血管新生与疾病

很多疾病均伴有血管的变化。血管 ,特别是微血管 ,常与组织、器官的生长、发育和功能密切相关。疾病时它们发生相应的改变。有些疾病的发生发展和治疗与微血管新生有密切的联系 ,治疗时要抑制血管新生 ,如肿瘤等 ;有些疾病的发生发展有微血管的闭塞和退化 ,治疗时要促进微血管新生 ,如血栓性疾病等。因此近年来血管新生与疾病的关系在整体、细胞和分子水平上开展了广泛的研究 ,下面作一简要介绍。１肿瘤的血管新生与抗血管新生治疗１．１肿瘤血管新生肿瘤是人体细胞异常分化增殖的恶性疾病。肿瘤在表现其生长、转移等生物学行为时与其中的微…     

血管新生抑制剂的研究进展

肿瘤的发生和转移依赖于血管新生 ,这一概念的提出为肿瘤及血管新生相关性疾病的治疗提供了新的方法。基于对肿瘤血管新生机制、血管新生抑制剂的作用机制及特点的研究 ,目前已开发出了多种血管新生抑制剂 ,其中多数已进入了临床实验     

VEGF、bFGF与抗肿瘤血管新生治疗

1 血管新生与肿瘤 血管新生与肿瘤生长有非常密切的关系,实体瘤要超过 2 mm2以上,必须要有新生血管的支持才能与肿瘤宿主的血管系统保持一定的连续性,而且肿瘤的转移和转移部位的生长也有赖于肿瘤组织血管新生。因此,血管新生是肿瘤增生、扩散和微转移灶发展的重要条件之一。开发新生血管生成抑制剂成为目前肿瘤治疗研究的一个新策略。主要优势在于:（1）血管生成抑制剂针对的是血管内皮细胞,血管内皮细胞遗传特性比较稳定,不易产生耐药性,也     

以抑制肿瘤新生血管为靶点的抗肿瘤药物研究进展

恶性肿瘤的生长和转移与肿瘤区域的血管密切相关,肿瘤区域的新生毛细血管是肿瘤赖以生长和生存的物质基础,肿瘤细胞需要新生血管为迅速生长的肿瘤提供营养物质和排出废物。早在七十年代初就有人提出把抑制肿瘤血管形成作为肿瘤治疗的一种途径,以后这种以肿瘤血管为靶标的治疗策     

治疗性血管新生的研究进展

近年来，随着对血管新生(angiogenesis)和血管生长因子研究的不断深入，治疗性血管新生(ther-aputic angiogenesis)的概念日益受到重视，即将外源性血管新生因子转入组织中增强缺血区的侧枝毛细血管新生。本文旨在综述近年来治疗性血管新生的研究进展。     

双特异抗体增效内皮祖细胞移植促进心肌血管新生

目的探讨在双特异抗体(BiAb)的辅助下,内皮祖细胞(EPCs)移植可否更好的定向归巢大鼠缺血心肌促进血管新生。方法体外分离培养鉴定SD大鼠骨髓源性内皮祖细胞;开胸结扎SD大鼠冠状动脉左前降支制备心肌梗死模型;以anti-CD34(能识别内皮祖细胞)和抗肌凝蛋白轻链抗体(AMLCA)(能特异性结合缺血心肌)2种抗体,化学交联法制备BiAb(CD34×AMLCA)。将此BiAb与EPCs经尾静脉输入心肌梗死大鼠(EPCs+BiAb组),另设单纯EPCs移植组、单纯BiAb组、对照组。细胞移植35 d后M型超声心动图检测大鼠左室收缩功能,免疫组织化学法行5-Brdu及VIII因子检测,实时荧光定量PCR及Western blot检测大鼠心肌VEGF mRNA与蛋白表达。结果与其余组相比,EPCs+BiAb组射血分数及短轴缩短率增加,心梗区周围5-BrdU阳性细胞数及微血管密度增加,心肌VEGF mRNA与蛋白表达增加(P<0.05)。结论 CD34×AMLCA双特异抗体可增效大鼠骨髓源性内皮祖细胞定向归巢到大鼠缺血心肌,改善心功能,更好的促进血管新生。     

前列腺素与血管新生

前列腺素(prostaglandins,PGs)是机体中由前列腺素环氧合酶催化细胞膜磷脂产生的一族二十碳不饱和脂肪酸,具有广泛的生物学活性。前列腺素具有强大的促进血管新生的作用,它们不仅可以介导炎症、发热和疼痛,而且在肿瘤的发生、发展、转移、预后及缺血性心脏病的治疗中具有重要作用。     

血管生成素与肿瘤新生血管生成

血管生成素Angiopoietin是特异性作用于血管内皮细胞的生长因子,主要由Angiopoietin-1和Angiopoietin-2组成.Tie-2是其共同受体.Angiopoietin-1能保持血管内膜的稳定性,与VEGF协同作用,促使血管成熟.Angiopoietin-2能拮抗Angiopoietin-1的作用,破坏血管的稳态.在肿瘤血管生成过程中,Angiopoietin-2表达于肿瘤侵袭的最前沿,是血管产生的早期信号.阻断Angiopoietin/Tie-2通路可能拮抗肿瘤的血管生成.     

CXC趋化因子与肿瘤血管新生

趋化因子在免疫调节、血管新生以及介导肿瘤的器官特异性转移中发挥重要作用。其中CXC趋化因子超家族由于N-端谷氨酸-亮氨酸-精氨酸基序(Glu-Leu-Arg,ELRmotif)的有无使其在血管新生过程中具有了促进或者抑制血管新生的不同作用:含有ELR(ELR )的CXC趋化因子经血管内皮组织上CXCR2介导血管新生促进作用;而不含有ELR(ELR-)的CXC趋化因子通过血管内皮组织上CXCR3介导血管新生抑制作用。     

血管新生与血液系统恶性肿瘤

血管新生（Ａｎｇｉｏｇｅｎｅｓｉｓ）是指通过内皮细胞的增殖和迁移,从先前存在的血管处以发芽或非发芽（又称套迭）的形式生成新的毛细血管［１］,是近年来新兴的一个医学研究领域,几乎涉及到医学领域的各个学科。血管新生受一系列刺激和抑制因子调节,这些因子控制着内皮细胞的增殖和迁移,对血管新生具有调节作用［２＿４］。其中主要的血管新生剌激因子有碱性纤维蛋白生长因子（ｂＦＧＦ）和血管内皮生长因子（ＶＥＧＦ）,主要的血管新生抑制因子有血管抑素（ａｎｇｉｏｓｔａｔｉｎ）、内皮抑素（ｅｎｄｏｓｔａｔｉｎ）、血小板第４…     

抗人VEGF单抗的研制及对肿瘤生长及转移的抑制作用

为了确定人血管内皮细胞生长因子在肿瘤生长及转移中的作用。方法：利用ＤＮＡ重组技术表达人ＶＥＧＦ,以其为抗原免疫Ｂａｌｂ／ｃ小鼠,应用杂交瘤技术获得１４株稳定分泌抗ＶＥＧＦ单抗的杂交瘤细胞株。结果ＥＬＩＳＡ测定所分泌的单抗只与ＶＥＧＦ特异结合,与ＥＧＦ、ＦＧＦ、ＰＤＧＦ、ＴＧＦα及ＴＮＦ等均无交叉反应。     

单克隆抗体在肿瘤治疗中的应用进展

近年来用于肿瘤治疗的单克隆抗体药物发展迅速.单克隆抗体与肿瘤细胞上特异性的抗原分子结合,通过抗体依赖性细胞介导的细胞毒作用和补体依赖性细胞毒作用等机制实现杀灭肿瘤细胞的目的.临床抗肿瘤单抗的靶分子主要包括表皮生长因子受体、血管内皮生长因子和部分白细胞分化抗原,用于淋巴瘤、自血病、乳腺癌、直结肠癌、肺癌等领域的治疗已取得瞩目的疗效.     

A new monoclonal antibody to human subcapsular thymic epithelial cells

Summary A monoclonal antibody, termed K-20, was generated against an anaplastic thymic carcinoma cell line, Ty-82. Subcapsular thymic epithelial cells of the thymus and blood vessels in various organs were shown to react with the K-20 monoclonal antibody by immunohistochemical staining. Immunofluorescent study revealed that various haematopoietic fresh cells and cell lines did not show any significant reactivity with K-20, except for one Epstein-Barr-virus-carrying lymphoma cell line (SP-50B). Western immunoblotting and affinity purification procedure revealed that K-20 was directed to a protein with a molecular weight of 28 kDa. K-20 is unique in its restrictive reactivity with human subcapsular thymic epithelial cells.     

Stimulation of angiogenesis and survival of endothelial cells by human monoclonal Tie2 receptor antibody

Angiopoietin-1 (Ang1) and its endothelium-specific receptor, tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2), play critical roles in vascular development. Although the Ang1/Tie2 system has been considered a promising target for therapeutic neovascularization, several imitations of large-scale production have hampered the development of recombinant Ang1 for therapeutics. In this study, we produced a fully human agonistic antibody against Tie2, designated 1–4h, and tested the applicability of 1–4h as an alternative to native Ang1 in therapeutic angiogenesis. 1–4h significantly enhanced the phosphorylation of Tie2 in a dose- and time-dependent manner in human Tie2-expressing HEK293 cells and human umbilical vein endothelial cells. Moreover, 1–4h induced the activation of Tie2-mediated intracellular signaling such as AKT, eNOS, MAPK, and Focal Adhesion Kinase p125^FAK. In addition, 1–4h increased the chemotactic motility and capillary-like tube formation of endothelial cells in vitro and enhanced the survival of serum-deprived endothelial cells. Taken together, our data clearly suggest that a human Tie2 agonistic antibody is a potentially useful therapeutic approach for the treatment of several ischemic diseases including delayed-wound healing and ischemic heart and limb diseases.     

Production of two novel monoclonal antibodies that distinguish mouse lymphatic and blood vascular endothelial cells

We produced two novel rat monoclonal antibodies (LA102 and LA5) to identify mouse lymphatic vessels and blood vessels, respectively. We characterized the two antibodies as to the morphological and functional specificities of endothelial cells of both types of vessels. The antibodies were produced by a rapid differential immunization of DA rats with collagenase- and neuraminidase-treated mouse lymphangioma tissues. LA102 specifically reacted with mouse lymphatic vessels except the thoracic duct and the marginal sinus of lymph nodes, but not with any blood vessels. In contrast, LA5 reacted with most mouse blood vessels with a few exceptions, but not with lymphatics. LA102 recognized a protein of 25–27 kDa, whereas LA5 recognized a molecule of 12–13 kDa. Neither antibody recognized any currently identified lymphatic or vascular endothelial cell antigens. Immunoelectron microscopy revealed that the antigens recognized by LA102 and LA5 were localized on both luminal and abluminal endothelial cell membranes of each vessel type. Interestingly, LA102 immunoreactivity was strongly expressed on pinocytic or transport vesicle membrane in the cytoplasm of lymphatic endothelium. Besides endothelial cells, both antibodies also recognized some types of lymphoid cells. Since, the LA102 antigen molecule is expressed on some lymphoid cells, it may play important roles in the migration of lymphoid cells and in some transport mechanisms through lymphatic endothelial cells.     

The role of vascular endothelial cells in tumor metastasis

Vascular endothelial cells (VECs) are an integral component of the inner lining of blood vessels, and their functions are essential for the proper functioning of the vascular system. The tight junctions formed by VECs act as a significant barrier to the intravasation and extravasation of tumor cells (TCs). In addition to that, the proliferation, activation, and migration of VECs play a vital role in the growth of new blood vessels, a process known as tumor angiogenesis, which is closely related to the malignant progression of tumors. However, during tumor progression, VECs undergo endothelial-to-mesenchymal transition (EndMT), which further promotes tumor progression. Furthermore, VECs act as the first line of defense against effector immune cells and help prevent immune cells from infiltrating into tumor tissues. VECs also secrete various cytokines that can contribute to regulating the stemness of tumor stem cells. Thus, it has been increasingly recognized that dysfunction of VECs is one of the key driving forces behind tumor metastasis, and therapeutic strategies targeting VECs have the potential to be an effective means of antitumor therapy. This review aims to present a comprehensive overview of the role and mechanisms of VECs in regulating tumor progression and metastasis, providing insights into the possibilities for the development of novel antitumor therapies that target VECs.     

A monoclonal antibody detecting dipeptidylpeptidase IV in human tissue

Summary Dipeptidylpeptidase IV (DPP IV) occurs among others in exocrine epithelia, hepatocytes, renal tubuli, endothelia, and myofibroblasts of man and laboratory animals. Also Tµ lymphocytes and their varying differentiated neoplastic counterparts reveal this enzyme activity. The present paper describes a new monoclonal antibody recognizing DPP IV.Additional efforts have been taken to detect the subcellular localization of DPP IV and its isoelectric focusing pattern in different tissue types. The monoclonal antibody anti-DPP IV (clone II-19) shows a reaction pattern indistinguishable from the corresponding enzymehistochemical reaction. These findings were further substantiated by immunoblotting analysis. In line with the results of direct enzyme measurements in different subcellular fractions a considerable portion of the enzyme is localized in the membrane fraction.Dedicated to Professor Dr.Dr. h.c. Karl Lennert, Kiel, on the occasion of his 65th birthdayThis study was supported by the Deutsche Forschungsgemeinschaft, SFB 111, program CL1     

Usefulness of a novel monoclonal antibody against human osteocalcin in immunohistochemical diagnosis

Summary A novel monoclonal antibody against human osteocalcin, recently established in our laboratory, was shown by immunoblotting and immunohistochemistry to react specifically with human osteoblasts. In the present study, the antibody was applied to the immunohistochemical diagnosis of human bone tumours, especially osteoblastic tumours. The antibody reacted with all 27 osteosarcomas. No positive reaction was found either in chondrosarcoma, giant cell tumours of bone, soft tissue tumours or epithelial tumours. A positive reaction was found preferentially in the cytoplasm of most of the osteosarcoma cells, but not in the extracellular matrix. Since the antibody reacted with formalin-fixed and paraffin-embedded tissues, it will be a useful tool for routine immunohistochemical diagnosis of osteoblastic lesions.     

抗人结肠癌相关抗原单克隆抗体的制备及初步研究

目的：制备抗人结肠癌相关抗原的单克隆抗体4D10，运用组织芯片技术研究其与人结肠癌组织反应的情况。方汪：用人结肠癌细胞株LOVO免疫小鼠，用间接细胞ELISA和免疫组化的方法筛选抗结肠癌相关抗原的单抗。结果：获得一株能够稳定分泌抗人结肠癌相关抗原的杂交瘤细胞株。4D10能够与不同分期的结肠癌组织切片反应，且与正常组织和其他癌组织几乎不反应。结论：4D10对结肠癌的病理分期及预后结果都具有一定的临床参考价值。     

人TEM7膜外段单克隆抗体的制备及其在不同来源肿瘤组织中的定位研究

目的　利用制备的抗人肿瘤血管内皮标志物 7(TEM7)单克隆抗体通过免疫组织化学的方法 ,检测TEM7蛋白在不同来源的肿瘤组织中的定位 ,为以TEM7为靶标的肿瘤血管导向治疗提供必要的理论基础。方法　利用PCR的方法 ,将TEM7膜外段重组到原核表达载体pET 32b中 ,在大肠杆菌中表达 ,蛋白经离子吸附层析纯化后免疫雌性BALB/c小鼠 ,传统的杂交瘤融合技术制备鼠抗人TEM7膜外段单克隆抗体。以酶联免疫吸附实验 (ELISA)、Westernblot筛选及鉴定分泌特异性抗人TEM7膜外段单克隆抗体的杂交瘤细胞株。最后采用免疫组织化学ABC的方法 ,分别对不同来源的70例肿瘤组织及癌旁正常组织进行了TEM7蛋白定位的研究。结果　制备了抗人TEM7单克隆抗体 ,经过Westernblot鉴定具有高度的特异性。对肿瘤及癌旁正常组织免疫组织化学ABC染色的结果可见TEM7蛋白定位于 :大肠癌、胃癌、乳腺癌、肺癌、肝细胞癌、肾细胞癌和前列腺癌的血管内皮细胞 ;大肠癌、胃癌、乳腺癌、肺癌和肝细胞癌的肿瘤细胞 ;大肠癌、胃癌和乳腺癌的血管平滑肌细胞 ;胃癌的胃壁平滑肌细胞 ;肝细胞癌的胆管上皮细胞。结论　成功制备了特异性抗人TEM7膜外段的单克隆抗体 ;TEM7在肿瘤组织中并非特异性地表达于肿瘤血管内皮细胞 ,还可见于肿瘤组织的癌细胞、血管平滑