血管内皮生长因子及其受体在肿瘤血管生成中的作用及与抗血管生成研究进展

血管内皮生长因子及其受体在肿瘤血管生成中的作用及与抗血管生成研究进展卞修武史景泉血管生成（ａｎｇｉｏｇｅｎｅｓｉｓ）存在于很多生理和病理过程中，对实体瘤的快速生长和转移尤为重要，因此，抑制血管生成成为不同于常规抗肿瘤治疗的新策略，并已成为肿瘤研究的热...     

肿瘤血管生成抑制剂的研究进展

70年代初，Folkman提出肿瘤生长依赖于血管形成的概念。随之国内外大量研究证明肿瘤血管生成与肿瘤生长、侵袭和转移等特性密切相关，从而产生了肿瘤血管生成抑制疗法。因此，以肿瘤血管生成为靶点，开发肿瘤血管生成抑制剂（tumor angiogenesis inhibitor）在抗肿瘤治疗中已成为一个研究热点。目前大部分肿瘤血管抑制剂仍处于Ⅰ、期临床实验阶段，部分进入Ⅲ期临床实验，并取得较理想的疗效。本文对几类常用的肿瘤血管生成抑制剂作一介绍。     

血管内皮生长因子与肿瘤血管生成的研究进展

肿瘤的无限制侵袭性生长及转移依赖于血管的生成。肿瘤血管生成是一个复杂的多步骤过程,且有众多生长因子的参与,其中血管内皮生长因子(Vascular endothelial growth factor,VEGF)是最重要的促血管生长因子,与肿瘤的生长、转移及预后有关,也是抗肿瘤血管生成治疗的重要靶点之一。本文旨在对VEGF与肿瘤血管生成的研究进展作一综述。     

干扰素治疗慢性粒细胞白血病前后骨髓血管生成的临床观察

有有研究表明，血管生成及其调控因子与血液系统恶性疾病的发生、演变和预后密切相关。血管内皮细胞生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）是血管新生的重要调控因子，观察慢性粒细胞白血病（CML）骨髓组织VEGF和bFGF表达以及微血管密度是研究血液肿瘤血管生成的常用方法。CML采用造血干细胞移植根治疾病或采用伊马替尼长期缓解病情，但由于经济原因，干扰素仍是大多数国内CML病人之首选。已知干扰素除有直接抗肿瘤细胞增殖作用外，还有明显的抗血管形成活性。我们对CML患者采用干扰素为主的治疗方法，观察治疗前后骨髓组织VEGF、bFGF和微血管数量变化，探讨干扰素抗血管生成的作用机制。     

血管内皮细胞生长因子与大肠癌治疗

血管内皮细胞生长因子（VEGF）在大肠癌组织中高表达，与肿瘤血管生成，肿瘤细胞增殖、转移，肿瘤预后关系密切。目前各种针对VEGF及其受体开展的抑制肿瘤血管生成的药物研究广泛开展，有的已经批准上市，用于大肠癌的临床治疗，为大肠癌的治疗开辟了新的途径。     

表达Tie2基因的单核细胞研究进展

肿瘤血管的生成和发展在肿瘤的生长和恶化过程中起着关键作用。一类表达Tie2基因的单核细胞（TEM）通过一些生长因子和化学信号被募集到肿瘤组织中,旁分泌细胞因子促进肿瘤血管的生成和发展。TEM在促进肿瘤血管形成中起着重要作用,与血管内皮细胞祖细胞（EPC）不同的是,TEM只是在肿瘤的血管生成中起促进作用,但在肿瘤周围临近的正常组织中没有发现其存在,TEM被认为是一类肿瘤组织特异性的细胞。以TEM为载体细胞,通过TEM表达抗肿瘤药物,靶向递送的抗肿瘤药物能够有效的抑制肿瘤的生长和恶化。     

抗血管生成在胃癌治疗中的研究进展

胃癌的生长、转移依赖于肿瘤血管生成。当血管生成开关打开，肿瘤内有足够的新生血管长入，提供营养并带走代谢产物，肿瘤便获得了进一步生长、转移的能力。已知包括血管内皮细胞生长因子、整合素、基质金属蛋白酶和表皮生长因子受体在内的20多种细胞因子与胃癌微血管密度（microvessel density, MVD）相关，是胃癌血管靶向治疗的有效靶点。     

血管内皮生长因子及受体对肿瘤的抑制作用及基因治疗研究进展

血管内皮生长因子（ＶＥＧＦ）是一种特异性的、与血管形成有关的主要调节因子。血管的发生和生长在胚胎发育、创伤修复生理过程中或炎症、视网膜病和肿瘤的快速生长及转移等病理过程都起着重要作用。因此抑制血管生成已成为抗肿瘤治疗的一个新策略［１－３］，我们可以利用ＶＥＧＥ的反义核酸和中和抗体，或通过屏蔽ＶＥＧＦ受体等方法来抑制肿瘤的生长和转移。１ＶＥＧＦ的结构和功能ＶＥＧＦ是１９８９年Ｄａｖｉｄ等［４］首先从牛垂体滤泡星状细胞培养液中分高纯化出来的，并证明是由两个相同的多肽链通过二、硫键构成的同源二聚体糖蛋…     

对肿瘤血管生成研究之肿瘤微血管构筑表型异质性的思考

血管生成是多种病理过程（如创伤愈合、慢性炎症和肿瘤等）中的基本事件。对血管生成过程及其机制的研究促进了治疗性血管生成和抗血管生成策略的应用。然而,无论是血管生成机制还是抗血管生成治疗效果方面,都存在着一些争议与挑战。其中,人们寄予极大希望的抗血管生成治疗肿瘤的障碍可能不在于该策略本身,而是肿瘤微血管内皮分子遗传学和微血管构筑上的差异性。从病理学角度研究这些差异的分子基础不仅有助于进一步认识肿瘤血管生成机制,而且对判断肿瘤生物学行为、确定包括抗血管生成治疗在内的肿瘤治疗策略以及评价疗效,都具有十分重要的生物学和肿瘤临床意义。     

血管内皮生长因子在肝癌中的表达及其与肝癌转移的关系

肿瘤的生长和转移是一个多步骤的复杂过程，其中肿瘤血管的生成起重要的作用。迄今为止，血管内皮生长因子（ＶＥＧＦ）被认为是肿瘤组织中促血管生成的最主要的血管生长因子。我们应用免疫组化和Ｎｏｒｔｈｅｒｎ印迹杂交技术从蛋白质水平和ＲＮＡ水平对ＶＥＧＦ在人原发...     

Angiogenesis: mechanistic insights,neovascular diseases,and therapeutic prospects

This review of angiogenesis aims to describe (a) stimuli that either elicit or antagonize angiogenesis, (b) the response of the vasculature to angiogenic or antiangiogenic stimuli, i.e., processes required for the formation of new vessels, (c) aspects of angiogenesis relating to tissue remodeling and disease, and (d) the potential of angiogenic or antiangiogenic therapeutic measures. Angiogenesis, the formation of new vessels from existing microvessels, is important in embryogenesis, wound healing, diabetic retinopathy, tumor growth, and other diseases. Hypoxia and other as yet ill-defined stimuli drive tumor, inflammatory, and connective tissue cells to generate angiogenic molecules such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor- (TGF-), platelet-derived growth factor (PDGF), and others. Natural and synthetic angiogenesis inhibitors such as angiostatin and thalidomide can repress angiogenesis. Angiogenic and antiangiogenic molecules control the formation of new vessels via different mechanisms. VEGF and FGF elicit their effects mainly via direct action on relevant endothelial cells. TGF- and PDGF can attract inflammatory or connective tissue cells which in turn control angiogenesis. Additionally, PDGF may act differently on specific phenotypes of endothelial cells that are engaged in angiogenesis or that are of microvascular origin. Thus phenotypic traits of endothelial cells committed to angiogenesis may determine their cellular responses to given stimuli. Processes necessary for new vessel formation and regulated by angiogenic/antiangiogenic molecules include the migration and proliferation of endothelial cells from the microvasculature, the controlled expression of proteolytic enzymes, the breakdown and reassembly of extracellular matrix, and the morphogenic process of endothelial tube formation. In animal models some angiogenesis-dependent diseases can be controlled via induction or inhibition of new vessel formation. Lifethreatening infantile hemangiomas are a first established indication for antiangiogenic therapy in humans. Treatment of other diseases by modulation of angiogenesis are currently tested in clinical trials. Thus the manipulation of new vessel formation in angiogenesis-dependent conditions such as wound healing, inflammatory diseases, ischemic heart and peripheral vascular disease, myocardial infarction, diabetic retinopathy, and cancer is likely to create new therapeutic options.Abbreviations VEGF Vascular endothelial growth factor - FGF Fibroblast growth factor - TGF Transforming growth factor - PDGF Platelet-derived growth factor - CAM Chorionic allantoic membrane assay     

Angiogenesis modulates the tumour immune response

Outgrowth of solid tumors and metastases is dependent on the process of angiogenesis. Tumors escape from the formation of an effective infiltrate by downregulation of endothelial adhesion molecules. This downregulation of adhesion receptors is governed by the exposure to angiogenic factors. In recent years proof for this has been provided by demonstrating that freshly isolated tumor endothelial cells exhibit a decreased expression of ICAM-1 and -2 as compared to endothelial cells in normal tissue. In addition, adhesion molecules are downregulated on normal tissue endothelial cells when cultured with angiogenesis stimulators such as basic fibroblast growth factor and vascular endothelial cell growth factor, while under these conditions endothelial cells become less responsive to cytokines such as tumor necrosis factor-alpha with respect to the upregulation of endothelial adhesion molecules. Very recently it has been demonstrated that this harmful endothelial cell anergy can be counteracted by inhibitors of angiogenesis.     

Basic fibroblast growth factor and its relation to angiogenesis in normal and neoplastic tissue

Summary Basic fibroblast growth factor is a protein widely distributed in the organism. It can stimulate the proliferation and differentiation of many cells and it is extremely potent in inducing angiogenesis, the formation of new blood vessels. In this article, some of its structural and biological properties are reviewed. In particular, the possible implications of basis fibroblast growth factor in normal and tumor angiogenesis are considered.Abbreviations bFGF basic fibroblast growth factor - kb kilobases - Mr relative molecular weight - pI isoelectric point - TAF tumor angiogenesis factor     

Immunogene therapy of tumors with a vaccine based on the ligand-binding domain of chicken homologous integrin beta3

The breaking of immune tolerance against angiogenesis-associated molecules should be a useful approach for cancer therapy by active immunity. We used chicken integrin beta3 as a model antigen to explore the feasibility of immunogene therapy of the tumors with a vaccine based on a single xenogeneic homologous gene, targeting the molecules associated with angiogenesis. To test this concept we constructed a plasmid DNA encoding the ligand-binding domain of chicken integrin beta3 (P-BD-C) and control vectors. We found that immunogene therapy of tumors with a vaccine based on the ligand-binding domain of chicken integrin beta3 (P-BD-C) was effective in both protective and therapeutic anti-tumor immunity in several tumor models in mice. Autoantibodies against integrin beta3 in sera of mice immunized with the ligand-binding domain of chicken integrin beta3 could be found by Western blot analysis and ELISA assay. The purified immunoglobulins were effective in the inhibition of endothelial cell proliferation in vitro, and in anti-tumor activity as well as in the inhibition of angiogenesis by adoptive transfer in vivo. The anti-tumor activity and the production of integrin beta3-specific autoantibodies (manifested by significantly elevated Ig G1 and Ig G2b) could be abrogated by the depletion of CD4+ T lymphocytes. These observations may provide a vaccine strategy for cancer therapy through the induction of the autoimmunity against the molecules associated with tumor growth in a cross-reaction with a single xenogeneic homologous gene and may be of importance in the further exploration of the applications of other xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.     

EGFL7在乳腺癌中的研究进展

表皮生长因子样结构域7是表皮生长因子样蛋白家族的成员,是一种极为关键的血管生成因子和血管发育调节因子,在不同类型细胞中均有表达。EGFL7在早期胚胎的血管中表达较高,主要调节发育过程中的血管生成,促进内皮细胞增殖,形成有功能的血管网,促进组织增长和再生。与其在胚胎期较强的表达相比,在成人体内的表达量微乎其微,异常高表达的EGFL7常在多种恶性肿瘤中出现。目前越来越多的证据表明,EGFL7可调节肿瘤血管生成、促进肿瘤转移和侵袭。肿瘤组织中EGFL7高表达常常提示肿瘤生长和转移较为活跃及不良的预后。近年来,一系列研究表明,EGFL7的表达与乳腺癌的发生发展、转移过程密不可分,且在提示预后方面发挥着关键作用。本文就EGFL7在乳腺癌中的研究进展作一综述,为临床诊断及治疗提供新思路。     

Angiogenesis: new insights and therapeutic potential

Angiogenesis, the formation of vessels from pre-existing vessels, is of critical importance not only during normal growth, but also in pathological situations. In the latter, some diseases are enhanced by excessive vascular growth (e.g., tumors), whereas in others inadequate vascular growth contributes to morbidity and mortality (e. g., ischemic heart disease). Our current state of knowledge makes it clear that the cascade of angiogenic events depends on complex processes that include cell-cell interactions, various intracellular signaling pathways, and the appropriate extracellular microenvironment. The literature regarding angiogenesis has increased exponentially during the last decade. Progress in this area is largely a consequence of advances in our understanding of angiogenic growth factor and cytokine function, in part due to the determination of their complete amino acid sequences and cloning of their genes. Other factors also play key roles in angiogenesis, including the extracellular matrix, adhesion molecules and their inhibitors, and metabolic and mechanical factors. The potential for developing therapeutic protocols has been enhanced by data from both in vitro and in vivo studies and has provided the rationale for clinic trials. Angiogenic therapy strategies include inhibition of aberrant angiogenesis, as seen in tumors or diabetes, as well as stimulation of angiogenesis in conditions of ischemia, such as ischemic heart or peripheral vascular disease. Anat Rec (New Anat) 261:126-135, 2000.     

Induction of angiogenesis by hyperplastic colonic mucosa adjacent to colon cancer

We determined whether hyperplastic mucosa adjacent to colon cancer contributes to neoplastic angiogenesis. Surgical specimens of human colon cancer (40 Dukes' stage B and 34 Dukes' stage C) were analyzed by immunohistochemistry for expression of proliferative and angiogenic molecules. The mucosa adjacent to Dukes' stage C tumors (but not Dukes' stage B tumors) had a higher Ki-67 labeling index and a higher expression of epidermal growth factor receptor and transforming growth factor-alpha than distant mucosa. The expression levels of vascular endothelial growth factor, basic fibroblast growth factor, interleukin-8, and the vascular density in the adjacent mucosa were similar to those in the tumor lesions and significantly higher than those in the distant mucosa. The expression of interferon-beta inversely correlated with the level of pro-angiogenic molecules and the vascular density. The injection of metastatic human colon cancer cells and murine colon cancer cells into the cecal wall of mice induced hyperplastic changes in the adjacent mucosa which expressed higher levels of epidermal growth factor receptor, basic fibroblast growth factor, and vascular endothelial growth factor, and lower levels of interferon-beta than did the control mucosa, which directly correlated with the degree of hyperplasia. These data suggest that metastatic human colon cancer cells can induce hyperplasia in the adjacent mucosa, which in turn produces angiogenic molecules that contribute to neoplastic angiogenesis.     

Angiogenesis in carcinosarcomas of the uterus: differences in the microvessel density and expression of vascular endothelial growth factor between the epithelial and mesenchymal elements.

Carcinosarcoma of the uterus is a highly aggressive neoplasm. However, the angiogenesis of this neoplasm is still unknown. This is the first study to examine the differences in angiogenesis between the epithelial and mesenchymal elements of this biphasic neoplasm. Surgical specimens from 21 primary uterine carcinosarcomas were histopathologically evaluated, and then immunohistochemically analyzed for tumor angiogenesis, using an anti-vascular endothelial growth factor (VEGF) antibody. The microvessel density (MVD) was also measured in each element of these neoplasms, using anti-CD34 monoclonal antibody. The MVD in the epithelial element was found to be higher than that of the mesenchymal element in 20 of 21 (95.2%) primary tumors. The epithelial elements showed a higher MVD (mean, 81.6 +/- 41.1) than the mesenchymal elements (mean, 36.7 +/- 23.8) in these primary tumors (P < .0001). Moreover, the epithelial elements showed a higher VEGF expression (mean, 0.78 +/- 0.23) than the mesenchymal elements (mean, 0.37 +/- 0.20) (P < .0001). The tumors with lymph-vascular invasion showed a higher VEGF expression (n = 17; mean, 0.85 +/- 0.17) than the tumors without lymph-vascular invasion (n = 4, mean, 0.47 +/- 0.12) (P < .01). Microscopically, neither lymph-vascular space invasion nor metastatic tumors consisted of sarcoma alone in this series. In addition, a decrease in the VEGF expression was found in the transitional areas between carcinomatous and sarcomatous elements in all 10 homologous and 4 heterologous tumors evaluated. These results suggest that the tumor angiogenesis in the epithelial element may be more active than that of the mesenchymal element and also substantiated the high metastatic potential of the epithelial element in uterine carcinosarcoma. Based on these findings, carcinoma cells thus may play a key role in the angiogenesis of this biphasic neoplasm.     

Tissue factor expression and angiogenesis in human prostate carcinoma

In tumors, the switch to the angiogenic phenotype is thought to be controlled by a balance of positive and negative angiogenic factors. Tissue factor (TF) produced by tumor cells has been implicated in the regulation of this "angiogenic switch" through its ability to concurrently induce the expression of angiogenic molecules such as vascular endothelial cell growth factor (VEGF), while inhibiting the expression of anti-angiogenic molecules such as thrombospondin 2. We have examined TF expression and its relationship to angiogenesis and tumor progression in human prostate carcinomas. Most of the prostate carcinoma specimens examined (73%; n = 67) express high levels of TF. Immunohistochemical analysis localized TF expression to the epithelial cells of malignant glands. TF expression was significantly correlated with tumor angiogenesis as measured by the microvessel density (MVD). In addition, TF expression was correlated with the preoperative PSA level, a strong predictor of recurrence in prostate carcinomas. Our findings show that TF expression by the malignant glands in prostate cancer is common and suggest a role for this molecule in regulating prostate cancer progression and angiogenesis.     

IMMUNOGENE THERAPY OF TUMORS WITH A VACCINE BASED ON THE LIGAND-BINDING DOMAIN OF CHICKEN HOMOLOGOUS INTEGRIN β3

The breaking of immune tolerance against angiogenesis-associated molecules should be a useful approach for cancer therapy by active immunity. We used chicken integrin β₃ as a model antigen to explore the feasibility of immunogene therapy of the tumors with a vaccine based on a single xenogeneic homologous gene, targeting the molecules associated with angiogenesis. To test this concept we constructed a plasmid DNA encoding the ligand-binding domain of chicken integrin β₃ (P-BD-C) and control vectors. We found that immunogene therapy of tumors with a vaccine based on the ligand-binding domain of chicken integrin β₃ (P-BD-C) was effective in both protective and therapeutic anti-tumor immunity in several tumor models in mice. Autoantibodies against integrin β₃ in sera of mice immunized with the ligand-binding domain of chicken integrin β₃ could be found by Western blot analysis and ELISA assay. The purified immunoglobulins were effective in the inhibition of endothelial cell proliferation in vitro, and in anti-tumor activity as well as in the inhibition of angiogenesis by adoptive transfer in vivo. The anti-tumor activity and the production of integrin β₃-specific autoantibodies (manifested by significantly elevated Ig G1 and Ig G2b) could be abrogated by the depletion of CD4⁺ T lymphocytes. These observations may provide a vaccine strategy for cancer therapy through the induction of the autoimmunity against the molecules associated with tumor growth in a cross-reaction with a single xenogeneic homologous gene and may be of importance in the further exploration of the applications of other xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.