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.     

血管紧张素受体AT1R与肿瘤血管形成关系的研究进展

肾素血管紧张素系统(renin-angiotensin-system,RAS)主要的生理作用是维持心血管功能稳态、电解质和体液平衡、调节血压，但是在一些恶性肿瘤中发现其局部活化。血管紧张素II是肾素血管紧张素系统中重要的成分，在肿瘤的生长、转移、血管的生成过程中发挥关键作用。在不同的肿瘤中可通过与血管紧张素II型1受体(angiotensin II type 1 receptor,AT1R)结合，激活相关信号通路引起血管生成相关因子的升高，促进血管生成，加速肿瘤进展。而AT1R的拮抗剂又能明显抑制或逆转这种生物效应，这些结果提示着AT1R将可能会成为肿瘤治疗新的分子靶点。     

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.     

微小RNA与肿瘤血管生成

 肿瘤细胞表达的相关微小RNA（miRNA）通过调控血管内皮生长因子（VEGF）的表达,影响肿瘤血管生成,而血管生成在肿瘤的生长发展等过程中起着十分重要的作用。因此深入研究miRNA的功能将为抑制肿瘤血管生成提供更有效的靶点,为肿瘤的临床诊治提供更可靠的依据。     

血管生成抑制因子的研究进展

血管生成与肿瘤的生长、侵袭和转移密切相关,目前,以抑制血管生成为靶点治疗肿瘤有望成为抗肿瘤新疗法之一。近年来,研究发现了多种内源性血管生成抑制因子,其中一些已进入了临床试验阶段。本文对内源性血管生成抑制因子的结构、功能、作用机制及其在肿瘤治疗中的应用进行综述。     

Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo

The Eph family of receptor tyrosine kinases and their ligands, known as ephrins, play a crucial role in vascular development during embryogenesis. The function of these molecules in adult angiogenesis has not been well characterized. Here, we report that blocking Eph A class receptor activation inhibits angiogenesis in two independent tumor types, the RIP-Tag transgenic model of angiogenesis-dependent pancreatic islet cell carcinoma and the 4T1 model of metastatic mammary adenocarcinoma. Ephrin-A1 ligand was expressed in both tumor and endothelial cells, and EphA2 receptor was localized primarily in tumor-associated vascular endothelial cells. Soluble EphA2-Fc or EphA3-Fc receptors inhibited tumor angiogenesis in cutaneous window assays, and tumor growth in vivo. EphA2-Fc or EphA3-Fc treatment resulted in decreased tumor vascular density, tumor volume, and cell proliferation, but increased cell apoptosis. However, EphA2-Fc had no direct effect on tumor cell growth or apoptosis in culture, yet inhibited migration of endothelial cells in response to tumor cells, suggesting that the soluble receptor inhibited blood vessel recruitment by the tumor. These data provide the first functional evidence for Eph A class receptor regulation of pathogenic angiogenesis induced by tumors and support the function of A class Eph receptors in tumor progression.     

Endothelial p70 S6 kinase 1 in regulating tumor angiogenesis

The p70 S6 kinase 1 (p70S6K1) exerts its function in regulating protein synthesis, cell proliferation, cell cycle progression, and cell survival in response to growth factors and other cellular signals. But the direct effect of p70S6K1 in regulating tumor growth and angiogenesis remains to be elucidated. Here, we investigated the effect of p70S6K1 expressed in human dermal microvascular endothelial cells (HDMEC) in regulating cancer cell-inducing tumor growth and angiogenesis and found that HDMECs enhance cancer cell-induced tumor growth and angiogenesis. Constitutive activation of p70S6K1 in HDMECs is sufficient to enhance tumor growth and angiogenesis. Inhibition of p70S6K1 by its dominant-negative mutant in HDMECs interferes with tumor growth and angiogenesis, indicating that p70S6K1 activity in endothelial cells is required for regulating tumor angiogenesis. We found that p70S6K1 regulates hypoxia-inducible factor-1alpha (HIF-1alpha) expression in the human endothelial cells. Knockdown of HIF-1alpha in the endothelial cells decreases tumor growth and angiogenesis. These results show that p70S6K1 and HIF-1 play an important role in regulating the endothelial functions for inducing tumor growth and angiogenesis. This study helps to understand the role and molecular mechanism of p70S6K1 in regulating angiogenesis and tumor growth, and the role of endothelial p70S6K1/HIF-1 signaling in the regulation of tumor microenvironment and angiogenesis.     

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.     

Molecular and pharmacologic targeting of angiogenesis factors — the example of pleiotrophin

Summary Polypeptide growth factors contribute to the development and maintenance of normal tissues and are essential for the growth and metastasis of solid tumors. During tumor progression these factors function as autocrine stimulators of tumor cells and/or serve to recruit stromal tissue and blood supply to the expanding tumor. In particular, tumor-induced angiogenesis appears to be significant not only for local tumor growth but also for metastasis to distant organ sites. We purified several years ago the heparinbinding growth factor pleiotrophin (PTN) from the supernatants of human breast cancer cells and demonstrated that PTN can serve as an angiogenesis factor. We found the gene expressed in a number of human tumor cell lines as well as in human tumor tissues. Here we present different approaches to inhibit production and function of this growth factor. Finally we discuss how the experience from this growth factor can be applied to improve our understanding of the role of other factors thought to contribute to tumor angiogenesis.     

Inflammation,inflammatory cells and angiogenesis: decisions and indecisions

Endothelial-immune cell cross-talk goes well beyond leukocyte and lymphocyte trafficking, since immune cells are able to intimately regulate vessel formation and function. Here we review the evidence that most immune cells are capable of polarization towards a dichotomous activity either inducing or inhibiting angiogenesis. In addition to the well-known roles of tumor associated macrophages, we find that neutrophils, myeloid-derived suppressor and dendritic cells clearly have the potential for influencing tumor angiogenesis. Further, the physiological functions of NK cells suggest that these cells may also show a potentially important role in pro- or anti-angiogenesis regulation within the tumor microenvironment. At the same time many angiogenic factors influence the activity and function of immune cells that generally favor tumor survival and tolerance. Thus the immune system itself represents a major pharmaceutical target and links angiogenesis inhibition to immunotherapy.     

超顺磁性氧化铁与肿瘤血管生成磁共振成像和靶向治疗研究

超顺磁性氧化铁(SPIO)具有磁靶向性好、低毒、灵敏和粒子小等特点,可定量评价肿瘤新生血管结构与功能,并可选择性地定位于肿瘤新生血管,发挥抗肿瘤血管生成分子靶向治疗的作用,是医学分子影像学中具有重要作用的选择性磁共振成像对比剂.