肺癌脑转移分子机制的研究进展

目的:总结肺癌脑转移的机制及近年的研究进展。方法:应用PubMed、Medline数据库检索系统,以"肺癌、脑转移和血管生成"等为关键词,检索2000-01-2012-06年的相关文献。纳入标准:1)肺癌脑转移;2)血管生成;3)分子机制。根据纳入标准分析文献34篇。结果:多种机制、多个环节参与肺癌脑转移瘤的发生和进展:肺癌脑转移瘤组织及脑转移瘤微血管内皮细胞中高度开放钙激活钾(KCa)通道,可作为血-脑瘤屏障(BTB)通透性调节的作用靶点;VEGF-C通过增强肿瘤和特异器官的亲和性并促进癌细胞向淋巴管方向运动,实现肺癌脑转移的发生进展;神经递质受体与神经元的相互作用促进肺癌细胞至脑的转移;CXCL12/CXCR4的表达能易化癌细胞穿越血脑屏障(BBB);抑癌基因、癌胚抗原和基质金属蛋白酶等相关蛋白的异常表达与肺癌脑转移相关。结论:肺癌脑转移机制是复杂的,深入探究肺癌脑转移的相关因素及发生发展机制,不但为临床药物研制提供新的思路,也将对延长患者生存时间和提高生存质量等具有重要意义。     

let-7在肺癌中的研究进展

目的总结let-7在肺癌发生发展中的研究现状,探讨let-7在肺癌诊断、治疗及预后方面发挥的作用。方法应用PubMed及CNKI期刊全文数据库检索系统,以"micro RNA、let-7和肺癌"为关键词,检索2008-01-01-2014-05-31相关文献,共检索到英文文献269篇,中文文献83篇。纳入标准:1)let-7在肺癌发生发展中的作用机制;2)let-7表达对肺癌诊断的关系;3)let-7在肺癌治疗中的潜在价值;4)let-7的表达对肺癌预后的意义。排除标准:1)综述类文献;2)重复及陈旧实验的文献;3)实验研究资料缺失或不全。符合分析的文献39篇。结果 let-7通过抑制相关癌基因的表达及肿瘤血管生成,抑制肺癌的发生、发展、侵袭和转移。let-7在多数肺癌组织中呈低表达,恢复let-7在肺癌组织中的表达,可以抑制肿瘤发展,提高肺癌患者对放疗及靶向治疗的敏感性。组织中let-7低表达的肺癌患者,往往提示预后不良。结论 let-7是肺癌组织中的重要标志,将对肺癌患者的诊断、治疗产生积极的影响。     

MTDH与肿瘤关系的研究进展

目的:总结异黏蛋白(MTDH)的功能及其作用的分子机制,探讨MTDH与肿瘤的关系。方法:应用Medline、PubMed及CNKI期刊全文数据库检索系统,以"MT-DHt、umor"等为检索词,检索2005-2010年相关文献29条。纳入标准:1)MTDH的功能;2)MTDH作用机制;3)MTDH与肿瘤的关系。根据纳入标准,符合分析的文献18篇。结果:MTDH基因在肿瘤进展中起着重要的作用,包括促进肿瘤细胞增殖、侵袭和转移、避免凋亡及促使肿瘤细胞对化疗药物产生耐药。MTDH通过激活NF-κB、PI3K/AKT、MAPK与wnt/-βcatenin信号通路来促进肿瘤的发生发展。结论:深入研究MTDH在恶性肿瘤中的表达及功能有助于理解肿瘤发生发展的分子机制。MTDH基因有望成为治疗肿瘤的有效靶点。     

ANGPT-TIE信号通路与肿瘤关系的研究进展

目的:总结ANGPT-TIE信号通路与肿瘤之间关系的进展.方法:应用PubMed、Science Direct、Springer及CNKI期刊全文数据库,以“Angiopoietin、Tie2、实体瘤、炎症和转移”为检索词,检索2000-01-2011-10的相关文献,共检索到英文文献287篇,中文文献122篇.文献纳入标准:1)Angiopoietin及Tie的生物学特征及作用机制;2)Angiopoietin、Tie与血管发生、炎症及肿瘤转移、预后之间的关系.根据纳入标准,将符合条件的24篇文献纳入分析,进行综述.结果:ANGPT-TIE信号系统在血管形成中起关键作用,它不仅对血管内环境稳定和血管成熟至关重要,而且也是血管发生和炎症通路中的一个主要环节,参与肿瘤的发生发展.结论:ANGPT-TIE信号系统在肿瘤诱导的血管发生中起重要作用,并且通过阻断该信号通路也可达到抑制肿瘤生长的作用,是抗血管生成治疗最有效的靶点之一.     

SDF-1/CXCR4与肝细胞肝癌淋巴结转移的关系

目的:探讨SDF-1/CXCR4与肝细胞肝癌淋巴结转移的关系及其可能的机制。方法:应用PubMed、CNKI、万方数据库、Medline数据库,以SDF-1、CX-CR4、VEGF、MMP、肝肿瘤和淋巴转移为关键词,检索2000-1010年相关文献,共检索到英文文献2 696篇,中文文献共105篇。纳入标准:1)SDF-1/CXCR4轴与肿瘤的关系;2)CXCR4参与了肿瘤淋巴结转移;3)肝细胞肝癌的淋巴结转移机制;4)CXCR4在肝细胞肝癌中的表达;5)VEGF与淋巴结转移的关系;6)MMP与淋巴结转移的关系。根据纳入标准符合分析的文献36篇。结果:SDF-1/CX-CR4在肝细胞肝癌的淋巴结转移过程中起重要作用,SDF-1/CXCR4有可能通过激活VEGF和MMP等细胞分子,通过多条信号途径来促进肝癌淋巴结的转移。结论:SDF-1/CXCR4可能通过激活VEGF和MMP等细胞因子来促进肝癌的淋巴转移,通过阻断SDF-1/CXCR4可以减少肝癌的淋巴转移。     

表观遗传学在肺癌诊治中的研究进展

目的:总结表观遗传学在肺癌诊疗中的研究现状,探讨表观遗传学在肺癌临床工作中的应用和前景。方法:应用Medline、PubMed及CNKI期刊全文数据库检索系统,以"表观遗传学、肺癌"等为关键词,检索2005-01-2011-12的相关文献,共检索到英文文献616条,中文文献53条。纳入标准:1)表观遗传学与肺癌的分类和早期诊断的关系;2)表观遗传学预测肺癌的转移复发;3)表观遗传学在肺癌治疗中的应用;4)表观遗传学对常规放疗、化疗的影响。根据纳入标准,符合分析的文献22篇。结果:表观遗传修饰,如DNA甲基化、组蛋白乙酰化和甲基化、RNA相关性沉默等,与细胞生长、分化、凋亡、转化及肿瘤进展相关基因的转录密切相关。肺癌的发生和发展与表观遗传修饰异常直接相关。结论:表观遗传学与肿瘤的诊断、分期、进展和预后密切相关,从而为肺癌的基因诊断和治疗提供了新的思路和手段。     

Numb与上皮间质转化关系的研究进展

目的:总结Numb与上皮间质转化(epithelial mesenchymal transitions,EMT)的研究进展,并讨论Numb在EMT中的可能作用机制。方法:应用PubMed及CNKI期刊全文数据库检索系统以"Numb、肿瘤和EMT"等为关键词,检索1990-01-2012-10的相关文献。共检索到英文文献815篇,中文文献285篇。纳入标准:1)以肿瘤中的Numb与EMT的关系;2)Numb在上皮间质转化中的作用机制研究。根据纳入标准分析文献38篇。结果:Numb是参与肿瘤信号转导途径的重要成分,新的研究表明,Numb表达下调或缺失,EMT的发生加剧。作用机制可能是其通过影响肿瘤细胞E-钙黏蛋白的定位、调控Notch等信号通路在肿瘤EMT过程中起关键作用,研究发现,10%的癌组织中伴有Notch1基因变异。通过参与EMT而诱导肿瘤形成和发展可能为Numb影响肿瘤发生、发展的又一重要机制。结论:肿瘤中Numb的表达水平及其相关信号通路在EMT中可能起重要作用,但具体作用方式和机制仍未阐明。     

miRNA对肺癌化疗耐药调控研究进展

目的:总结miRNA对肺癌耐药调控的研究状况,并探讨其在预测肺癌对药物敏感性和耐药性中的作用。方法:应用PubMed及CNKI期刊全文数据库检索系统,以"miRNA和肺癌"等为关键词,检索2007-01-2013-01的相关文献,共检索到英文文献732篇,中文文献88篇。纳入标准:1)肺癌耐药相关机制;2)miRNA在肺癌耐药中的作用;3)miRNA预测肺癌细胞的药物敏感性。根据纳入标准,符合分析的文献33篇。结果:肺癌耐药机制包括药物吸收降低或排出增多、药物靶点改变、细胞修复功能增强及细胞凋亡的减弱等,涉及药物作用各个环节关键基因突变可能导致耐药发生。而miRNA为一类高度保守的非编码RNAs,通过对上述各环节关键基因表达的调控进而调节肺癌细胞对化疗药物的敏感性。在肺癌化疗耐药的患者中,肺癌细胞miRNA突变或表达异常,导致miRNA对靶基因如药物转运相关基因、细胞解毒功能相关基因、细胞损伤后自我修复能力相关基因、细胞凋亡相关基因及肿瘤上皮间质化相关基因等表达的异常调控,致使肺癌细胞化疗耐药产生。同时,根据这些miRNA表达情况可预测肺癌患者对药物的反应。结论:miRNA对肺癌细胞耐药调控发挥着重要作用,从而为肺癌化疗耐药预测提供了新的思路和手段。     

αvβ6整合素与肿瘤关系的研究进展

目的:总结国内外关于αvβ6整合素与肿瘤关系的研究进展。方法:应用Medline和CNKI期刊全文数据库检索系统,以"αvβ6整合素"和"肿瘤"为关键词,检索1992-01-2008-05相关αvβ6整合素的文献174篇,其中英文文献172篇,中文文献2篇。纳入标准:1)αvβ6整合素的结构和功能;2)αvβ6在恶性肿瘤中的表达情况;3)αvβ6促进肿瘤进展的分子机制;4)以αvβ6为靶点的肿瘤靶向研究。根据纳入标准,精选73篇文献,最后纳入分析29篇文献。结果:αvβ6作为一类上皮限制性的特殊整合素亚型,在多种上皮源性恶性肿瘤中诱导表达,通过促进肿瘤细胞迁移、参与细胞外基质降解、激活细胞因子TGF-β1以及抑制肿瘤细胞凋亡等途径促进肿瘤侵袭和转移。结论:深入研究αvβ6在恶性肿瘤中的表达及功能,有助于进一步理解肿瘤侵袭和转移的分子机制,有望在肿瘤的靶向治疗方面取得新的突破。     

乳腺癌化疗耐药中肿瘤干细胞的作用及其机制

目的:了解肿瘤干细胞在乳腺癌化疗耐药中的作用及其相关机制的研究进展。方法:应用检索Pubmed及CNKI数据库检索系统,以肿瘤、干细胞、乳腺癌、化疗和耐药等为关键词,检索1999-01-2011-05的相关文献,纳入标准:肿瘤干细胞与乳腺癌化疗耐药。根据纳入标准分析42篇文献。结果:肿瘤干细胞是导致乳腺癌化疗耐药和治疗失败的主要细胞,其耐药的机制包括ATP结合盒转运子的过度表达、细胞解毒酶的过度活化、细胞存活和凋亡相关信号转导通路的异常激活、肿瘤壁龛对肿瘤干细胞的保护作用以及大部分肿瘤干细胞处于静止期。通过对这些耐药机制的干预,可以逆转肿瘤干细胞的耐药性。结论:肿瘤干细胞是导致乳腺癌化疗耐药的关键细胞,对其耐药机制的研究有助于展开针对肿瘤干细胞的靶向治疗,改善患者的预后。     

反义核酸抑制RON 基因表达对A549 的体外作用

 目的 探讨针对人RON基因跨膜区段(RONm)反义核酸对肺癌细胞系A549活性和细胞增殖的抑制作用，研究以RON基因为靶的肺癌基因治疗的可能性。方法 将人RONm cDNA反向插入到真核表达载体pcDNA3、1中，转染肺癌细胞A549，利用ELISA检测细胞模型RON基因的表达水平，同时利用MTT方法监测细胞生物学活性的变化。结果 转染后的肺癌细胞RON基因表达量和细胞活性明显降低，并出现明显的细胞凋亡。结论 RONm反义核酸明显抑制RON基因的表达，同时对肺癌细胞的生长有抑制作用，促进细胞凋亡。     

RON及其变异体在肺癌中的表达

目的研究RON及其变异体在肺腺癌中的表达及意义。方法应用免疫组化方法检测106例肺腺癌及35例肺鳞癌中RON的表达情况,并结合临床资料进行统计学分析;通过Western-Blot技术检测31例新鲜肺腺癌组织及9例肺鳞癌组织中RON及其变异体的表达情况,并对RON在不同组织学分级和不同组织学类型中的表达进行统计学分析。结果RON在肺腺癌及鳞癌中都有不同程度的表达,两组比较RON的表达差异具有统计学意义（P〈0.05）;不同分化程度的肺腺癌比较,RON的表达也有差异,低分化的肺腺癌明显高于中分化的腺癌和高分化的腺癌（P〈0.05）;Western-Blot结果显示在肺腺癌和肺鳞癌中均有RON表达;在肺腺癌中观察到RON的变异体,而肺鳞癌中则没有。结论肺癌组织中有RON的过表达,并且肺腺癌中RON的表达明显高于鳞癌（P〈0.05）。肺腺癌中RON的表达与肿瘤分级相关,并存在变异体,而鳞癌则无变异体的表达。     

RON is not a prognostic marker for resectable pancreatic cancer

ABSTRACT: BACKGROUND: The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown. METHODS: RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed. RESULTS: RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study. CONCLUSIONS: Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.     

Targeted expression of the receptor tyrosine kinase RON in distal lung epithelial cells results in multiple tumor formation: oncogenic potential of RON in vivo

RON, a member of the MET proto-oncogene family, has been implicated in the progression of certain epithelial cancers. The purpose of this study was to determine the oncogenic potential of RON in vivo in lung epithelial cells. Transgenic mice were established using surfactant protein C promoter to express human RON in the distal lung epithelial cells. These mice were born normal but developed multiple lung tumors with distinct morphology and growth patterns. Tumors appeared as a single mass in the lung around 2 months of age and gradually developed into multiple nodules located mostly in the peripheral portions of the lung. A transition from early adenomas to later adenocarcinomas was observed. Morphologically, tumors were characterized as cuboidal epithelial cells with a type II cell phenotype, grew along the alveolar walls, and projected into the alveolar septa. RON was highly expressed and constitutively activated in tumors. These results indicate that overexpression of human wild-type RON causes the formation of lung tumors with unique biological characteristics in vivo. This model provides opportunities to study the role of RON in the pathogenesis of lung tumors and to elucidate the mechanisms underlying this distinct lung tumor.     

Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member

RON is a member of the c-MET receptor tyrosine kinase family. Like c-MET, RON is expressed by a variety of epithelial-derived tumors and cancer cell lines and it is thought to play a functional role in tumorigenesis. To date, antagonists of RON activity have not been tested in vivo to validate RON as a potential cancer target. In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED50 = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC50 = 2 nmol/L). We found IMC-41A10 to be a potent inhibitor of receptor and downstream signaling, cell migration, and tumorigenesis. It antagonized MSP-induced phosphorylation of RON, mitogen-activated protein kinase (MAPK), and AKT in several cancer cell lines. In HT-29 colon, NCI-H292 lung, and BXPC-3 pancreatic cancer xenograft tumor models, IMC-41A10 inhibited tumor growth by 50% to 60% as a single agent, and in BXPC-3 xenografts, it led to tumor regressions when combined with Erbitux. Western blot analyses of HT-29 and NCI-H292 xenograft tumors treated with IMC-41A10 revealed a decrease in MAPK phosphorylation compared with control IgG-treated tumors, suggesting that inhibition of MAPK activity may be required for the antitumor activity of IMC-41A10. To our knowledge, this is the first demonstration that a RON antagonist and specifically an inhibitory antibody of RON negatively affects tumorigenesis. Another major contribution of this report is an extensive analysis of RON expression in approximately 100 cancer cell lines and approximately 300 patient tumor samples representing 10 major cancer types. Taken together, our results highlight the potential therapeutic usefulness of RON activity inhibition in human cancers.     

浸润性乳腺癌中酪氨酸激酶受体的表达及其与预后的关系

目的研究酪氨酸激酶受体 C-Met和RON在浸润性乳腺癌中的表达及其与预后的关系。方法采用免疫组织化学PV-6000两步法测定106例浸润性乳腺癌及30例乳腺良性病变组织中C-Met和RON的表达。结果C-Met、RON的阳性表达在浸润性乳腺癌与乳腺良性病变组织中有明显差异,与浸润性乳腺癌的临床分期、病理分级、淋巴结转移呈正相关。106例浸润性乳腺癌组织中C-Met、RON的单独阳性表达及联合阳性表达均与患者生存期呈负相关。106例浸润性乳腺癌中RON阳性表达与C-Met阳性表达呈明显正相关性。结论C-Met、 RON在乳腺癌的发生、发展、浸润和转移过程中发挥了重要的作用,联合检测可以更加有效地预测患者的预后,为临床治疗提供新的基因靶点。     

Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients.

PURPOSE: RON and MET belong to a subfamily of tyrosine kinase receptors. They both can induce invasive growth, including migration, cell dissociation, and matrix invasion. Cross-linking experiments show that RON and MET form a noncovalent complex on the cell surface and cooperate in intracellular signaling. We wanted to examine the clinical significance of RON and MET expression patterns in node-negative breast cancer. EXPERIMENTAL DESIGN: We studied the protein expressions of RON and MET in five breast cancer cell lines and a homogeneous cohort of 103 T(1-2)N(0)M(0) breast carcinoma patients, including 52 patients with distant metastases and 51 patients with no evidence of disease after at least a 10-year follow-up. RESULTS: Both HCC1937 and MDA-MB-231 cancer cell lines co-overexpressed RON and MET. The MCF-7 cell line did not express RON or MET. In multiple logistic regression analysis, RON expression (odds ratio, 2.6; P = 0.05) and MET expression (odds ratio, 4.7; P = 0.009) were independent predictors of distant relapse. RON+/MET+ and RON-/MET+ tumors resulted in a large risk increase for 10-year disease-free survival after adjusting for tumor size, histologic grade, estrogen receptor, bcl-2, HER-2/neu, and p53 status by multivariate Cox analysis (risk ratio, 5.3; P = 0.001 and risk ratio, 3.76; P = 0.005). The 10-year disease-free survival was 79.3% in patients with RON-/MET- tumors, was only 11.8% in patients with RON+/MET+ tumors, and was 43.9% and 55.6% in patients with RON-/MET+ and RON+/MET- tumors. CONCLUSIONS: Co-expression of RON and MET seems to signify an aggressive phenotype in node-negative breast cancer patients.     

Multiple pulmonary adenomas in the lung of transgenic mice overexpressing the RON receptor tyrosine kinase. Recepteur d'origine nantais

The receptor tyrosine kinase RON (recepteur d'origine nantais), a member of the MET proto-oncogene family, has been implicated in the pathogenesis of certain epithelial cancers including lung adenocarcinomas. To determine the oncogenic potential of RON, transgenic mice were generated using the surfactant protein C promoter to express human wild-type RON in the distal lung epithelial cells. The mice were born normal without morphological defects in the lung, however, multiple lung adenomas with distinct morphology and growth pattern were observed. Tumors appeared as a single mass in the lung around 2 months of age and gradually developed into multiple nodules throughout the lung. Most of the tumors were characterized as cuboidal epithelial cells with type II cell phenotypes. They grew along the alveolar walls and projected into the alveolar septa. A transition from pre-malignant adenomas to adenocarcinomas was observed. The RON transgene is highly expressed and constitutively activated in the tumors as evident by immunohistochemical staining and western blot analyses. Moreover, we found that Ras expression was dramatically increased in the majority of tumors. However, no mutation in the 'hot spots' of the K-Ras or p53 gene was observed, although limited genomic instability occurs in individual tumors. Taken together, this is a mouse lung tumor model with unique biological characteristics. The model may provide an opportunity to study the role of RON in lung tumors and to elucidate the mechanisms underlying this distinct lung tumor.