血管生成素及其在肿瘤血管新生中的作用

血管生成素是新近发现的一个与血管新生密切相关的蛋白家族，其共同受体是Tie2。由于Ang1和Ang2在体内具有与VEGF共同调节生理性和病理性血管新生的功能，其研究进展受到广泛关注。本文综述了血管生成素家族中主要成员Ang1,Ang2,Ang3,Ang4等在克隆、生化性质，血管生成素受体Tie2在信号转导中的作用，血管生成素在生理发育和血管新生中的作用等方面的研究进展。     

促血管生成素在肿瘤血管新生中的作用

促血管生成素(angiopoietin,Ang)是一族分泌性蛋白因子，作用于内皮特异受体酪氨酸激酶Tie-2，影响内皮的增殖、迁移及管状结构形成，在胚胎期血管发生及成年机体的生理、病理性血管新生中发挥重要作用。Ang及其受体在肿瘤组织表达明显高于周围正常组织，特别是Ang-2，特异表达于肿瘤边缘的血管重建区，参与肿瘤血管新生的起始及延续过程，影响肿瘤生长和转移，并有望成为一种新的抗肿瘤血管新生靶向因子。     

血红素加氧酶-1在肿瘤新生血管化中的作用

研究证明血红素加氧酶-1(HO-1)与一些促新生血管因子如血管内皮生长因子(VEGF)、基质细胞衍生因子-1等相互作用,促进肿瘤的新生血管化.另外,也有研究者认为血红素加氧酶-1可以通过抑制核因子-кB(NF-кB)转录来抑制肿瘤新生血管化过程.HO-1可能参与了肿瘤新生血管形成的病理生理过程,可能成为肿瘤治疗新的作用靶点.     

可溶性血管内皮生长因子受体2片段的克隆、表达及其在肿瘤血管形成中的作用

目的 对可溶性血管内皮生长因子受体2(VFGFR2)片段阻断血管内皮细胞生长因子(VEGF)与相应受体结合抑制血管形成的作用进行体内外实验研究。方法 应用RT-PCR技术,从胎鼠肝脏扩增Flk-1／KDR片段,重组于逆转录病毒载体PLXSN和表达载体pFT-28b( ),并行表达、纯化和鉴定。以原代培养的小鼠内皮细胞,观察可溶性受体蛋白对内皮细胞生长的影响。以脂质体法转染肿瘤细胞系S180和B16,观察基因转染后的体内生物学特点。结果 在受精后第9,11天的胎鼠肝组织中分离出1000bp大小的可溶性VEGFR2片段,连接TA克隆载体,经测序此片段为VEGFR2胞外段部分序列。将可溶性VEGFR2片段克隆入表达载体pET-28b( ),体外实验显示,可溶性受体蛋白能有效抑制内皮细胞的生长和增殖。将可溶性VEGFR2片段克隆入逆转录病毒载体PLXSN并成功转染肿瘤细胞系S180和B16,体内实验显示,转基因细胞系的瘤重减轻,体积明显缩小,且其血管密度明显降低,而Flkl蛋白表达明显增高。结论 可溶性VEGFR2片段是一种有效的抑制血管形成的生物工程产品,有望作为抗血管形成基因治疗的靶点。     

Survivin与VEGF在结直肠肿瘤血管形成中的作用

目的 探讨Survivin、血管内皮生长因子(VEGF)在结直肠肿瘤血管形成中的作用.方法 对11例增生性息肉、23例低度异型增生腺瘤、20例高度异型增牛腺瘤、29例腺瘤恶变组织和65例腺癌组织使用Survivin多克隆抗体、VEGF和CD34单克隆抗体、标准化的链霉菌抗生物素蛋白-过氧化物酶技术(SP法)对存档组织块切片进行免疫组化染色,并用MIRS-2000图像分析系统分析其阳性率及表达程度,并行微血管密度(MVD)计数.结果 Survivin表达与VEGF表达及MVD密切相关,且呈明显正相关(r均为0.711,P<0.01).MVD与VEGF表达呈明显正相关(r=0.711,P<0.01).Survivin/VEGF双阳性组较阴性/阳性组及双阴性组MVD值显著增高(P均<0.01),同时对于survivin/VEGF阳性/阴性组,其MVD值与双阳性组筹异无统计学意义(P0.05).结论 Survivin与VEGF表达密切相关,二者协同作用促进结直肠肿瘤血管生成;VEGF可能是结直肠癌中Survivin冉表达的原因之一.     

VEGF及其受体KDR在胃癌组织新生血管中的作用

目的探讨血管内皮生长因子VEGF及其受体KDR在胃癌新生血管形成中的作用.方法应用免疫组织化学技术,检测60例胃癌组织VEGF及KDR蛋白表达和以CD105标记的微血管密度,分析VEGF、KDR和MVD及其与肿瘤大小、肿瘤分化、浸润深度、淋巴结转移、组织学分级和预后关系.结果VEGF及KDR阳性者MVD值显著高于阴性者(t=3.85,t=3.76,P＜0.01).VEGF、KDR表达和MVD与胃癌浸润深度(x2=8.31,P＜0.01;x2=5.05,P＜0.05;t=2.24,P＜0.05)、淋巴结转移(x2=10.62,P＜0.01;x2=5.66,P＜0.05;t=5.19,P＜0.05)、组织学分级(x2=11.05,P＜0.01;x2=8.21,P＜0.01;t=2.11,P＜0.05)密切相关.VEGF及KDR表达阳性或高MVD的胃癌患者5年生存率较低(x2=5.18,P＜0.05;x2=8.94,P＜0.01;t=3.51,P＜0.01).结论VEGF及KDR与胃癌新生血管生成密切相关,对胃癌的生长和浸润转移有促进作用,VEGF及KDR和以CD105标记的MVD可作为反映胃癌生物学行为的客观指标.     

Survivin与VEGF在结直肠肿瘤血管形成中的作用

目的探讨Survivin、血管内皮生长因子（VEGF）在结直肠肿瘤血管形成中的作用。方法对11例增生性息肉、23例低度异型增生腺瘤、20例高度异型增生腺瘤、29例腺瘤恶变组织和65例腺癌组织使用Survivin多克隆抗体、VEGF和CD34单克隆抗体、标准化的链霉菌抗生物素蛋白-过氧化物酶技术（SP法）对存档组织块切片进行免疫组化染色,并用MIRS-2000图像分析系统分析其阳性率及表达程度,并行微血管密度（MVD）计数。结果Survivin表达与VEGF表达及MVD密切相关,且呈明显正相关（r均为0．711,P〈0．01）。MVD与VEGF表达呈明显正相关（r=0．711,P〈0．01）。Survivin／VEGF双阳性组较阴性／阳性组及双阴性组MVD值显著增高（P均〈0．01）,同时对于Survivin／VEGF阳性／阴性组,其MVD值与双阳性组差异无统计学意义（P〉0．05）。结论Survivin与VEGF表达密切相关,二者协同作用促进结直肠肿瘤血管生成;VEGF可能是结直肠癌中Survivin再表达的原因之一。     

微小RNA在肿瘤血管生成中的信号调控作用

微小RNA(miRNA)在转录后水平通过降解或抑制靶标信使RNA的翻译来介导基因的表达.肿瘤的血管生成涉及了一系列的信号调控通路,miRNA可能通过调控其靶基因所参与的信号通路影响肿瘤的血管生成.因此,研究肿瘤血管生成相关miRNA调控其靶基因所参与的信号通路在肿瘤的诊断及治疗中具有较高的价值.     

缺氧诱导因子-1在肿瘤血管生成中的研究进展

缺氧诱导因子-1(HIF-1)影响多种血管生成因子的转录,对缺氧环境下肿瘤血管生成的调节发挥重要作用.对HIF-1结构功能及其在肿瘤血管生成过程中作用机制的研究为抗肿瘤治疗提供了新靶点.     

转化生长因子β1及其在肝癌形成中的作用

转化生长因子β1(TGF-β1)是一种多功能细胞因子,在细胞生长、分化、细胞外基质形成、凋亡、细胞迁移等方面扮演重要角色。许多研究表明肝癌细胞中TGF-β1的mRNA和蛋白质的含量比正常组织的肝细胞显著升高。TGF-β1是肿瘤抑制因子,然而在许多肿瘤中却表现为促进肿瘤的形成,如促进细胞外基质沉积、抑制凋亡、降低患者免疫力。     

Jagged-1在子宫颈癌组织中的表达

目的检测Jagged-1在子宫颈癌组织中的表达情况,探讨其在子宫颈癌发生、发展中的作用机制。方法采用免疫组织化学EnVision法检测60例子宫颈癌和21例正常子宫颈组织中Jagged-1的表达情况。结果Jagged-1在子宫颈鳞癌、腺癌组织中及正常组织中的阳性率分别为72.5%、80.0%和23.8%,在子宫颈鳞癌、腺癌组织中的表达水平高于正常子宫颈组织,差异有统计学意义(P<0.05)。结论 Jagged-1在子宫颈癌中的表达升高,提示其可能参与了子宫颈癌的发生、发展过程。     

SNHG1在肿瘤中的表达和作用

长链非编码RNA（long non-coding RNA,lncRNA）是一类转录本长度大于200 nt的不编码蛋白质的RNA分子。近年来研究发现长链非编码RNA在诸多肿瘤的发生发展过程中发挥重要作用。小核糖体管家基因RNA 1（small nucleolar RNA host gene 1,SNHG1）是由11号染色体上作为18s核糖体RNA重要组成部分的UHG基因转录而来的lncRNA。随研究不断深入,SNHG1在多种肿瘤中（胶质瘤、食管癌、胃癌等）的异常表达以及其对肿瘤恶性生物学行为的调控作用逐渐被揭示。SNHG1功能较为复杂并在肿瘤中通过多种机制发挥致癌作用,并且SNHG1的高表达预示着患者不良预后。本文结合国内外最新报道,对SNHG1在肿瘤中的表达水平及作用进行简要综述。     

Relevance of angiogenesis in neuroendocrine tumors

While traditional cytotoxic drugs have shown limited efficacy in neuroendocrine tumors (NETs), their biological features have been characterized and can be exploited therapeutically. Their most prominent trait is an extraordinary vascularization in low-grade NETs and an hypoxia-dependent angiogenesis in high-grade NETs, which is associated to a significant expression of many proangiogenic molecules. Therefore, several antiangiogenic compounds have been tested in these malignancies, and among these, sunitinib has demonstrated activity in pancreatic NET patients by dually targeting the VEGFR and PDGFR pathways. In spite of these efficacious clinical results, apparent resistance to antiangiogenic therapies has been described in NET animal models and in clinical trials. Therefore, overcoming antiangiogenic resistance is a crucial step in the subsequent development of antiangiogenic therapies. Several strategies have been postulated to fight resistance, but preclinical studies and clinical trials will investigate and address these therapeutic approaches in the coming years in order to overcome resistance to antiangiogenic therapies in NETs.     

长非编码 RNA UCA1在肿瘤中的表达及作用

尿路上皮癌相关抗原1（UCA1）是一种膀胱癌特异性长非编码 RNA,无编码蛋白质的功能。UCA1差异性表达于各种胎儿组织,而大多数成人组织不表达 UCA1,在肿瘤形成过程中 UCA1再次表达。研究表明 UCA1可调控膀胱癌、乳腺癌和肝癌等肿瘤的增殖、凋亡、转移和耐药性。     

The dynamic roles of angiopoietins in tumor angiogenesis

Angiopoietin (Ang)-1 and -2, and mouse Ang-3/human Ang-4 are ligands of the receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie)-2. It is well established that the Ang-Tie-2 pathway is involved in tumor angiogenesis. However, the exact effects of angiopoietins on tumor angiogenesis are under debate. Experimental and clinical studies have demonstrated that increased expression of Ang-1 and -2 promotes or inhibits tumor angiogenesis, and correlates with a reduced or extended survival time of patients, and with a declined or improved clinical outcome. In general, these studies suggest that Ang-1 is a proangiogenic factor that promotes endothelial cell survival and tumor angiogenesis, especially in the presence of vascular endothelial growth factor; whereas Ang-2 destabilizes vasculature that leads to the initiation of angiogenesis or apoptosis of endothelial cells/vessel regression in the presence or absence of vascular endothelial growth factor, respectively, and that the cell-surface tethered Ang-3 displays antiangiogenic activity. Together, these results suggest that the Ang-Tie-2 functional axis is an attractive target for antiangiogenesis-based cancer therapy.     

Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs

Human sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) has been identified as a GTP or dGTP-dependent deoxynucleotide triphosphohydrolase (dNTPase) and acts as an antiviral factor against certain retroviruses and DNA viruses. Genetic mutation in SAMHD1 causes the inflammatory Aicardi-Goutières Syndrome and abnormal intracellular deoxyribonucleoside triphosphates (dNTPs) pool. At present, the role of SAMHD1 in numerous types of cancer, such as chronic lymphocytic leukemia, lung cancer and colorectal cancer, is highly studied. Furthermore, it has been found that methylation, acetylation and phosphorylation are involved in the regulation of SAMHD1 expression, and that genetic mutations can cause changes in its activities, including dNTPase activity, long interspersed element type 1 (LINE-1) suppression and DNA damage repair, which could lead to uncontrolled cell cycle progression and cancer development. In addition, SAMHD1 has been reported to have a negative regulatory role in the chemosensitivity to anticancer drugs through its dNTPase activity. The present review aimed to summarize the regulation of SAMHD1 expression in cancer and its function in tumor growth and chemotherapy sensitivity, and discussed controversial points and future directions.     

Oncogenic roles of SMARCB1/INI1 and its deficient tumors

SMARCB1/INI1 is one of the core subunit proteins of the ATP‐dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16‐RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway. Initially, no detectable SMARCB1/INI1 protein expression was found in malignant rhabdoid tumor cells, whereas all other kinds of tumor cells and non‐tumorous tissue showed SMARCB1/INI1 protein expression. Therefore, immunohistochemical testing for the SMARCB1/INI1 antibody has been considered useful in confirming the histologic diagnosis of malignant rhabdoid tumors. However, recently, aberrant expression of SMARCB1/INI1 has been found in various tumors such as epithelioid sarcomas, schwannomatosis, synovial sarcomas, and so on. In addition, it has been reported that aberrant expression can be classified into three patterns: complete loss, mosaic expression and reduced expression. Although the various pathways related to mechanisms of tumorigenesis and tumor proliferation are complexly intertwined, the clarification of these mechanisms may contribute to therapeutic strategies in SMARCB1/INI1‐deficient tumors. In terms of pathological classifications, SMARCB1/INI1‐deficient tumors may be re‐classified by genetic backgrounds.