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目的:检测IGF信号通路关键蛋白IGF1、IGF1R及AKT在顺铂耐药卵巢癌患者血清中的表达,检测血清CA125的动态变化,探讨与卵巢癌耐药患者预后的关系.方法:利用ATP-TCA法对40例卵巢癌标本进行药敏试验,其中16例对顺铂耐药,24例对顺铂敏感,ELISA法分别检测顺铂耐药和敏感组患者血清中IGF1、IGF1R及AKT的表达.采用微粒子捕捉免疫发光技术(MEIA)测定40例卵巢上皮癌患者治疗前、手术前及手术后7-14天、每疗程化疗后血清中CA125浓度,计算CA125半衰期,探讨与预后的关系.结果:IGF1、IGF1R及AKT在卵巢癌顺铂耐药组的表达显著高于敏感组(P值均为0.0001),顺铂耐药患者CA125半衰期与敏感组患者相比有统计学意义.结论:IGF信号通路关键蛋白IGF1、IGF1R及AKT可能参与卵巢癌顺铂耐药,CA125半衰期联合IGF1、IGF1R及AKT检测可早期预测卵巢癌化疗耐药. 相似文献
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目的:检测IGF信号通路关键蛋白IGF1、IGF1R及AKT在顺铂耐药卵巢癌患者血清中的表达,检测血清CA125的动态变化,探讨与卵巢癌耐药患者预后的关系。方法:利用ATP-TCA法对40例卵巢癌标本进行药敏试验,其中16例对顺铂耐药,24例对顺铂敏感,ELISA法分别检测顺铂耐药和敏感组患者血清中IGF1、IGF1R及AKT的表达。采用微粒子捕捉免疫发光技术(MEIA)测定40例卵巢上皮癌患者治疗前、手术前及手术后7-14天、每疗程化疗后血清中CA125浓度,计算CA125半衰期,探讨与预后的关系。结果:IGF1、IGF1R及AKT在卵巢癌顺铂耐药组的表达显著高于敏感组(P值均为0.0001),顺铂耐药患者CA125半衰期与敏感组患者相比有统计学意义。结论:IGF信号通路关键蛋白IGF1、IGF1R及AKT可能参与卵巢癌顺铂耐药,CA125半衰期联合IGF1、IGF1R及AKT检测可早期预测卵巢癌化疗耐药。 相似文献
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IGF信号通路关键蛋白IGF1、IGF1R和AKT在原发性肺腺癌中的表达及意义 总被引:1,自引:0,他引:1
目的检测IGF信号通路关键蛋白IGF1,IGF1R和AKT在原发性肺腺癌中的表达,探讨其与临床病理学特征和生存时间的关系。方法采用免疫组化方法和免疫印迹技术检测IGF1,IGF1R和AKT在31例原发性肺腺癌及12例良性肺病变组织中的表达。结果IGF1、IGF1R和AKT在肺腺癌中的表达率分别为41.9%(13/31)、67.7%(21/31)和51.6%(16/31),显著高于良性肺组织(P值分别为0.0252、0.0016和0.0071)。IGF1和IGF1R及IGF1和AKT在肺腺癌中表达呈显著相关(P值分别为0.0344和0.0179)。晚期肺癌(Ⅲ+Ⅳ)IGF1和IGF1R表达显著高于早期(Ⅰ+Ⅱ)(P值分别为0.0109和0.0303)。IGF1、IGF1R和AKT在伴有淋巴结转移肺癌中的表达显著高于无淋巴结转移肺癌(P值分别为0.0468、0.0490和0.0443)。低分化肺癌中IGF1和IGF1R表达显著高于中或高分化肺癌(P值分别为0.0484和0.0291)。IGF1和IGF1R阳性患者的生存时间显著短于阴性者(IGF1:10比14个月,P=0.0103;IGF1R:13比26个月,P=0.0056)。IGF1和IGF1R是肺腺癌预后的影响因素,AKT无预后意义。结论IGF信号通路关键蛋白IGF1、IGF1R和AKT表达在肺腺癌的发生和发展中可能起重要作用,进一步的研究有望展示其在肺癌预后和治疗方面的意义。 相似文献
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目的 探讨趋化因子CX3CL1及其受体CX3CR1与卵巢癌患者耐药及预后的关系,以及裸鼠耐药模型中CX3CL1、CX3CR1在铂类耐药过程中的变化,分析其表达水平与Fas信号通路的相关性。方法 利用癌症基因图集(TCGA)数据库中卵巢癌患者的全基因组表达谱,分析CX3CL1和CX3CR1在铂类敏感和耐药患者中的表达与临床病理特征的关系。利用已构建的带有绿色荧光标记的卵巢癌SKOV3敏感细胞(SKOV3-GFP)和顺铂耐药细胞(SKOV3-GFP/DDPⅢ)进行裸鼠皮下种植,成瘤后分次给予顺铂体内注射;qRT-PCR检测第0、2、5、8次顺铂注射后移植瘤组织中CX3CL1、CX3CR1与Fas信号通路上基因的表达水平。结果 CX3CL1表达与卵巢癌FIGO分期和铂类耐药产生呈负相关(r=-0.112,P=0.030;r=-0.106,P=0.044);CX3CR1表达与无进展生存时间呈负相关(r=-0.130,P=0.029)和1年复发率呈正相关(r=0.119,P=0.045)。铂类敏感组卵巢癌患者的卵巢组织中CX3CL1的平均表达量为3.96±0.039,显著高于耐药组的3.64±0.55(P=0.000)。顺铂干预后,裸鼠皮下移植瘤体质量随时间推移而增加,SKOV3-GFP/DDPⅢ组形成的移植瘤体质量始终高于SKOV3-GFP组,在第5次给药后移植瘤开始逐渐变小。顺铂干预后,SKOV3-GFP组CX3CL1、CX3CR1表达水平明显升高(P=0.001,P=0.002),SKOV3-GFP/DDPⅢ组CX3CL1、CX3CR1基因表达始终处于较低水平。SKOV3-GFP/DDPⅢ组中Fas信号通路上的Fas、FADD的表达较SKOV3-GFP组明显降低(P<0.001);而PARP1基因的相对表达较SKOV3 GFP组明显上调(P<0.001)。CX3CL1和CX3CR1的表达与Fas信传导通路上节点基因Fas、FADD表达呈正相关,与下游PARP1基因的表达呈负相关。结论 CX3CL1、CX3CR1表达下调与铂类耐药形成相关,两者可能具有维持肿瘤细胞对铂类药物敏感性的作用。CX3CL1、CX3CR1在耐药细胞中的低表达可能通过某种机制抑制Fas信号传导通路,使其传导失调,抑制细胞凋亡及诱发卵巢癌对铂类耐药。 相似文献
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目的 探讨胰岛素样生长因子1受体(IGF-1R)和胰岛素样生长因子结合蛋白-3(IGFBP-3)在原发性结肠癌中的表达及与临床病理参数间的关系,以及二者在结肠癌淋巴结转移中的作用.方法 应用免疫组织化学SP法检测78例结肠癌组织和78例正常结肠黏膜中IGF-1R、IGFBP-3的表达,并对二者的表达与结肠癌临床病理参数进行统计分析.结果 IGF-1R在结肠癌中的阳性率(66.7%,52/78)显著高于对照组(24.4%,19/78),x2=28.150,P=0.000.IGFBP-3在结肠癌中的阳性率(73.1%,57/78)显著低于对照组(89.7%,70/78),x2=7.158,P=0.007.IGF-1R在结肠癌中的表达与浸润深度(x2=5.804,P=0.016)、TNM分期(x2=5.246,P=0.022)、淋巴结转移(x2=12.955,P=0.000)呈明显相关性.IGFBP-3在结肠癌中的表达与TNM分期(x2=7.096,P=0.008)、淋巴结转移(x2=5.893,P=0.015)、远处转移(P=0.003)呈明显相关性.二者均与其他因素无明显相关性(均P>0.05).IGF-1R与IGFBP-3的表达呈负相关(r=-0.245,P=0.03).结论 IGF-1R高表达和IGFBP-3低表达与结肠癌TNM分期、淋巴结转移有关,IGF-1R和IGFBP-3可能成为治疗结肠癌新的作用靶点. 相似文献
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目的 探讨肿瘤坏死因子受体相关蛋白1(TRAP1)在顺铂耐药性卵巢癌中的表达以及对顺铂耐药性卵巢癌细胞氧化磷酸化的影响。方法 收集2019-01-10-2020-01-10郑州人民医院手术切除的卵巢癌组织样本41例,其中顺铂敏感26例(顺铂敏感组),顺铂耐药15例(顺铂耐药组),癌旁组织10例(对照组),及细胞株A2780与顺铂耐药株A2780CP,测定上述对象中TRAP1表达。通过转染siRNA沉默A2780CP细胞中TRAP1表达,检测细胞全细胞及线粒体耗氧率(OCR)、ATP产量变化,检测加药顺铂时细胞增殖活性和凋亡率的变化。结果 顺铂耐药组、顺铂敏感组和对照组TRAP1蛋白表达水平分别为1.00±0.30、0.60±0.14和0.22±0.08,差异有统计学意义,F=47.640,P<0.001。A2780CP细胞TRAP1蛋白表达水平(2.24±0.10)高于A2780细胞(1.00±0.05),差异有统计学意义,t=11.383,P=0.001。与A2780细胞相比,A2780CP细胞的顺铂IC50浓度升高,全细胞及线粒体OCR、ATP产量均升高... 相似文献
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《中华肿瘤杂志》2020,(5)
目的了解伴有2型糖尿病的结直肠癌(CRC)患者癌组织中胰岛素样生长因子1受体(IGF1R)-Ras和晚期糖基化终产物受体(RAGE)-高迁移率族蛋白1(HMGB1)通路蛋白的表达特点, 并探讨其意义。方法选取行手术切除治疗的59例CRC患者, 其中伴有2型糖尿病者29例(CRC/DM组), 单纯CRC患者30例(CRC组)。采用免疫组织化学的方法检测手术切除癌组织中IGF1R、Ras、RAGE和HMGB1的表达, 比较两组间表达的差异, 分析表达与患者临床病理特征的关系。结果 CRC/DM组IGF1R和Ras表达的阳性率均为65.5%(19/29),具有IGF1R+ Ras+免疫表型的患者占51.7%(15/29), 均明显高于CRC组[分别为33.3%(10/30)、36.7%(11/30)和20.0%(6/30);P值分别为0.013、0.027和0.011], 二者的表达在CRC/DM组呈正相关(r=0.479, P=0.017)。CRC组和CRC/DM组RAGE蛋白表达的阳性率分别为70.0%(21/30)和72.4%(21/29), HMGB1蛋白表达的阳性率分别为46.7%... 相似文献
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目的:探讨干扰素介导的跨膜蛋白1(IFITM1)与卵巢上皮性癌化疗耐药性的相关性。方法:应用免疫组化测定68例初治卵巢上皮性癌组织和卵巢癌顺铂敏感细胞株A2780、顺铂耐药细胞株CP70中IFITM1的表达,Western blotting检测两种卵巢癌细胞株中IFITM1蛋白的表达。结果:免疫组织化学显示铂类化疗敏感性卵巢癌组和耐药性卵巢癌组的表达强度之间的差异有统计学意义(P=0.043),Western blot实验显示卵巢癌CP70细胞株中IFITM1表达水平明显高于A2780细胞株。结论:IFITM1表达强度与卵巢癌铂类化疗的敏感性相关,检测IFITM1对判断卵巢癌化疗疗效具有临床意义。 相似文献
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目的:研究p38MAPK在卵巢上皮癌顺铂化疗耐药中的作用,并探讨其作用机制.方法:蛋白质印迹法检测顺铂对卵巢癌中p38MAPK的激活情况 ;MTT法检测p38MAPK抑制剂SB203580处理后及p38 shRNA干扰后细胞顺铂耐药指数的变化 ;实时定量PCR技术检测SB203580处理后及p38 shRNA干扰后,耐药蛋白ERCC1、MDR、LRP、GST-π及凋亡蛋白Caspase-3、Survivin等mRNA的表达变化.结果:在一定时间浓度梯度下,顺铂可诱导卵巢癌顺铂敏感株COC1及耐药株COC1/DDP细胞内p38MAPK的激活,但耐药株的激活程度弱于敏感株 ;p38MAPK抑制剂SB203580及p38 shRNA干扰可增加卵巢癌细胞株的耐药指数(t=4.610,P=0.041 ;t=11.621,P=0.000) ;SB203580及p38 shRNA干扰后Survivin mRNA(t=5.152,P=0.007 ;t=6.008,P=0.004)、ERCC1 mRNA(t=13.742,P=0.005;t=11.621,P=0.000)及LRPmRNA(t=8.173,P=0.001 ;t=16.815,P=0.000)的表达明显上调.结论:p38MAPK受抑制可能导致卵巢上皮性癌顺铂耐药的产生,其机制可能是通过上调Survivin、ERCC1及LRP的mRNA表达来实现. 相似文献
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Mauro De Santi Giosuè Annibalini Elena Barbieri Anna Villarini Luciana Vallorani Serena Contarelli Franco Berrino Vilberto Stocchi Giorgio Brandi 《Cellular oncology (Dordrecht)》2016,39(2):149-159
Background
IGF1 is a key regulator of tissue growth and development and has been implicated in the initiation and progression of various cancers, including breast cancer. Through IGF1 mRNA splicing different precursor pro-peptides, i.e., the IGF1Ea, IGF1Eb and IGF1Ec pro-forms, are formed whose biological roles in the pathogenesis of breast cancer have not been established yet. The objective of this study was to assess the biological activity of the IGF1 pro-forms in human breast cancer-derived cells.Methods
The different IGF1 pro-forms were generated through transient transfection of HEK293 cells with the respective vector constructs. The resulting conditioned media were applied in vitro to MCF7, T47D and ZR751 breast cancer-derived cell cultures. The recombinant human IGF1 pro-forms were also tested for their binding affinity to an anti-IGF1 specific antibody by immunoprecipitation. To determine whether the IGF1 pro-forms induce cell proliferation, mature IGF1 was neutralised in HEK293-derived conditioned media.Results
We found that the IGF1 pro-forms were the only forms that were produced intra-cellularly, whereas both mature IGF1 and the IGF1 pro-forms were detected extra-cellularly. We also found that E peptides can impair the IGF1 pro-form binding affinity for the anti-IGF1 antibody and, thus, hamper an accurate measurement of the IGF1 pro-forms. Additionally, we found that the IGF1 antibody can completely inhibit IGF1-induced breast cancer cell proliferation and IGF1 receptor (IGF1R) phosphorylation, wheras the same antibody was found to only partially inhibit the biological activity of the pro-forms. Moreover, we found that the IGF1 pro-form activities can completely be inhibited by neutralising the IGF1R. Finally, we compared the bioactivity of the IGF1 pro-forms to that of mature IGF1, and found that the IGF1 pro-forms were less capable of phosphorylating the IGF1R in the breast cancer-derived cells tested.Conclusions
Our data indicate that IGF1 pro-forms can induce breast cancer cell proliferation via the IGF1R, independent from the mature IGF1 form. These results underline the importance of an accurate assessment of the presence of IGF1 pro-forms within the breast cancer microenvironment.13.
Gao Y Katki H Graubard B Pollak M Martin M Tao Y Schoen RE Church T Hayes RB Greene MH Berndt SI 《International journal of cancer. Journal international du cancer》2012,131(2):E105-E113
The insulin-like growth factor (IGF) signaling pathway is involved in cell proliferation and differentiation. Elevated serum IGF1 levels have been associated with increased colorectal cancer risk; however, studies of this association with colorectal adenoma are inconclusive. We examined serum IGF1, IGF2 and IGFBP3 levels in relation to risk of advanced colorectal adenoma in a case-control study within the prostate, lung, colorectal and ovarian cancer screening trial. A total of 764 advanced, left-sided colorectal adenoma cases and 775 controls frequency-matched on gender and ethnicity, without evidence of a left-sided polyp on sigmoidoscopy were included in the current study. Serum levels of IGF1, IGF2 and IGFBP3 were measured using an enzyme linked immunosorbent assay in serum samples collected at baseline. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations adjusting for age, race, sex, year of blood draw, body mass index, smoking and education. Higher IGF1 levels were associated with increased adenoma risk: ORs = 1.58 (95% CI = 1.16-2.16), 1.42 (95% CI = 1.04-1.93), and 1.80 (95% CI = 1.30-2.47) for the second, third and fourth quartiles, respectively (p(trend) = 0.002). Elevated IGF2 levels were also associated with increased adenoma risk (OR = 1.43, 95% CI = 1.05-1.96 for the fourth vs. first quartile, p(trend) = 0.02), but the association was no longer significant after adjustment for IGF1 (p(trend) = 0.28). IGFBP3 levels were not associated with adenoma risk. Our analysis showed a significant positive association between circulating IGF1 levels and risk of advanced colorectal adenoma, suggesting that IGF1 is associated with the pivotal precursor to colorectal cancer. 相似文献
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Katherine A. Janeway Mei‐Jun Zhu Jordi Barretina Antonio Perez‐Atayde George D. Demetri Jonathan A. Fletcher 《International journal of cancer. Journal international du cancer》2010,127(11):2718-2722
Wildtype (WT) gastrointestinal stromal tumors (GISTs), lacking mutations in KIT or PDGFRA, represent 85% of GISTs in pediatric patients. Treatment options for pediatric WT GIST are limited. Recently, expression profiling of a limited number of pediatric and adult WT GISTs and more in depth study of a single pediatric WT GIST implicated the insulin‐like growth factor 1 receptor (IGF1R) as a potential therapeutic target in pediatric WT GIST. We performed immunoblotting, SNP and FISH studies to determine the extent of expression, biochemical activation and genomic amplification of IGF1R in a larger number of pediatric WT GISTs. Pediatric WT GISTs expressed IGF1R strongly, whereas typical adult KIT mutant GISTs did not. IGF1R gene amplification was not detected in pediatric WT GISTs, and some KIT‐mutant GISTs had IGF1R gene deletion due to monosomy 15. Despite the absence of apparent genomic activation mechanisms accounting for overexpression, clinical study of IGF1R‐directed therapies in pediatric WT GIST is warranted. 相似文献
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Brigid C. Browne Alex J. Eustace Susan Kennedy Neil A. O’Brien Kasper Pedersen Martina S. J. McDermott Annemarie Larkin Jo Ballot Thamir Mahgoub Francesco Sclafani Stephen Madden John Kennedy Michael J. Duffy John Crown Norma O’Donovan 《Breast cancer research and treatment》2012,136(3):717-727
Insulin-like growth factor-1 receptor (IGF1R) signalling is implicated in resistance to trastuzumab. However, the benefit of co-targeting HER2 and IGF1R has not been extensively studied, and the relationship between activated IGF1R and clinical response to trastuzumab has not been reported. This study aimed to evaluate the combination of trastuzumab with IGF1R tyrosine kinase inhibitors (TKIs) in a panel of HER2-positive breast cancer cell lines, and to examine the relationship between IGF1R expression and activation and response to trastuzumab in HER2-positive breast cancer patients. The anti-proliferative effects of trastuzumab combined with IGF1R TKIs BMS-536924 or NVP-AEW541 were measured in nine HER2-positive cell lines. IGF1R and phosphorylated IGF1R/insulin receptor (pIGF1R/IR) were measured by immunohistochemistry in 160 tumour samples from trastuzumab-treated patients (ICORG 06-22). The HER2-positive cell lines displayed varying sensitivity to IGF1R TKIs alone (IC50s: 0.7 to >10???M). However, when combined with trastuzumab, a significantly enhanced effect was observed in five cell lines treated with BMS-536924, and three with NVP-AEW541. While IGF1R levels correlated with reduced response to NVP-AEW541 alone, neither IGF1R nor pIGF1R were predictive of response to BMS-536924 or NVP-AEW541 in combination with trastuzumab. Low HER2 levels correlated with response to BMS-536924 in combination with trastuzumab. Akt levels correlated with improved response to trastuzumab and NVP-AEW541 (P?=?0.039). Cytoplasmic IGF1R staining was observed in all tumours, membrane IGF1R was detected in 13.8?%, and pIGF1R/IR was detected in 48.8?%. Although membrane IGF1R staining was associated with larger tumour size (P?=?0.041), and lower tumour grade (P?=?0.024), no association between IGF1R or pIGF1R/IR and patient survival was observed. In conclusion, while neither IGF1R expression nor activation was predictive of response to trastuzumab, these pre-clinical data provide evidence that co-targeting HER2 and IGF1R may be beneficial in some HER2-amplified breast cancers. 相似文献
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Transmembrane 4 L six family member 4 (TM4SF4) is a member of the tetraspanin L6 domain family. Other members of this family, TM4SF1 (also known as L6-Ag) and TM4SF5, have been shown to be upregulated in multiple tumors and involved in epithelial-to-mesenchymal transition and cell migration. However, unlike its homologs, little is known about TM4SF4. Here, we show that TM4SF4 was highly expressed in radiation-resistant lung adenocarcinoma cells, such as A549 and Calu-3 cells, and its expression activated cell growth, migration, and invasion. Overexpression of TM4SF4 in A549 cells increased the activation of PI3K, AKT, and NF-kappaB and the expression of PTEN. IGF1R was clearly activated by overexpression of TM4SF4, although EGFR was also slightly activated. TM4SF4 expression was correlated with the increased expression of IGF1, consequently resulting in IGF1R activation. Tumorigenic activity of TM4SF4 in lung adenocarcinoma cells was also demonstrated by xenograft assay; however, this activity was almost completely suppressed by treatment with anti-TM4SF4 antibody. Our results suggest that TM4SF4 overexpression in lung carcinoma cells results in resistance to radiotherapy via IGF1-induced IGF1R activation and blocking the activity of TM4SF4 using specific antibody can be a promising therapeutics against TM4SF4-overexpressing lung adenocarcinoma. 相似文献
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目的研究胰岛素样生长因子1和2(IGF1、IGF2,合称为IGFs)在非小细胞肺癌(NSCLC)组织中的表达,探讨其与NSCLC区域淋巴结转移的关系。方法采用免疫组织化学和免疫印迹技术检测IGF1和IGF2在65例NSCLC、29例癌旁肺组织和19例良性肺病变组织中的表达。结果IGF1和IGF2在NSCLC中的表达率显著高于良性肺组织。IGF1和IGF2在伴有区域淋巴结转移肺癌中的表达显著高于无淋巴结转移肺癌组织。IGF1和IGF2在伴有N2或≥5个转移淋巴结肺癌组织中的表达显著高于在仅伴有N1或<5个转移淋巴结肺癌组织。IGF2在伴有多组转移淋巴结肺癌组织中的表达显著高于仅有一组转移淋巴结肺癌组织。结论IGFs不仅在NSCLC中过表达,而且与区域淋巴结转移的部位、数量及组数相关联,提示IGFs在NSCLC发生和发展中可能起重要作用,IGFs为NSCLC生物学行为尤其是淋巴结转移的判断提供一个新的有意义的指标。 相似文献
18.
Summary The first step of the action of IGF1 and IGF2 (IGFs) is their binding to membrane receptors. IGF binding sites have been characterized by competitive binding and cross-linking techniques in human breast cancer cell lines as well as in human breast cancers and in human benign breast diseases. IGF2 is a good competitor of125I-IGF1 binding to IGF1-R; insulin competes but with a potency 1/100 lower than the IGF1 potency. Chemical cross-linking experiments revealed that the apparent molecular weight of the IGF1-binding sites is 130,000. Alpha IR-3, a murine monoclonal antibody against the IGF1-R, blocks IGF1-binding to this receptor. This antibody inhibits the IGF1-stimulated growth of breast cancer cells. Therefore, the IGF1 specific binding sites correspond to the previously described type 1 IGF receptors (IGF1-R) in normal tissues. Cross-linking experiments with labeled IGF2 resulted in a major band of apparent Mr 260,000–270,000 that was inhibited by unlabeled IGF2 but not by insulin, and corresponds to the type 2 IGF receptor; a second band of apparent Mr 130,000 was inhibited by excess IGFs and insulin (Type I receptor). The alpha-IR3 inhibition of the IGF2 mitogenic activity suggest that IGF1-R partially mediates the growth effect of IGF2 in these cells.We and others have demonstrated that most breast cancer cell lines contain IGF1-R. This is also the case in breast cancer biopsies in which histo-autoradiographic analyses allowed the localization of IGF1-R on the epithelial component. IGF1-R concentrations were positively correlated to estradiol and progesterone receptor concentrations. In our experience, the presence of IGF1-R is associated with a better prognosis. Finally, IGF1-R are found less frequently and at lower concentrations in benign breast diseases. These results suggest that IGF1-R could be a marker of the proliferative epithelial component within the tumor. 相似文献
19.
Many tumors have chronically elevated activity of PI 3-kinase-dependent signaling pathways, caused largely by oncogenic mutation of PI 3-kinase itself or loss of the opposing tumor suppressor lipid phosphatase, PTEN. Several PI 3-kinase-dependent feedback mechanisms have been identified that may affect the sensitivity of upstream receptor signaling, but the events required to initiate an inhibited state have not been addressed. We show that in a variety of cell types, loss of PTEN via experimental knockdown or in tumor cell lines correlates with a block in insulin-like growth factor 1 (IGF1)/insulin signaling, without affecting the sensitivity of platelet-derived growth factor or epidermal growth factor signaling. These effects on IGF/insulin signaling include a reduction of up to five- to tenfold in IGF-stimulated PI 3-kinase activation, a failure to activate the ERK kinases and, in some cells, reduced expression of insulin receptor substrate 1, and both IGF1 and insulin receptors. These data indicate that chronically elevated PI 3-kinase-dependent signaling to the degree seen in many tumors causes a selective loss of sensitivity in IGF1/insulin signaling that could significantly reduce the selective advantage of deregulated activation of IGF1/IGF1-R signaling in tumor development. 相似文献