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。     

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。     

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…     

血管内皮细胞迁移与肿瘤血管生成

肿瘤生长和转移均依赖于肿瘤的血管生成,而血管内皮细胞迁移是肿瘤血管生成过程的一个重要环节,有着重要的研究意义.现从肿瘤血管生成过程中促血管生成因子、骨架蛋白解聚、细胞外基质的降解三个方面对血管内皮细胞迁移的影响进行综述.     

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。     

抗肿瘤血管生成与消化道肿瘤

该文综述了肿瘤血管生成及其调控因素如肿瘤血管生成因子和肿瘤血管生成抑制因子以及它们应用于消化道肿瘤抗血管生成治疗的研究进展，为治疗消化道肿瘤提供了新思路和新方法。     

胰腺肿瘤血管形成机制的研究进展

肿瘤血管形成已成为近年来肿瘤研究的热点之一。实体瘤的生长、转移过程中，肿瘤血管形成起着必不可少的作用。胰腺癌的生长、浸润、转移过程中也同样存在着肿瘤血管形成的依赖性，但也有其特殊性。本文将对胰腺肿瘤血管形成机制的研究进展状况作一简单的综述。     

肿瘤血管生成及其抗血管生成治疗的研究进展

肿瘤的生长和转移依赖于新生血管形成,血管内皮生长因子及其受体是目前发现的最重要的促肿瘤血管生长因子,在肿瘤血管生成过程中发挥关键作用。鉴于肿瘤血管生成在肿瘤生长、浸润和转移中的重要作用,近年来开始了抗血管生成治疗肿瘤的新方法——抗血管生成疗法。本文着重综述了肿瘤血管生成及其抗肿瘤血管生成治疗的研究进展。     

血管生成拟态在消化道肿瘤中的研究进展

血管生成拟态是近几年来在发现的一种与经典的肿瘤血管生成途径完全不同、不依赖机体内皮细胞的全新肿瘤血管模式,他描述了高度侵袭性肿瘤细胞可以发生基因逆转,表达内皮细胞相关基因,在三维基质中培养时形成管状结构或网络样管道的特有能力.研究证实,与肿瘤生长、侵袭、转移及患者预后密切相关.本文就血管生成拟态的特点、发生机制、对肿瘤治疗的意义以及在消化道肿瘤中的研究进展等作一综述.     

抗肿瘤血管生成基因治疗的研究

肿瘤血管为肿瘤生长提供氧气、营养、营养、排泄代谢产物，对肿瘤转移也有重要意义。与肿瘤血管生成有关的刺激因子有VEGF、bFGF等，抑制因子有血管生成抑素、内皮抑素sFlt-1等。基因治疗在抗肿瘤血管生成治疗中主要利用病毒载体通过下调VEGF及其受体表达、阻断Ap-Tie受体配体途径、上调血管生成抑素、内皮抑素的表达发挥治疗作用。对抗肿瘤血管生成基因治疗的若干问题尚有争议。抗肿瘤血管生成的基因治疗真正走向临床还有一定距离。     

Role of thrombin in angiogenesis and tumor progression

Clinical, laboratory, histopathological, and pharmacological evidence support the notion that the coagulation system, which is activated in most cancer patients, plays an important role in tumor biology. Our laboratory has provided evidence that thrombin activates angiogenesis, a process which is essential in tumor growth and metastasis. This event is independent of fibrin formation. At the cellular level many actions of thrombin can contribute to activation of angiogenesis: (1). Thrombin decreases the ability of endothelial cells to attach to basement membrane proteins. (2). Thrombin greatly potentiates vascular endothelial growth factor- (VEGF-) induced endothelial cell proliferation. This potentiation is accompanied by up-regulation of the expression of VEGF receptors (kinase insert domain-containing receptor [KDR] and fms-like tyrosine kinase [Flt-1]). (3). Thrombin increases the mRNA and protein levels of alpha (v)beta (3) integrin and serves as a ligand to this receptor. Furthermore, thrombin increases the secretion of VEGF and enhances the expression and protein synthesis of matrix metalloprotease-9 and alpha (v)beta (3) integrin in human prostate cancer PC-3 cells. These results could explain the angiogenic and tumor-promoting effect of thrombin and provide the basis for development of thrombin receptor mimetics or antagonists for therapeutic application.     

IL-1 is required for tumor invasiveness and angiogenesis

Here, we describe that microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1 beta knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1 beta KO mice. The addition of exogenous IL-1 into B16-containing Matrigel plugs in IL-1 beta KO mice partially restored the angiogenic response. Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs. In IL-1 alpha KO mice, local tumor development and induction of an angiogenic response in Matrigel plugs was less pronounced than in WT mice, but significantly higher than in IL-1 beta KO mice. These effects of host-derived IL-1 alpha and IL-1 beta were not restricted to the melanoma model, but were also observed in DA/3 mammary and prostate cancer cell models. In addition to the in vivo findings, IL-1 contributed to the production of vascular endothelial cell growth factor and tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells. Host-derived IL-1 seems to control tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.     

IL-17A通过增强肿瘤血管生成和侵袭促进肿瘤发展

目的探讨IL-17A在非小细胞肺癌血管形成和侵袭中的作用。方法Lewis肺癌细胞（LLC）在不同浓度IL-17A（0、25、50、100和200μg／L）条件下行增殖实验,LLC在50μg／L IL-17A和0μg／LIL-17A刺激下行侵袭实验。LLC在IL-17A刺激不同时间点下用实时定量PCR（RT—PCR）测定血管内皮生长因子-A（VEGF—A）、血管生成素-2（Ang-2）、基质金属蛋白酶-2（MMP-2）、MMP-9mRNA表达。C57BL／6小鼠接种LLC后随机分为3组,每组6只,分别予以瘤内注射PBS、对照腺病毒（Ad—NC）和干扰腺病毒（Ad—si—IL-17a,IL-17a基因沉默）,16d后处死小鼠,提取肿瘤组织RNA,RT-PCR检测VEGF-A、Ang-2、MMP-2和MMP-9mRNA表达。结果体外培养条件下IL-17A对肿瘤细胞的增殖能力没有影响,与无IL-17A组相比,50μg／L浓度的IL-17A组的肿瘤细胞VEGF-A、Ang-2、MMP-2和MMP-9mRNA表达水平明显升高,且肿瘤细胞侵袭能力增强（P〈0．01）。Ad—si—IL-17a组小鼠在13d（P〈0．05）和16d（P〈0．01）时肿瘤明显小于Ad-NC组和PBS组。Ad-si-IL-17a组肿瘤VEGF-A、Ang-2、MMP-2和MMP-9ITIRNA表达水平低于Ad—NC组和PBS组。结论靶向IL-17A的治疗可能为肿瘤治疗提供新思路。     

Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression

The secreted Bv8 protein has been recently characterized as a regulator of myeloid cell mobilization and a neutrophil-derived mediator of tumor angiogenesis in several xenografts, but its role in tumor progression in an endogenous setting was unknown. The rat insulin promoter (RIP)-T-antigen (Tag) is a well characterized transgenic mouse model of multistage pancreatic beta-cell tumorigenesis. Also, the role of neutrophils in RIP-Tag angiogenic switching, as assessed by systemic ablation using anti-Gr1 antibodies at different stages of tumor progression, has been recently described. Here, we show that early treatment of RIP-Tag mice with anti-Bv8 antibodies resulted in a significant reduction in the number of angiogenic islets relative to control antibody-treated mice, implicating Bv8 in the angiogenic switch during neoplasia. Histological analysis showed a significant reduction in vascular surface areas in hyperplastic and angiogenic lesions in pancreatic islets from anti-Bv8-treated mice. Anti-Bv8 treatment also inhibited the mobilization and homing of CD11b+Gr1+ cells to the peripheral blood and the emerging neoplastic lesions. However, anti-Bv8 treatment had no effect on tumor vascularization or burden when initiated at later stages of tumor progression. The stage-dependent efficacy of anti-Bv8 treatment appears remarkably similar to that reported after neutrophil ablation, suggesting that Bv8 is an important mediator of neutrophil-dependent angiogenesis in this transgenic model. In summary, our studies verify a role for Bv8 in the mobilization and recruitment of myeloid cells and in the induction of tumor angiogenesis in the early stages of neoplastic progression.     

Stem cells in tumor angiogenesis

Contribution from diverse tissue-specific stem cell types is required to create the cell populations necessary for the activation of angiogenesis and neovascular growth in cancer. Bone marrow (BM)-derived circulating endothelial progenitors (EPCs) that would differentiate to bona fide endothelial cells (ECs) were previously believed to be necessary for tumor angiogenesis. However, numerous recent studies demonstrate that EPCs are not needed for tumor angiogenesis and indicate EPCs to be artifactual rather than physiological. It is evident that tumor infiltrating hematopoietic cells produced by BM-residing hematopoietic stem cells (HSCs) may contribute to tumor angiogenesis in a paracrine manner by stimulating ECs or by remodeling the extracellular matrix. Therefore, identification of the various hematopoietic cell subpopulations that are critical for tumor angiogenesis and better understanding of their proangiogenic functions and mechanisms of action have potential therapeutic significance. Stem and progenitor cell subsets for also other vascular or perivascular cell types such as pericytes or mesenchymal/stromal cells may provide critical contributions to the growing neovasculature. Furthermore, we hypothesize that the existence of a yet undiscovered—and largely unsearched—tissue-specific adult vascular endothelial stem cell (VESC) would provide completely novel targeted approaches to block pathological angiogenesis and cancer growth. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited".     

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。     

Semaphorins and tumor angiogenesis

Semaphorins belong to a large family of proteins well-conserved along evolution from viruses to mammalians. Secreted and membrane-bound semaphorins participate in a wide range of biological phenomena including development and regeneration of nervous system, cardiovascular development, and immune system activities. Different classes of semaphorins are bifunctional and often exert opposite effects (i.e., repellent or attractive) by acting through the plexin receptor family. However, some classes use other membrane receptors and the same plexin-mediated signals may be modulated by co-receptors, in particular neuropilins or some tyrosine kinase receptors. In cancer, semaphorins have both tumor-suppressor and tumor-promoting functions, by acting on both tumor and stromal components. Here, we review the role of semaphorins in tumor angiogenesis and propose that an unbalance between autocrine loops respectively involving angiogenic inducers and class 3 semaphorin is instrumental for structural and functional abnormalities observed in tumor vasculature. An erratum to this article can be found at     

Epigenetic control of tumor angiogenesis

The term “epigenetic” is used to refer to heritable alterations in chromatin that are not due to changes in DNA sequence. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of genes. The aim of this article is to analyze the role of epigenetic mechanisms in the control and regulation of tumor angiogenetic processes. The reversibility of epigenetic events in contrast to genetic aberrations makes them potentially suitable for therapeutic intervention. In this context, DNA methyltransferase (DNMT) and HDAC inhibitors indirectly—via the tumor cells—exhibit angiostatic effects in vivo, and inhibition of miRNAs can contribute to the development of novel anti‐angiogenesis therapies.