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…     

消化道肿瘤抗血管生成治疗的临床研究进展

消化道肿瘤的生长，转移与复发是血管生成依赖的，故以肿瘤血管生成的各个环节及其发生过程中的生化改变为靶点，研制血管生成的抑制剂，可使肿瘤处于休眠状态，有效地抑制肿瘤生长，侵袭，转移和复发，将成为肿瘤防治的一条新途径。本文主要综述消化道肿瘤抗血管生成治疗的临床试验研究进展。     

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。     

抗血管生成治疗肿瘤研究的进展

肿瘤血管生成是一个多步骤复杂的调控事件。针对肿瘤血管形成分子机制所设计的抗血管生成策略,已经成为目前肿瘤治疗的热点研究领域。本文就肿瘤血管生成特点及其调控、抗肿瘤血管生成治疗研究现状、存在问题和今后研究方向作一综述。     

胃癌的血管生成及抗血管生成治疗

自从1971年Folkman基于对肿瘤血管生成的研究而提出“肿瘤生长依赖于血管生成”的观点以来，血管生成在肿瘤的生长和转移中的作用越来越受到人们的重视，其活跃程度无论是对组织病理分级、放射治疗、化学治疗还是对预后的判断都有重要的评估价值。胃癌是最常见的恶性肿瘤之一，其血管生成已引起临床的广泛重视，一些血管生成因子已被研究。本文就胃癌发生发展过程中相关因子的生物学表达以及胃癌的抗血管生成治疗进行综述。     

血管生成调控因子与肿瘤生长及治疗的研究进展

1968年Tannock IF发现肿瘤细胞分裂速率的减慢与营养血管的距离增大相关,肿瘤的氧气和营养供应限制了肿瘤生长.20世纪70年代,美国学者Folkman提出了肿瘤生长是依赖血管的.     

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。     

胃癌血管生成及抗血管生成治疗的研究进展

作为肿瘤间质组成的一部分,肿瘤内血管生成不仅为原发肿瘤生长所必需,也是肿瘤细胞向远处播散的必备条件之一.超微结构和免疫组化的观察发现,不同人类肿瘤组织中的血管密度和数量与肿瘤的侵袭转移潜能密切相关.最近许多研究证实了血管生成与胃癌侵袭性之间的联系,同时也有许多研究证实抑制血管生成能显著抑制肿瘤的生长及转移,在胃癌的治疗实验中已初步显示出良好的应用前景.     

抗血管生成治疗在胰腺癌治疗中的研究进展

血管生成是包括胰腺癌在内的实体肿瘤生长和转移的必要因素,抗血管生成治疗为胰腺癌的治疗带来了新的希望.其中血管内皮生长因子(VEGF)处于核心地位.但由于胰腺癌生长和转移的复杂性,抗VEGF治疗需与其它抗血管生成通路治疗、放疗和化疗联合应用.     

抗血管生成--动脉粥样硬化治疗的新策略

器官和组织的血管系统形成有3种方式,即“血管发生”(vasculogenesis)、“血管生成”(angiogenesis)和“动脉生成”(arteriogenesis).“血管发生”是在胚胎形成早期,由内皮细胞的前体成血管细胞形成血管腔结构的过程;“血管生成”则是指无发育完整中膜的新血管的形成;而“动脉生成”是指有发育完整的中膜的新动脉的出现[1,2].生理意义的血管形成在胚胎发育,创伤修复和侧支循环代偿缺血等方面发挥重要作用,而病理意义的血管形成,即血管生成异常则在动脉粥样硬化(AS)[BFQ、肿瘤生长及转移、糖尿病性视网膜病变、风湿性关节炎等疾病的发生中发挥重要作用.近年来,血管生成在AS发生、发展中的作用已日益得到阐明,抗血管生成将成为AS治疗一个引人注目的新策略.     

内皮抑素抑制肿瘤生长和转移的机制

恶性肿瘤的生长和转移离不开新生血管.抗肿瘤血管生成是近年来出现的倍受关注的一种种肿瘤治疗新方法,并得到了较为广泛和深入的研究.内皮抑素是胶原蛋白ⅩⅧ的C末端水解片段,是重要的内源性血管抑制因子,在抗肿瘤血管生成方面表现出显著效果,其为治疗恶性肿瘤提供了新的途径.本文就内皮抑素的生物学特性及其在抑制肿瘤生长和转移作用机制中的研究进展作一介绍.     

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。     

Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives

Developing medicines for hemodynamic disorders that are characteristic of cirrhosis of the liver is a relevant problem in modern hepatology. The increase in hepatic vascular resistance to portal blood flow and subsequent hyperdynamic circulation underlie portal hypertension(PH) and promote its progression, despite the formation of portosystemic collaterals. Angiogenesis and vascular bed restructurization play an important role in PH pathogenesis as well. In this regard, strategic directions in the therapy for PH in cirrhosis include selectively decreasing hepatic vascular resistance while preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis. The aim of this review is to describe the mechanisms of angiogenesis in PH and the methods of antiangiogenic therapy. The Pub Med database, the Google Scholar retrieval system, and the reference lists from related articles were used to search for relevant publications. Articles corresponding to the aim of the review were selected for 2000-2017 using the keywords: "liver cirrhosis", "portal hypertension", "pathogenesis", "angiogenesis", and "antiangiogenic therapy". Antiangiogenic therapy for PH was the inclusion criterion. In this review, we have described angiogenesis inhibitors and their mechanism of action in relation to PH. Although most of them were studie donly in animal experiments, this selective therapy for abnormally growing newly formed vessels is pathogenetically reasonable to treat PH and associated complications.     

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。     

肿瘤血管生成的实验研究方法

血管生成在肿瘤的生长与转移中具有重要的意义。各种促血管生成因子与血管生成抑制因子之间的平衡与失衡是肿瘤血管生成重要的调控因素。血管生成的实验研究模型各自有其优缺点,根据研究内容来选择合适的研究方法非常重要。离体模型简便易行,容易定量研究,可用于初步研究,但需在体模型的研究来进一步证实。在体模型操作繁琐、耗时,但更接近体内复杂的血管生成过程。     

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     

Cancer gene therapy targeting angiogenesis： An updated review

INTRODUCTION Angiogenesis is the formation of new blood vessels frompre-existing ones. Many developmental and pathological processes require angiogenesis[1]. As proposed by Folkman in 1971, angiogenesis is required for tumor growth[2]. Angiogenesis consists of several steps: endothelial cell (EC) proliferation, migration, basement membrane degradation, and new lumen organization[3]. This multi-step process is determined by a net balance between pro- and anti- angiogenesis regulators in t…     

Current status of tumor radiogenic therapy

Although tumor gene therapy falls behind its clinical use, the combination of irradiation and gene therapy is full of promise in cancer therapy based on traditional radiotherapy, chemotherapy and surgery. We have termed it as radiogenic therapy. This review focuses on the following aspects of radiogenic therapy in recent years: improvement of gene transfer efficiency by irradiation, radiotherapy combined with cytokine gene delivery or enhancement of the immunity of tumor cells by transgene, direct stimulation by radiation to produce cytotoxic agents, increase of tumor cell radiosensitivity in gene therapy by controlling the radiosensitivity genes and adjusting the fraction dose and interval of radiation so as to achieve the optimum antitumor effect while reducing the normal tissue damage, radioprotective gene therapy enhancing radiation tumor killing effect while protecting the normal tissue and organs with transgene using transfer vectors.     

Nestin:A novel angiogenesis marker and possible target for tumor angiogenesis

Abnormal vasculature,termed tumor vessels,is a hallmark of solid tumors.The degree of angiogenesis is associated with tumor aggressiveness and clinical outcome.Therefore,exact quantification of tumor vessels is useful to evaluate prognosis.Furthermore,selective detection of newly formed tumor vessels within cancer tissues using specific markers raises the possibility of molecular targeted therapy via the inhibition of tumor angiogenesis.Nestin,an intermediate filament protein,is reportedly expressed in repair processes,various neoplasms,and proliferating vascular endothelial cells.Nestin expression is detected in endothelial cells of embryonic capillaries,capillaries of the corpus luteum,which replenishes itself by angiogenesis,and proliferating endothelial progenitor cells,but not in mature endothelial cells.Therefore,expression of nestin is relatively limited to proliferating vascular endothelial cells and endothelial progenitor cells.Nestin expression is also reported in blood vessels within glioblastoma,prostate cancer,colorectal cancer,and pancreatic cancer,and its expression is more specific for newly formed blood vessels than other endothelial cell markers.Nestin-positive blood vessels form smaller vessels with high proliferation activity in tumors.Knockdown of nestin in vascular endothelial cells suppresses endothelial cell growth and tumor formation ability of pancreatic cancers in vivo.Using nestin to more accurately evaluate microvessel density in cancer specimens may be a novel prognostic indicator.Furthermore,nestin-targeted therapy may suppress tumor proliferation via inhibition of angiogenesis in numerous malignancies,including pancreatic cancer.In this review article,we focus on nestin as a novel angiogenesis marker and possible therapeutic target via inhibition of tumor angiogenesis.     

Angiogenesis of hepatocellular carcinoma: An immunohistochemistry study

BACKGROUND Although hepatocellular carcinoma(HCC) is one of the most vascular solid tumors, antiangiogenic therapy has not induced the expected results.AIM To uncover immunohistochemical(IHC) aspects of angiogenesis in HCC.METHODS A retrospective cohort study was performed and 50 cases of HCC were randomly selected. The angiogenesis particularities were evaluated based on the IHC markers Cyclooxygenase-2(COX-2), vascular endothelial growth factor(VEGF) A and the endothelial area(EA) was counted using the antibodies CD31 and CD105.RESULTS The angiogenic phenotype evaluated with VEGF-A was more expressed in small tumors without vascular invasion(pT1), whereas COX-2 was rather expressed in dedifferentiated tumors developed in non-cirrhotic liver. The CD31-related EA value decreased in parallel with increasing COX-2 intensity but was higher in HCC cases developed in patients with cirrhosis. The CD105-related EA was higher in tumors developed in patients without associated hepatitis.CONCLUSION In patients with HCC developed in cirrhosis, the newly formed vessels are rather immature and their genesis is mediated via VEGF. In patients with non-cirrhotic liver, COX-2 intensity and number of mature neoformed vessels increases in parallel with HCC dedifferentiation.