论多囊卵巢综合征患者子宫内膜异常增生可能与局部IGF-I和INS-R表达异常有关。     

Amplified in breast cancer 1 expression in breast cancer

Aims: The amplified in breast cancer 1 (AIB1), steroid receptor co‐activator family member, acts as an oestrogen receptor (ER) co‐activator. Acting with HER‐2, it is thought to play a role in endocrine resistance by facilitating ER–growth factor crosstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. Methods: A tissue microarray comprising tumours from 438 patients with 15.4 years’ median follow‐up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. Results: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER‐2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. Conclusions: AIB1 expression correlates with HER‐2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER–growth factor interactions.