Vasohibin蛋白质家族与肿瘤血管新生

血管新生存在于包括肿瘤在内的多种生理和病理过程中,且受到局部环境中血管生成促进因子和抑制因子的共同调节,这一过程对肿瘤增殖、侵袭、转移能力尤为重要。体内存在着许多内源性血管生成调节因子。最近,vasohibin家族作为一个新的血管新生调节因子进入人们的视线,备受关注。本文就vasohibin家族在肿瘤血管新生过程中的重要角色及其在抗血管生成治疗中的应用做一综述。     

肿瘤干细胞与血管新生的研究进展

肿瘤生长及转移依赖于新生血管的形成,大量研究认为肿瘤干细胞与血管新生之间存在密切联系,肿瘤干细胞可能转分化为内皮细胞参与新生血管生成,并通过分泌促血管生长因子、基质衍生因子和低氧诱导因子参与对血管新生的调控。     

血管内皮细胞生长因子研究进展

从不同侧面阐述了血管内皮细胞生长因子（VEGF）在新生血管形成中的作用.VEGF诱导新生血管形成,具有血管渗透性,是新生血管形成的主要调控者之一.VEGF mRNA不同剪接,形成5种VEGF变异体(isoform)即VEGF121-206.VEGF诱导新生血管的调控过程、拮抗VEGF成为大家竞相研究的领域.     

肿瘤血管生成调节因子的研究进展

血管生成促进因子和血管生成抑制因子的平衡控制着肿瘤新生血管的形成。当促进因子的作用强于抑制因子时,便会引起肿瘤血管的生长。因此,了解血管生成调节因子的特点及其作用机制是一项非常重要的研究任务,针对肿瘤血管的抗血管新生治疗有着重要的理论意义和临床实用价值。这为肿瘤的诊断、分期、治疗和预后提供了新的参数指标,为寻找有效的治疗靶点提供了有利的依据。该文就有关的重要血管生成调节因子作一综述。     

源于Ⅳ型胶原α3、α6链的肿瘤新生血管生成抑制剂

肿瘤抑素（Tumstatin）和Hexastatin是分别源于Ⅳ型胶原α3、α6链的肿瘤新生血管生成抑制剂.肿瘤的发生、发展和转移都依赖于新生血管的生成.通过抑制肿瘤新生血管的生成,阻断肿瘤细胞赖以生存的氧气及营养供给,肿瘤细胞便会发生凋亡.这是肿瘤治疗的新策略.Tumstatin和Hexastatin是近年来研究比较多的两种肿瘤新生血管生成抑制剂,其中Tumstatin的结构、活性位点、抑制肿瘤新生血管形成机制研究得比较清晰;Hexastatin虽与Tumstatin有许多相似之处,但是还有很多问题需要进一步研究解决.该文就这两种肿瘤新生血管生成抑制剂等的最新研究进展做一综述.     

子宫内膜癌血管生成相关因子的研究进展

血管内皮生长因子（VEGF）是近年研究较广泛的参与内皮细胞活化和血管生成的重要因子,它通过与其特异性受体结合发挥生物学作用。缺氧诱导因子-1α（HIF-1α）是缺氧条件下被激活,参与肿瘤发生、发展的一类核转录因子,通过激活下游基因发挥促进肿瘤血管生成的作用。葡萄糖转运蛋白（GULT-1）是新近研究发现的与子宫内膜癌血管生成相关的因子。血小板衍化生长因子（PDGF）一类重要的促有丝分裂多肽生长因子。其在肿瘤血管新生中的作用有待于进一步研究。目前许多研究发现,以上几种因子与子宫内膜癌关系密切,直接或间接参与了子宫内膜癌的病理生理过程。对这几种因子的深入研究将为子宫内膜癌的防治与抗血管生成治疗提供新的理论依据及治疗靶点。     

血管内皮生长因子和抗肿瘤血管新生药物研究进展

肿瘤的生长与迁移离不开新血管的形成,这使得抗血管新生成为肿瘤治疗的重要途径之一。血管内皮生长因子（VEGF）是针对内皮细胞作用最强、特异性最高的血管新生促进因子,因而VEGF是抗肿瘤治疗的重要靶点。我们简要介绍了VEGF的一些生物学特点及肿瘤血管新生,着重介绍了一些抗血管新生药物的最新研究成果及其临床应用。     

内皮抑素研究进展

新生血管的生成 (Angiogenesis)与多种生理过程相关 ,受多种促进和抑制因子的调节 ,细胞外基质蛋白经酶解产生的小片段中很多都参与了这一过程的调节。内皮抑素 (Endostatin)是 1997年首先从小鼠血管内皮瘤EOMA细胞培养上清中发现的 ,是细胞外基质蛋白胶原XVⅢα1链NC1结构域C末端 184个Aa的片段。可抑制bFGF和VEGF刺激的血管内皮细胞的增殖和迁移 ,抑制新生血管的形成 ,抑制肿瘤的形成和转移。由于其作用对象是血管内皮细胞 ,而不是转化的肿瘤细胞本身 ,长期反复治疗中不会引起耐药性。它在肿瘤治疗中的应用前景引起多方关注 ,相关研究广泛开展起来。本文综述了近几年在其生物功能、作用机理及应用等方面的研究进展     

血管内皮细胞生长因子在非血管新生方面的重要功能

血管内皮细胞生长因子(vascular endothelial growth factor,VEGF或VEGF-A),又称为血管通透因子(vascular permeable factor,VPF)是一种具有多种功能的生物大分子,它是分泌性糖蛋白生长因子超家族中的一员.VEGF主要通过两个高亲和力的酪氨酸激酶受体来传递各种信号:VEGF受体1和2(VEGFR1,VEGFR2),从而引起细胞的多种生理反应.在胚胎时期,VEGF可以促进血管内皮细胞的增殖、迁移、管状形成和提高内皮细胞的存活率,对于血管新生和发育十分关键;而在成体时期,VEGF则主要参与正常血管结构的维持,并调节生理和病理性血管新生.近几年来的临床试验表明,使用多种阻断VEGF作用的抑制剂能有效促进肿瘤血管的退化和减小肿瘤的体积,但是同时在部分病人中也观察到了多方面的副作用.这些结果显示,VEGF也具有非血管新生方面的重要功能.因此,在研制基于拮抗VEGF作用的抗癌药物时,这些功能更不容忽视.研究表明,在成体的小肠、胰岛、甲状腺、肾脏和肝脏等器官组织中,VEGF都发挥着十分重要的作用,如果VEGF水平降低,这些器官组织的毛细血管网状结构将部分退化.VEGF还可以促进骨髓形成、组织修复与再生、促进卵巢囊泡成熟,并且参与血栓、炎症反应和缺氧缺血的病理过程.本文主要对VEGF在血管新生之外的功能及其分子机制进行了简要探讨.     

自噬与血管新生相关细胞因子

血管新生发生于机体多种生理病理过程中,已成为诸多病理过程的标志之一。自噬参与调节机体血管新生。在病变组织中,自噬不仅与血管形成密切相关,而且经调节血管新生向病理组织提供必要的氧与能量。通过抑制自噬可以抑制缺氧、能量缺乏等刺激诱导的血管新生。血管新生过程中相关细胞因子参与调节自噬而影响新生血管的形成。通过二者的作用,既可以促进血管新生,也可抑制血管新生,这种机制在机体生理和病理过程中具有重要的作用。本文从自噬通过血管新生细胞因子促进血管新生以及自噬通过血管新生细胞因子抑制血管新生两个方面概述了自噬在血管新生过程中的作用,为疾病的治疗提供新的思路与方法。     

胃癌血管生成素和血管内皮生长因子的表达及其意义

目的探讨血管内皮生长因子(VEGF)和血管生成素(angiopoietin,Ang)在胃癌的表达及其与肿瘤血管生成和临床病理因素的关系。方法采用免疫组化SP法检测84例胃癌和30例癌旁正常组织中VEGF、Ang-1、Ang-2的表达,应用CD34抗体标记微血管内皮细胞,计数微血管密度(MVD),结合临床病理资料进行分析。结果胃癌组织VEGF、Ang-2阳性表达率、MVD值明显高于癌旁正常组织(P(0.05)。VEGF表达与肿瘤大小、侵袭深度、临床分期、淋巴结转移有关(P(0.05),而与患者年龄、性别、组织学类型和分化程度无关,其阳性组的Ang-2阳性表达率、MVD值明显高于阴性组,VEGF的表达与Ang-2、MVD呈正相关。胃癌组织Ang-2表达与肿瘤大小、侵袭深度、淋巴结转移有关(P(0.05),与MVD呈正相关。胃癌Ang-1表达略低于对照组,但无统计学差异(P(0.05),Ang-1的表达与肿瘤侵袭深度和MVD值呈负相关。结论胃癌中VEGF、Ang-2蛋白的过度表达以及Ang-1蛋白的低表达可能在肿瘤血管生成和肿瘤浸润、转移中起重要作用。     

促血管生成素的生物学特点和应用前景

促血管生成素（Ang）家族是调节血管生成的一类细胞因子,包括Ang-1、Ang-2、Ang-3和Ang-4等4个成员,Ang-1和Ang-2是其中最重要的成员。Tie-2是Ang家族的共同受体。Ang-1与Tie-2结合后激活下游信号通路,起到抑制内皮凋亡、促进内皮存活和迁移、维持血管完整性的作用;Ang-2则是Ang-1天然的抑制剂,其拮抗的效应与局部血管内皮生长因子（VEGF）的水平有关,VEGF存在时促进新生血管形成,VEGF缺乏时则有利于血管的消退。Ang参与生理和病理性的血管新生,与肿瘤和其他疾病有密切的关系,有广泛的应用前景。     

Modeling the effects of vasculature evolution on early brain tumor growth

Mathematical modeling of both tumor growth and angiogenesis have been active areas of research for the past several decades. Such models can be classified into one of two categories: those that analyze the remodeling of the vasculature while ignoring changes in the tumor mass, and those that predict tumor expansion in the presence of a non-evolving vasculature. However, it is well accepted that vasculature remodeling and tumor growth strongly depend on one another. For this reason, we have developed a two-dimensional hybrid cellular automaton model of early brain tumor growth that couples the remodeling of the microvasculature with the evolution of the tumor mass. A system of reaction-diffusion equations has been developed to track the concentration of vascular endothelial growth factor (VEGF), Ang-1, Ang-2, their receptors and their complexes in space and time. The properties of the vasculature and hence of each cell are determined by the relative concentrations of these key angiogenic factors. The model exhibits an angiogenic switch consistent with experimental observations on the upregulation of angiogenesis. Particularly, we show that if the pathways that produce and respond to VEGF and the angiopoietins are properly functioning, angiogenesis is initiated and a tumor can grow to a macroscopic size. However, if the VEGF pathway is inhibited, angiogenesis does not occur and tumor growth is thwarted beyond 1-2mm in size. Furthermore, we show that tumor expansion can occur in well-vascularized environments even when angiogenesis is inhibited, suggesting that anti-angiogenic therapies may not be sufficient to eliminate a population of actively dividing malignant cells.     

Regulation of the expression balance of angiopoietin-1 and angiopoietin-2 by Shh and FGF-2

Sonic hedgehog (Shh) is a typical morphogen to regulate epithelial–mesenchymal interactions during embryonic development. Shh is also an indirect angiogenic agent upregulating other angiogenic factors, including angiopoietin-1 (Ang-1). Recent studies revealed that angiogenesis induced by Shh is characterized by distinct large-diameter vessels with less branching. Ang-1 promotes blood vessel maturation, and angiopoietin-2 (Ang-2) counteracts Ang-1 activity and regulates vascular branching. Thus, we hypothesized that Shh-induced angiogenesis is affected by expression of Ang-1 and Ang-2, and we investigated the regulatory system of angiopoietins by Shh in vitro. Shh enhanced Ang-1 expression but did not enhance vascular endothelial growth factor in fibroblasts. The upregulation of Ang-1 expression by Shh was significantly decreased by fibroblast growth factor-2 (FGF-2), a potent angiogenic factor. Furthermore, FGF-2 increased the expression of Ang-2 in endothelial cells. These findings suggest that Shh and FGF-2 regulate the expression balance of vascular morphogens Ang-1 and Ang-2 and are involved in angiogenesis.     

Molecular mechanisms of tumor angiogenesis

The maintenance of growth of malignant tumors is closely related with the development of the vascular network supplying the tumor with blood. The vascularization of tumor tissue is similar to physiological angiogenesis, but in tumors it has some specific features. During the last 25 years a vast number of biomolecules have been found and described which are involved in the regulation of tumor angiogenesis. This review considers the action mechanisms and specific features of expression of the main angiogenic growth factors, such as the vascular endothelium growth factor (VEGF), angiopoietins (Ang-1, Ang-2), and the basic fibroblast growth factor (bFGF). The roles of cytokines, growth factors, proteolytic enzymes, and cell adhesion molecules in the regulation of the key steps of blood vessel generation in the tumor are considered. The significance of angiogenesis in the treatment of oncological diseases and possible approaches for inhibition of the regulatory signals of angiogenic factors are discussed.     

Characterization of a novel form of angiopoietin-2 (Ang-2B) and expression of VEGF and angiopoietin-2 during chicken testicular development and regression.

The complex process of angiogenesis is controlled by the vascular endothelial growth factor (VEGF) and its receptors and by the recently isolated angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) that signal through the transmembrane endothelial receptor tyrosine kinase Tie2. We report here the characterization of a novel form of Ang-2 (Ang-2B) with a truncated amino-terminal domain resulting from an alternative splicing of the gene. While previous reports have found the expression of Ang-2 limited to the embryo, female reproductive organs, and tumor tissues, we have observed striking changes in Ang-2 expression during chicken testicular development and regression. The expression of Ang-2 and VEGF is abundant in prepuberal testis and low in quiescent adult testis. Testicular regression is accompanied by high expression of Ang-2 and very low expression of VEGF. These observations are in accordance with the proposal that Ang-2 induces angiogenesis in the presence of VEGF and vascular regression in its absence.     

Overexpression of angiopoietin-2 impairs myocardial angiogenesis and exacerbates cardiac fibrosis in the diabetic db/db mouse model

The angiopoietins/Tie-2 system is essential for the maintenance of vascular integrity and angiogenesis. The functional role of angiopoietin-2 (Ang-2) in the regulation of angiogenesis is dependent on other growth factors such as VEGF and a given physiopathological conditions. This study investigates the potential role of Ang-2 in myocardial angiogenesis and fibrosis formation in the diabetic db/db mouse. Diabetic db/db mice received intramyocardial administration of either adenovirus Ang-2 (Ad-CMV-Ang-2) or Ad-β-gal. The levels of Tie-2, VEGF, caspase-3, Wnt7b, fibroblast-specific protein-1 (FSP-1), and adhesion molecules (ICAM-1 and VCAM-1) expression were measured. Apoptosis, capillary density, and cardiac fibrosis were also analyzed in the db/db mouse hearts. Overexpression of Ang-2 suppressed Tie-2 and VEGF expression in db/db mouse hearts together with significant upregulation of Wnt7b expression. Overexpression of Ang-2 also sensitizes ICAM-1 and VCAM-1 expression in db/db mouse hearts. Immunohistochemical analysis revealed that overexpression of Ang-2 resulted in a gradual apoptosis as well as interstitial fibrosis formation, these leading to a significant loss of capillary density. Data from these studies were confirmed in cultured mouse heart microvascular endothelial cells (MHMEC) exposed to excessive Ang-2. Exposure of MHMEC to Ang-2 resulted in increased caspase-3 activity and endothelial apoptosis. Knockdown of Ang-2 attenuated high glucose-induced endothelial cell apoptosis. Further, counterbalance of Ang-2 by overexpression of Ang-1 reversed loss of capillary density and fibrosis formation in db/db mouse hearts. Our data demonstrate that Ang-2 increases endothelial apoptosis, sensitizes myocardial microvascular inflammation, and promotes cardiac fibrosis and thus contributes to loss of capillary density in diabetic diseases.     

Blockade of EphA receptor tyrosine kinase activation inhibits vascular endothelial cell growth factor-induced angiogenesis

Angiogenesis is a multistep process involving a diverse array of molecular signals. Ligands for receptor tyrosine kinases (RTKs) have emerged as critical mediators of angiogenesis. Three families of ligands, vascular endothelial cell growth factors (VEGFs), angiopoietins, and ephrins, act via RTKs expressed in endothelial cells. Recent evidence indicates that VEGF cooperates with angiopoietins to regulate vascular remodeling and angiogenesis in both embryogenesis and tumor neovascularization. However, the relationship between VEGF and ephrins remains unclear. Here we show that interaction between EphA RTKs and ephrinA ligands is necessary for induction of maximal neovascularization by VEGF. EphA2 RTK is activated by VEGF through induction of ephrinA1 ligand. A soluble EphA2-Fc receptor inhibits VEGF-, but not basic fibroblast growth factor-induced endothelial cell survival, migration, sprouting, and corneal angiogenesis. As an independent, but complementary approach, EphA2 antisense oligonucleotides inhibited endothelial expression of EphA2 receptor and suppressed ephrinA1- and VEGF-induced cell migration. Taken together, these data indicate an essential role for EphA receptor activation in VEGF-dependent angiogenesis and suggest a potential new target for therapeutic intervention in pathogenic angiogenesis.     

Angiopoietins-1 and -2 play opposing roles in endothelial sprouting of embryoid bodies in 3D culture and their receptor Tie-2 associates with the cell-cell adhesion molecule PECAM1

Angiopoietins 1 and 2, ligands for the receptor kinase Tie-2, have been proposed to play critical but opposing roles in vascular development. Since signaling by Tie-2 is likely affected by other endothelial cell receptors such as Flk-1, the receptor for VEGF, and cell–cell adhesion receptors PECAM1 and VE-cad, we explored their interactions in a 3D model of vasculogenesis. When murine embryoid bodies (EBs) were treated with VEGF in Matrigel in the presence or absence of Ang-1 or Ang-2 for eight days, Ang-1 abrogated vascular sprouting for treatments started at days 0 or 3. In contrast, Ang-2 greatly accelerated vascular sprouting compared to untreated EBs. These results were confirmed in a second model system where VEGF treated HUVECs were grown in Matrigel in the presence or absence of Ang-1 or Ang-2. Since vascular sprouting must be precisely controlled in the developing embryo, it is likely that cell–cell adhesion molecules play a role in sensing the density of vascular sprouts. In this respect, we have shown that PECAM1 and CEACAM1 play essential roles in vascular sprouting. We now show that PECAM1 is associated with Tie-2, becomes phosphorylated on its ITIMs, and recruits the inhibitory phosphatases SHP-1 and SHP-2. In addition, PECAM1 is associated with VE-cad and may similarly regulate its signaling via recruitment of SHP-1/2.     

幽门螺杆菌L型感染及血管生成素的表达与胃癌血管生成的关系

目的探讨幽门螺杆菌L型(Hp-L)感染和血管生成素(Ang)在胃癌中的表达及与肿瘤血管生成的关系。方法采用革兰染色和免疫组化方法检测84例胃癌和30例癌旁正常组织中Hp-L型感染,应用免疫组化方法检测Ang-1、Ang-2蛋白表达水平,计数微血管密度(MVD),结合临床病理因素进行分析。结果胃癌组织中Hp-L型感染率、Ang-2阳性表达率、MVD值明显高于正常组织(P0.05),胃癌中Hp-L型感染与肿瘤分化程度、侵袭深度、临床分期、淋巴结转移有关(P0.05),与Ang-2表达、MVD呈正相关。胃癌组织中Ang-2表达与肿瘤大小、侵袭深度、淋巴结转移有关(P0.05),与MVD呈正相关。Ang-1在胃癌中表达略低于对照组,但无统计学差异(P0.05),Ang-1表达与侵袭深度和MVD呈负相关。结果 胃癌Hp-L型感染在肿瘤血管生成中起重要作用,其机制与Ang-2表达上调,Ang-2/Ang-1比例失衡有关。