凝血酶敏感蛋白-1在肿瘤中的研究进展

凝血酶敏感蛋白-1(TSP-1)在多种肿瘤中表达,并通过诱导内皮细胞凋亡等机制抑制肿瘤血管生成,从而阻止肿瘤生长.其功能结构域(Type I序列)3TSR保留了抑制新生血管形成的功能,在临床肿瘤治疗中具有一定的实际应用意义.     

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.     

血管形成抑制因子HIAF-1的克隆及其抗肿瘤作用

目的　克隆和表达一种新的血管形成抑制因子 ,并研究其抗肿瘤活性。方法　应用逆转录聚合酶链反应从人胎儿肝脏组织中克隆到一种新的血管形成抑制因子 (humaninhibitingangiogenesisfactor 1,HIAF 1) ,经测序后克隆到表达载体pET30a( )上 ,在E .coliBL2 1∶DE3菌中表达。用MTT法体外检测HIAF 1对内皮细胞的作用 ,采用小鼠乳癌自发性肺转移模型IVTA2MA 891,体内研究重组蛋白对肿瘤血管形成的作用和抑瘤作用。结果　从胎儿肝脏组织中首次克隆到人源血管形成抑制因子HIAF 1,经测序为人胶原ⅩⅧC 末端的一部分。在E .coli细胞中高效表达了该因子的重组蛋白 ,蛋白表达量为 88mg/L。体外实验表明HIAF 1能抑制内皮细胞的增殖 ,IC50 值为 7.5 μg/ml。动物实验表明该重组蛋白能够显著抑制肿瘤血管形成 ,原发瘤的生长 (抑瘤率为 46 .6 % )及肿瘤的转移 (抑制转移率为 6 8.9% )。结论　成功的克隆了血管形成抑制因子HIAF 1,其能够抑制肿瘤血管的形成 ,在肿瘤的治疗中显示出良好的应用前景。     

Survivin在肺癌中的研究进展

存活素(Survivin)是凋亡抑制蛋白(1AP)家族成员之一,在绝大多数恶性肿瘤中高表达,具有抑制凋亡、增强细胞增殖和促进血管形成功能.研究显示,Survivin可能作为一种肿瘤诊断标记物和抗肿瘤治疗的理想靶点.     

TIMP-1在乳腺癌中的作用机制和临床意义

金属蛋白酶(MMPs)是促进肿瘤侵袭转移的关键酶,金属蛋白酶组织抑制剂-1(TIMP-1)可以特异性抑制MMPs的水解活性,两者在乳腺癌中表达均升高,但很多研究却提示TIMP-1过表达和乳腺癌预后不良相关,很难单用其MMP抑制功能来解释,最近有研究发现TIMP-1具有独特的肿瘤刺激功能,参与细胞凋亡,细胞增殖,肿痛血管发生等过程,从而解释了这一矛盾的现象,本文将着重围绕TIMP-1促进肿瘤的作用机制及其在乳腺癌中的临床意义的进展进行综述.     

血管能抑素canstatin治疗肿瘤研究进展

血管能抑素canstatin是一种来源于Ⅳ型胶原α2链非胶原(NC1)区的血管生成和肿瘤生长内源性抑制因子.相比放疗、化疗等传统的肿瘤治疗方法,canstatin具有特异性高,不易产生抗药性等特点.临床研究表明,canstatin联合抑制肿瘤血管生成的其它疗法协同作用,在未来肿瘤的治疗中有着广阔的应用前景.     

髓系抑制性细胞与肿瘤

髓系抑制性细胞(MDSC)是一群髓系来源具有抑制功能的天然免疫细胞,在肿瘤进展中发挥负向免疫调控作用.MDSC具有强大的抑制功能及显著的异质性,通过多种机制调控固有免疫及适应性免疫系统,发挥促肿瘤作用,同时可通过非免疫机制促进肿瘤血管生成及肿瘤转移等.近年来对其分化、增殖、抑制功能等的研究日趋成熟,由此衍生的靶向针对MDSC的肿瘤免疫治疗研究将为肿瘤疫苗的增效及肿瘤的治疗等带来新的希望.     

细胞因子信号抑制因子1在树突状细胞肿瘤疫苗中的作用

在肿瘤疫苗中树突状细胞(DC)是启动抗肿瘤免疫的主要辅助细胞.细胞因子信号抑制因子l (SOCS1)对细胞因子信号转导具有抑制作用.最近的研究表明,抑制DC中SOCS1的功能对提高肿瘤疫苗的抗肿瘤活性具有重要作用,并且在如何抑制其功能的方法上也取得了重大进展.     

肿瘤血管生成抑制物的研究

肿瘤的生长及转移依赖于血管的生成(angio-genesis),抑制肿瘤血管生成可以抑制肿瘤的生长,已经成为不同于常规肿瘤治疗的方法和热点.与直接杀伤肿瘤细胞的化学药物治疗相比,血管生成抑制剂有以下优点:(1)血管生成抑制剂直接作用于血管内皮细胞,而抗癌药物经组织扩散时受到组织坏死、纤维化、组织内高压的影响,常常在组织内达不到有效浓度;(2)血管内皮细胞属正常细胞,其基因型稳定,不易产生耐药性,而肿瘤细胞基因型不稳定,易产生耐药性;(3)原发肿瘤和继发肿瘤的血管内皮细胞相同,而原发灶与继发灶中肿瘤细胞的生物学特性差异较大,化疗反应各异;(4)肿瘤血管内皮细胞的增殖速度较正常组织快许多倍,血管生成抑制剂对正常组织的影响轻微;(5)不引起严重的胃肠道反应及骨髓抑制.本文就肿瘤的血管生成及调控、抗血管生成治疗肿瘤作一综述.     

程序性细胞死亡因子10与肿瘤

程序性细胞死亡因子10(PDCD10)是一个在多种组织中保守表达的基因.研究表明,其具有细胞凋亡抑制功能及血管生成重建功能,且在多种肿瘤组织中表达明显上调,提示其可能在肿瘤的信号转导通路中起重要作用,并可能作为一个新的诊断肿瘤及预测预后的重要肿瘤学标志物应用于临床.     

膜型基质金属蛋白酶-1上调人乳腺癌细胞血管内皮生长因子的表达并诱导肿瘤血管新生

目的 研究膜型基质金属蛋白酶-1(MT1-MMP)在肿瘤血管新生过程中的作用,探讨其诱导肿瘤血管新生的作用途径.方法 应用基因转染方法 ,将MT1-MMP导入人乳腺癌细胞系MCF-7细胞;应用半定量逆转录聚合酶链反应(RT-PCR)和免疫荧光染色,比较转染前后肿瘤细胞血管内皮生长因子(VEGF)表达的变化;通过裸鼠异种移植瘤模型,检测MT1-MMP对肿瘤生长速度、肿瘤组织微血管密度(MVD)和VEGF表达的影响.结果 在MT1-MMP稳定转染后的MCF-7细胞中,VEGF189、VEGF165和VEGF121 mRNA表达水平显著上调(P＜0.001).免疫荧光检测结果 显示,MT1-MMP组的VEGF蛋白免疫荧光强度为93.8±10.3,明显强于MCF-7组(42.9±5.3)和pcDNA3.1组(41.0±5.4,P＜0.001).裸鼠异种移植瘤模型结果 显示,MTI-MMP能够加快肿瘤生长速度.肿瘤组织MVD检测结果 显示,MT1-MMP能够显著提高肿瘤组织的MVD(P＜0.05).免疫组织化学染色结果 显示,VEGF在MT1-MMP组呈强阳性表达.结论 MT1-MMP能够通过上调肿瘤细胞VEGF表达水平而有效诱导肿瘤血管新生.MT1-MMP的这一作用途径可能为临床抗肿瘤研究及抗肿瘤药物开发提供新思路.     

Rap1b在肿瘤中的功能及意义

Rap1是一种小的Ras样GTP酶,在调控多种信号通路如增殖、分化、形态形成以及凋亡中起分子开关的作用。Rap1共有两种异构体,即Rap1a和Rap1b。Rap1b缺失可以导致血管生成、内皮细胞迁移及增殖功能受损以及MAPK信号通路受阻。无论是血管发生、内皮迁移以及MAPK通路都在肿瘤的发生发展中发挥重要作用,因此,Rap1b在肿瘤中意义重大。本文就国内外对Rap1b在肿瘤中的作用及意义的研究进展做一综述。     

The neuropilins and their role in tumorigenesis and tumor progression

The neuropilins were originally described as receptors for the six axon guidance factors belonging to the class-3 semaphorins. They were subsequently found to function in addition as receptors for specific splice forms of angiogenic factors belonging to the VEGF family. The neuropilins are expressed in many types of cancer cells, in endothelial cells and in additional many types of normal diploid cell types. Recent findings indicate that the neuropilins and their associated plexin and tyrosine-kinase VEGF receptors play a regulatory role in developmental angiogenesis as well as in tumor angiogenesis. The neuropilin ligands belonging to the semaphorin family as well as the various VEGF's function as modulators of angiogenesis and tumor angiogenesis. Furthermore, since many types of cancer cells express neuropilins and neuropilin associated receptors, it is not surprising that various neuropilin ligands can modulate the behavior of cancer cells directly leading to the potentiation or inhibition of tumor progression.     

神经菌毛素促进VEGF介导的血管生成作用及其机制研究进展

Neuropilin-1(NRP-1), acted as one important member of NRP family,expressed in endothelial cellsand certain tumour cells and conducted common receptor of Sema 3A,VEGF,PDGF and TGF. Therefore, itplays an important role in axon growth,angiogenesis and tumor growth. VEGF acts as one important regulatingfactor in angiogenesis, also played an important role in tumor angiogenesis, growth and development. Moreand more researches had confi rmed that VEGF could facilitate angiogenesis, tumor growth and developmentas combined with NRP-1. This article mainly summarizes angiogenesis and mechanism of VEGF promotedby NRP-1.     

Latest therapeutic target for gastric cancer: Anthrax toxin receptor 1

Anthrax toxin receptor 1 (ANTXR1), also known as tumor endothelial marker 8, is a highly conserved cell surface protein overexpressed in tumor-infiltrating vessels. It was first found in vascular endothelial cells of human colorectal cancer. Although our understanding of its physiological function is limited, it has been found that ANTXR1 binds collagen and promotes migration of endothelial cells in vitro. ANTXR1 is upregulated in vessels of different tumor types in mice and humans, and is also expressed by tumor cells themselves in some tumors, such as gastric, lung, intestinal and breast cancer. Developmental angiogenesis and wound healing were not disturbed in ANTXR1 knockout mice, but compared with wild-type mice, growth of melanoma was impaired after ANTXR1 knockout, indicating that host-derived ANTXR1 can promote tumor growth on the basis of immune activity. Previous studies have shown that ANTXR1 vaccines or sublethal doses of anthrax toxin can inhibit angiogenesis, slow tumor growth and prolong survival. These studies suggest that ANTXR1 is necessary for tumor rather than physiological angiogenesis. It has been found that ANTXR1 plays an important role in tumor angiogenesisas well as in the growth and metastasis of many kinds of tumors. This article reviews the physiological function of ANTXR1 and its role in different kinds of cancer.     

Fibroblast growth factors are required for efficient tumor angiogenesis

Although the function of vascular endothelial growth factor in the induction of tumor angiogenesis is well understood, the role of a second group of angiogenic factors, the fibroblast growth factors (FGFs), remains elusive. We used a recombinant adenovirus expressing soluble FGF receptor (AdsFGFR) to interfere with FGF function in tumor angiogenesis. AdsFGFR repressed endothelial cell proliferation in vitro and inhibited tumor angiogenesis in an ex vivo bioassay, in which endothelial cells were cocultured with angiogenic tumor biopsies in a collagen gel. Moreover, AdsFGFR repressed tumor angiogenesis and hence tumor growth in vivo in allograft transplantation experiments. Whereas adenoviral expression of a soluble form of VEGF receptor 1 (AdsFlt) predominantly affected the initiation of tumor angiogenesis, soluble FGF receptor (sFGFR) appeared to impair the maintenance of tumor angiogenesis. The combination of sFGFR and soluble Flt exhibited a synergistic effect in the repression of tumor growth. Finally, i.v. injection of AdsFGFR resulted in a dramatic repression of tumor growth in a transgenic mouse model of pancreatic beta cell carcinogenesis. Similar to control infections with AdsFlt, tumor-associated vessel density was decreased, indicating that the expression of sFGFR impaired tumor angiogenesis. These data indicate that FGFs play a critical role in tumor angiogenesis.     

Endothelial Robo4 suppresses breast cancer growth and metastasis through regulation of tumor angiogenesis

Targeting tumor angiogenesis is a promising alternative strategy for improvement of breast cancer therapy. Robo4 (roundabout homolog 4) signaling has been shown to protect endothelial integrity during sepsis shock and arthritis, and inhibit Vascular Endothelial Growth Factor (VEGF) signaling during pathological angiogenesis of retinopathy, which indicates that Robo4 might be a potential target for angiogenesis in breast cancer. In this study, we used immune competent Robo4 knockout mouse model to show that endothelial Robo4 is important for suppressing breast cancer growth and metastasis. And this effect does not involve the function of Robo4 on hematopoietic stem cells. Robo4 inhibits breast cancer growth and metastasis by regulating tumor angiogenesis, endothelial leakage and tight junction protein zonula occludens protein‐1 (ZO‐1) downregulation. Treatment with SecinH3, a small molecule drug which deactivates ARF6 downstream of Robo4, can enhance Robo4 signaling and thus inhibit breast cancer growth and metastasis. SecinH3 mediated its effect by reducing tumor angiogenesis rather than directly affecting cancer cell proliferation. In conclusion, endothelial Robo4 signaling is important for suppressing breast cancer growth and metastasis, and it can be targeted (enhanced) by administrating a small molecular drug.     

Caveolin-1 in tumor progression: the good, the bad and the ugly

Caveolin-1 (Cav1) is a multifunctional scaffolding protein with multiple binding partners that is associated with cell surface caveolae and the regulation of lipid raft domains. Cav1 regulates multiple cancer-associated processes including cellular transformation, tumor growth, cell migration and metastasis, cell death and survival, multidrug resistance and angiogenesis. However, Cav1 has been reported to impact both positively and negatively on various aspects of tumor progression and while reported to function as a tumor suppressor, it has also been identified as a poor prognostic factor in various human cancers. In this review, we survey the functional roles of Cav1 in cancer and argue that Cav1 function is interdependent on tumor stage and the expression of molecular effectors that impact on its role during tumor progression. Goetz and Lajoie contributed equally to this paper.     

Neuropilin-1在消化道恶性肿瘤发生发展中的生物学作用

消化道肿瘤是最常见的恶性肿瘤,发病率高,死亡率亦高。神经纤毛蛋白-1（Neuropilin-1）在消化道恶性肿瘤发生发展中的作用成为近年来研究的热点,其调控恶性肿瘤血管生成过程,介导肿瘤细胞的增殖与侵袭,从而促进肿瘤进展与转移。本文就Neuropilin-1在肿瘤血管生成、肿瘤增殖与侵袭、转移及肿瘤治疗靶标中的作用作一综述。