海水浸泡降低血管内皮细胞迁移能力并抑制血管生成

目的:观察海水浸泡对血管内皮细胞迁移和血管生成的影响,为探讨海水致伤机制、制定科学救治原则提供实验依据.方法:建立ECV304细胞划痕创伤模型,分别给予生理盐水和人工海水浸泡处理,划痕创伤愈合修复分析观察细胞迁移能力;建立人食管鳞癌EC0156裸鼠皮下移植瘤模型,分别给予生理盐水和人工海水干预,监测肿瘤体积并绘制肿瘤生长曲线,观察肿瘤边缘血管的生成,免疫组织化学染色检测肿瘤组织内微血管密度.结果:海水浸泡后,ECV304细胞失去正常形态,并随浸泡时间的延长,呈明显"脱水"状态.在划痕后17 h,对照组划痕已基本愈合,而实验组仍可见清晰划痕,且以实验4 h组划痕尤其明显.与对照组相比,实验组细胞划痕愈合明显延迟,细胞迁移能力降低;与对照组相比实验组肿瘤边缘新生血管较少,前者肿瘤边缘新生血管较丰富,两者有显著性差异(微血管密度值:1.2±0.44 vs 3.2±0.83,P<0.05).实验组肿瘤生长缓慢,肿瘤体积较小(P<0.05).结论:海水浸泡能够降低血管内皮细胞迁移能力并抑制血管生成.     

肿瘤血管生成和抑制在结直肠癌中的研究现状

结直肠癌是我国常见恶性肿瘤。15％-35％的患者在发现原发癌时已有肝转移，手术切除后5年生存率不到40％。肿瘤血管生成（angiogenesis）是指肿瘤细胞诱导的微血管持续、失控性生长和肿瘤血液循环建立的过程。包括毛细血管基底膜降解，血管内皮细胞迁移、增殖、形成管状结构，基底膜形成以及血流贯通等诸多环节。该过程受肿瘤细胞和肿瘤基质细胞表达的癌基因和生长因子调控，亦受机体神经内分泌等因素的影响，其中血管调节因子（包括肿瘤血管生成因子和肿瘤血管生成抑制因子）起中心调控作用，当两者的平衡被打破．肿瘤血管生成因子占优势时，即发生肿瘤血管生成。     

抗血管生成靶向药物在肿瘤治疗中的研究进展

由于肿瘤微环境中促血管生成因子,如血管内皮生长因子(VEGF)、成纤维细胞生长因子2(FGF-2)等持续存在,大量血管化导致肿瘤快速生长扩散。Folkman最早提出将肿瘤血管生成作为潜在治疗靶点的假设,将关注点从以肿瘤细胞为中心的传统治疗转移到抗肿瘤血管生成,开辟了肿瘤学的新领域。抗血管生成靶向药物因其可以抑制肿瘤血管生成、促进血管正常化、改善肿瘤微环境已广泛应用于结肠癌、肺癌等治疗。然而适应性抵抗或代偿性耐药限制了靶向抗血管生成药物的应用,目前尚无规范成熟的治疗方案弥补这一缺点。     

细胞外基质在血管平滑肌细胞迁移中的作用

血管损伤后新生内膜形成的过程,也是基质重建的过程,一方面血管平滑肌细胞增生、迁移,分泌大量的细胞外基质,另一方面又产生基质金属蛋白酶使基质不和解,最终导致再狭窄的发生。     

肿瘤血管生成拟态的研究进展

恶性肿瘤的生长和转移必须以匹配合适的血液供应为前提，而阻断肿瘤的血液供应是攻克肿瘤治疗的一大策略，因此，肿瘤治疗的微循环机制及其结构与功能等，一直是国内外学者们研究的热点。以往的研究认为肿瘤血管是宿主正常的血管系统在肿瘤血管生成因子（Tumor angiogenesis factor，TAF）作用下，血管在形态和功能上发生了一系列改变而形成的。     

前列腺癌组织中血管生成与细胞外基质的相关性

目的探讨前列腺癌（PCa）组织中血管生成与细胞外基质（ECM）的相关性,及其与肿瘤生物学行为之间的关系。方法应用免疫组织化学LSAB法检测38例PCa患者癌组织中微血管密度（MVD）以及Ⅳ型胶原（COLⅣ）、纤维连接蛋白（FN）、层粘连蛋白（LN）等ECM。结果高分化癌组织中MVD）明显低于低分化和未分化者（P〈0．05）;有淋巴结转移的癌组织中MVD明显高于元转移者（P〈0．001）;高分化癌组织中COLⅣ、FN、LN呈连续型分布的百分率明显高于未分化者;有淋巴结转移者COLⅣ及FN呈连续型分布的百分率明显低于元转移者。COLⅣ、FN、LN呈连续型分布者的MVD均明显低于呈非连续型分布者,呈负相关。结论血管生成和ECM在PCa侵袭和转移过程中均起重要作用,两者关系密切,相互影响、相互作用。     

IL-8在肿瘤血管生成中的作用

一、简介血管生成是从已有的微血管系统形成新生血管的过程 ,是一种对生理和病理进程都十分关键的生物学过程。血管生成的调节依赖于血管生成因子和血管静止因子之间的平衡 ,它们分别促进和抑制肿瘤血管的生成。这两种因子调节的失平衡有助于肿瘤的生长和转移及促进慢性纤维增生的形成。如果没有血管 ,氧气和营养物质的扩散就会受到限制 ,那么肿瘤的大小不会超过直径 1～2mm ,然而这些微小的肿瘤组织可从周围成熟的宿主血管得到血液供应 ,通过某种方式形成在肿瘤组织内生长和浸润的毛细血管 ,最终导致血管生成 ,于是肿瘤便可有效地扩散和通…     

肿瘤血管生成的研究进展

血管生成 (angiogenesis)是指在原有微血管 (毛细血管和小静脉 )的基础上通过“出芽”的方式形成的毛细血管[1] 。 2 0世纪 70年代初 ,Folkman首先提出“肿瘤生长和转移都依赖于新生血管的形成”的概念[2 ] ,并得到大量实验结果的证实[3,4 ] ,目前这一概念已经形成共识。本文综述肿瘤血管生成特点、调控及抗血管生成治疗肿瘤的进展。　　一、肿瘤内血管生成特点　　早期的研究表明 ,在胚胎发育过程中造血细胞和血管发生的最初步骤开始于胚外卵黄囊的血岛形成。在受精卵发育第 7天时 ,中胚层细胞聚集并形成卵黄囊 ,其后 12小时中心部分的细…     

Vasostatin与肿瘤血管生成

血管生成在肿瘤生长和转移的过程中具有重要作用,涉及一系列血管生成、抑制因子的表达和调控。内源性血管抑制因子vasostatin具有显著的抑制内皮细胞增殖和血管生成的功能,已有研究显示va-sostatin单独应用或联合其他治疗对多种恶性肿瘤有较好的治疗效果。其作用机制可能与vasostatin与层黏连蛋白(Laminin)结合,阻止由bFGF等引起的内皮细胞增生等作用有关。进一步研究vasostatin对肿瘤血管生成的抑制作用及其机制,有助于临床寻找新的有效分子靶向药物。     

血管内皮细胞生长因子与治疗性血管新生

本文概述了血管内皮细胞生长因子(VEGF)家族及其受体的组成,介绍了调控VEGF表达的因素及VEGF信号传导途径。着重阐述了VEGF促血管新生的作用机制,以及VEGF在治疗性血管新生中的研究与应用现状、存在问题及未来发展前景。还简要介绍了VEGF其他的生物学作用。     

慢病毒Hoxa3载体的构建及其对人脐静脉内皮细胞迁移和血管新生的影响

目的构建慢病毒Hoxa3载体,观察其对人脐静脉内皮细胞(HUVEC)的转染效率,研究其对细胞迁移和血管新生的影响,并探讨Hoxa3促进血管新生的机制。方法以基因合成法从聚合酶链式反应文库获取人Hoxa3基因,酶切后插入慢病毒骨架载体,以三质粒联合转染293T细胞获得慢病毒Hoxa3载体,并进行滴度测定。转染HUVEC,获取最大转染效率。转染HUVEC后分对照组和慢病毒Hoxa3转染组,进行HUVEC迁移实验和小管形成实验,观察Hoxa3对HUVEC迁移和小管形成的影响。Western blot检测慢病毒Hoxa3载体转染HUVEC后尿激酶型纤溶酶原激活物受体(uPAR)和基质金属蛋白酶14(MMP-14)蛋白表达的变化。结果成功构建慢病毒Hoxa3载体,病毒的滴度为8×1011TU/L; 30 MOI慢病毒载体对HUVEC的转染效率达到99%以上。Western blot结果显示慢病毒Hoxa3载体转染HUVEC后Hoxa3能够有效在HUVEC中表达。与对照组比较,慢病毒Hoxa3载体转染HUVEC后显著增强HUVEC的迁移和小管形成,显著增加uPAR和MMP-14蛋白的表达(P0.05)。结论成功构建的慢病毒Hoxa3载体可促进HUVEC的迁移和小管形成,其作用机制可能为上调HUVEC的uPAR和MMP-14蛋白表达。     

血管内皮生长因子及其受体与非小细胞肺癌血管新生

肿瘤生长和转移都依赖于新生血管的形成.血管内皮生长因子(vascular endothelial growth factor,VEGF)是血管新生最重要的诱导因子.不同VEGF及其受体的亚型功能相异.目前,对VEGF信号转导通路机制的研究取得了很大进展.通过阻断VEGF的某些环节来抑制血管新生的靶向治疗成为非小细胞肺癌的治疗热点.     

Role of endothelial cell survival and death signals in angiogenesis

Angiogenesis, the process of new microvessel development, is encountered in a select number of physiological processes and is central to the pathogenesis of a wide variety of diseases. There is now convincing evidence that regulated patterns of endothelial cell survival and death, a process known as apoptosis, play a central role in the periodic remodeling of the vasculature, and in the timely evolution and regression of angiogenic responses. In this review we discuss the current evidence suggesting a role for inducers and inhibitors of angiogenesis as well as other mediators that modify endothelial cells functions in the survival and death of endothelial cells. We also discuss how dysregulation of apoptosis can lead to aberrant angiogenesis as demonstrated in the pathogenesis of retinopathy of prematurity and cancer. This revised version was published online in June 2006 with corrections to the Cover Date.     

Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus

Purpose: Both platelet-derived endothelial cell growth factor (PD-ECGF) and vascular endothelial growth factor (VEGF) are known to promote the development of new blood vessels, which are fundamental to tumor growth and metastasis. We aimed at evaluating the gene expression of PD-ECGF and VEGF in hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). Patients and methods: Surgical specimens (28 HCC, 28 nontumorous liver tissues and 18 PVTT) were studied by Northern blot analysis. The levels of PD-ECGF mRNA and VEGF mRNA expression were measured by densitometric scanning of the autoradiographs, and they were normalized to the level of expression of an internal control (glyceraldehyde-phosphate dehydrogenase) mRNA. Results: The expression rates of PD-ECGF mRNA in PVTT, HCC and nontumorous liver tissues were 77.8% (14/18), 67.9% (19/28) and 35.7% (10/28), being 88.9% (16/18), 75.0% (21/28) and 17.9% (5/28) respectively for VEGF mRNA. The expressions of PD-ECGF mRNA and VEGF mRNA were higher in HCC with PVTT than when PVTT was absent (P < 0.05). The PVTT was more often seen in patients with positive expression of both PD-ECGF mRNA and VEGF mRNA in HCC than in patients who were positive for only one of these factors or negative for both (P < 0.05). Conclusion: Both PD-ECGF and VEGF correlated well with the formation of PVTT of HCC. Received: 20 June 1999 / Accepted: 20 July 1999     

Regulation of angiogenesis and endothelial cell motility by matrix-bound fibroblasts

This study sought to examine the effect of matrix-bound fibroblasts on angiogenesis and endothelial cell motility. Promotion of angiogenesis by matrix-bound fibroblasts was assessed using rat aortic ring and endothelial tube formation assays. Enhancement of human endothelial cell motility by matrix-bound fibroblasts was assessed using cytodex-2 bead and colloidal gold phagokinetic motility assays. Antibody to hepatocyte growth factor/scatter factor (HGF/SF) but not vascular endothelial growth factor (VEGf) decreased fibroblast-enhanced motility of endothelial cells. The promotion of tube formation by matrix-bound fibroblasts was neutralised with antibodies to HGF/SF and VEGf, both known promoters of angiogenesis. HGF/SF presence was detected by ELISA; whilst the presence of VEGf was detected by Western blotting. These data show that matrix-embedded fibroblasts regulate the motility of vascular endothelial cells and enhance angiogenesis, an effect partly attributed to production of angiogenesis-promoting cytokines HGF/SF and/or VEGf. This revised version was published online in June 2006 with corrections to the Cover Date.     

血管内皮生长因子与脑梗死

血管内皮生长因子(vascular endothelial growth factor,VEGF)是血管内皮细胞的一种特异性促分裂原,是最重要的促血管新生因子.VEGF在脑梗死后高度表达,在血管新生和神经保护中起着重要作用;同时,其过度表达也会使血管通透性增加,进而可能加重脑水肿.文章对VEGF及其受体与脑梗死的研究进展进行了综述.     

Vascular endothelial growth factor and microvascular permeability.

Vascular Endothelial Growth Factors (VEGFs) are endogenously produced vascular cytokines which result in angiogenesis, vasodilatation, and increased microvascular permeability in vivo. They are endothelial specific and result in mitosis, migration, stress fiber formation and increased permeability of endothelial cells in culture. They have been critically implicated in a host of pathological conditions including solid tumor growth and diabetes, and been proposed as a therapy for coronary and peripheral ischemic disease. However, the potent permeability-enhancing properties of VEGFs are very poorly understood. The pharmacology, signal transduction pathways, intracellular signaling mechanisms, and ultrastructural changes which result in increased permeability are still not clear. This review discusses the available evidence for how VEGFs increase permeability in vivo, and some of the pitfalls in interpreting experiments which do not take into account the vasoactive properties of VEGFs. It also discusses the clinical implications of the permeability enhancing effect of VEGFs, and the relevance of these studies to development of new therapies.     

Effect of non-anticoagulant N-desulfated heparin on expression of vascular endothelial growth factor, angiogenesis and metastasis of orthotopic implantation of human gastric carcinoma

AIM： To investigate the effect of N-desulfated heparin on tumor metastasis and angiogenesis, and expression of vascular endothelial growth factor （VEGF） of orthotopic implantation of human gastric carcinoma in male severe combined immune deficiency （SCID） mice.
METHODS： Human gastric cancer SGC-7901 cells were orthotopically implanted into the stomach of SC/D mice. The mice were randomly divided into normal saline group and N-desulfated heparin group. One week after operation, the mice in N-desulfated heparin group reo ceived i.v. injections of N-desulfated heparin （Shanghai Institute of Cell Biology, Chinese Academy of Sciences, 10 mg/kg.d） twice weekly for 3 wk. The mice in normal saline group received i.v. injections of normal saline （100 μL） twice weekly for 3 wk. The mice were sacrificed six weeks after implantation. Tumor metastasis was evaluo ated histologically for metastasis under microscope. Intratumoral microvessel density （MVD） and VEGF expression were evaluated immuohistochemically. VEGF mRNA expression in gastric tissue of SC/D mice was detected by real time PCR.
RESULTS： The tumor metastasis rate was 80% in normal saline group and 20% in N-desulfated heparin group （P 〈 0.05）. MVD was 8.0 ± 3.1 in normal saline group and 4.3 ± 1.8 in N-desulfated heparin group （P 〈 0.05）. VEGF positive immunostaining was found in cytoplasm of cancer cells. The rate of VEGF positive expression was higher in normal saline group than in N-desulfated hepa- rin treated group （90% vs 20%, P 〈 0.05）. VEGF mRNA expression was significantly inhibited by N-desulfated heparin and was higher in normal saline group than in N-desulfated heparin group （Ct value 19.51 ± 1.01 vs 22.55± 1.36, P 〈 0.05）. N-desulfated heparin significantly inhibited the expression of VEGF mRNA in cancer cells. No bleeding occurred in N-desulfated heparin group. CONCLUSION： N-desulfated heparin can inhibit metastasis of gastric cancer by suppressing tumor VEGF expression and tumor angiogenesis     

雷公藤内酯醇抑制胰腺癌细胞生长及血管生成的实验研究

目的 探讨雷公藤内酯醇(TL)对胰腺癌细胞生长及肿瘤新生血管生成的抑制作用.方法 采用CCK-8试剂盒检测TL对胰腺癌SW1990细胞的生长抑制作用;采用TUNEL法检测TL对细胞凋亡的诱导作用;观察尾静脉注射TL对裸鼠移植瘤生长抑制作用和对瘤组织VEGF表达、微血管密度(MVD)的影响.结果 TL呈浓度和时间依赖性抑制SW1990细胞增殖,160 mg/ml的TL干预SW1990细胞24 h,细胞抑制率达50.6%,细胞凋亡率从对照组的9.6%升高到45.1%(P<0.01);TL0.5 mg/kg体重瘤内注射对移植瘤的抑瘤率达89.9%,瘤组织VEGF表达减少,MVD从36.25±8.64减少到9.87±3.34(P<0.01).结论 TL可显著抑制胰腺癌细胞增殖并诱导细胞凋亡;通过抑制肿瘤新生血管生成可抑制裸鼠SW1990细胞移植瘤的生长.