Targeting angiogenesis in ovarian cancer

Results of standard chemotherapy in ovarian cancer are hampered by the development of drug resistance leading to disease recurrence. This prompted interest in the development of therapies targeting critical pathways responsible for tumor progression. Angiogenesis is a key process that enables ovarian cancer growth and metastasis in the peritoneal space. Its regulation relies on signaling mechanisms initiated by the vascular endothelial growth factor, the platelet-derived growth factor, the fibroblast growth factor, angiopoietins, and others. These pathways are not only important to the modulation of the tumor microenvironment and vasculature, but also control cancer cell proliferation and survival. In this review, we discuss preclinical evidence supporting the rationale for inhibiting these pathways and provide an overview for the clinical development of agents targeting them. Clinical trials evaluating such agents alone and in combination with chemotherapy are ongoing. Early clinical results position antiangiogenic therapy at the forefront of change to the standard treatment of difficult to treat ovarian cancer.     

血管生成素相关蛋白基因多态性与冠心病的关系

目的:研究中国人群血管生成素相关蛋白(ANGPTL3)基因单核苷酸多态性与冠心病的关系。方法:采用聚合酶链反应和限制性酶切的片段长度多态分析方法检测冠心病患者389例,健康人503例的AN-GPTL3基因 90782C/G多态性并统计各组的多态性频率。结果:冠心病亚组与对照组、冠心病心肌梗死组与对照组之间的基因型频率分布差异有统计学意义,C等位基因频率在冠心病组、冠心病心肌梗死亚组和对照组分别为49.6%、51.5%和41.6%(P<0.05)。结论:ANGPTL3基因rs1168013位点C/G多态性与中国人冠心病心肌梗死发病相关,ANGPTL3可能是冠心病发病的易感基因。     

血管生成素样蛋白1和2水平在急性心肌梗死患者中的表达及临床意义

目的 探讨血管生成素样蛋白1（Ang-1）和血管生成素样蛋白2（Ang-2水平）在急性心肌梗死（AMI）患者中的表达以及与肌钙蛋白T（cTnT）的相关性.方法 选取AMI患者75例,同期选择健康体检者50例为对照组,采用酶联免疫吸附试验（ELISA）和化学发光法分别检测研究对象中Ang-1、Ang-2和cTnT水平,并与对照组作比较.结果 AMI患者Ang-2、Ang-2/Ang-1水平分别为（2310.2±131.6） ng/L和（11.9±1.3）,显著高于对照组的（905.8±171.4） ng/L和（4.6±1.8）,差异有统计学意义（P＜ 0.05）;AMI患者Ang-1水平为（19 589.3±2033.4） ng/L,对照组为（19 612.1±1824.1） ng/L,差异无统计学意义（P＞0.05）.Ang-2水平和Ang-2/Ang-1与cTnT均呈正相关（r=0.597,0.604,P＜0.05）.结论 高Ang-2水平和Ang-2/Ang-1是心肌梗死的危险因素,并与cTnT正相关.     

Expression and significance of Tie-1 and Tie-2 receptors, and angiopoietins-1, 2 and 4 in colorectal adenocarcinoma： Immunohistochemical analysis and correlation with clinicopathological factors

AIM: There is strong evidence that tyrosine kinases are involved in the regulation of tumor progression, cellular growth and differentiation. Recently, many kinds of tyrosine kinase receptors have been reported, among them Tie-1 and Tie-2 receptors constitute a major class. Angiopoietin (Ang)-1 is known as a ligand of Tie-2 tyrosine kinase receptor. The objective of this study was to establish a comprehensive Tie-1 and Tie-2 and Ang-1, 2 and 4 expression profile in human colorectal adenocarcinomas. METHODS: We examined 96 cases of surgically resected human colorectal adenocarcinoma by immunohistochemistry and investigated the statistical correlation between the expressions of Ties and Angs and clinicopathological factors. RESULTS: Among the 96 cases of adenocarcinoma, 87 (90.6%), 92 (95.8%), 83 (86.5%), 89 (92.7%), and 76 cases (79.2%) showed positive staining in the cytoplasm of carcinoma cells for the Tie-1 and Tie-2 and Ang-1, 2 and 4 proteins, respectively. Histologically, the expressions of Ties and Angs were variable. The expressions of Ties and Angs were correlated with several clinicopathological factors, but did not correlate with the presence of lymph node metastasis. Ties and Angs were highly expressed in human colorectal adenocarcinoma cells. CONCLUSION: These findings suggest that the Tie-Ang receptor-ligand complex is one of the factors involved in the cellular differentiation and progression of human colorectal adenocarcinoma.     

Angiopoietin balance in septic shock patients with acute lung injury: effect of direct hemoperfusion with polymyxin B-immobilized fiber

Acute lung injury (ALI) in sepsis is characterized by an increase in microvascular permeability, resulting in pulmonary edema. Several studies have suggested that angiopoietin-1 and -2 play a contributory role in the pathogenesis of ALI. Polymyxin B-immobilized fiber column hemoperfusion is effective for sepsis-induced ALI. We investigated the angiopoietin levels before and after direct hemoperfusion with polymyxin B-immobilized fiber column (PMX) therapy. Enzyme-linked immunoassay was used to measure the serum angiopoietin-1 and -2 levels in 25 patients with septic shock treated with PMX. Eleven of the 25 patients were diagnosed with ALI. There was a significant positive correlation between the angiopoietin-1 level and the PaO(2) /FiO(2) ratio, but there was a significant inverse correlation between the angiopoietin-2 level and the PaO(2) /FiO(2) ratio. The mean angiopoietin-1 level before PMX therapy in the ALI group was significantly lower and the mean angiopoietin-2 level was significantly higher than in the non-ALI group. The mean angiopoietin-1 level of the ALI patients in response to PMX therapy was increased during PMX therapy, but that of the non-ALI patients with newly occurring ALI showed a decreased angiopoietin-1 level. On the other hand, the mean angiopoietin-2 level of the responders was decreased during PMX therapy, but that of patients with newly occurring ALI showed an increased angiopoietin-2 level. This result suggested that each angiopoietin-1 and -2 level may play a role in the pathogenesis of ALI and that PMX therapy ameliorates the angiopoietin balance in patients with ALI in sepsis.     

多发伤患者早期血浆血管生成素2水平变化与内皮损伤和预后的关系

目的 探讨多发伤患者早期血浆血管生成素2(angiopoietin2,Ang2)的水平变化与血管内皮损伤和预后的关系及临床意义.方法 为前瞻性观察研究,选择2008年1月至2010年1月收入聊城市人民医院急诊科的多发伤患者59例,纳入标准:创伤至入院时间在1 h以内;年龄大于18周岁;既往身体健康,排除有心、脑、肝、肾等器质性疾病,糖尿病、高血压,肿瘤;急慢性感染性疾病;严重颅脑损伤(GCS<12分);两周前用过抗凝及溶栓类药物患者.共纳入59例患者包括男36例,女23例,年龄(32.3±11.5)岁.按创伤严重度评分(ISS)分为重伤组(ISS≥16分,29例),轻伤组(ISS<16分,30例)2组.另取30例健康人为健康对照组,均为接受体检的健康人.其中男19例,女11例,年龄均大于18周岁,年龄(33.5±10.6)岁.各组性别、年龄构成均具有可比性.患者到达急诊科后10 min内抽取外周静脉血 10 mL,分离血浆.应用酶联免疫吸附法(ELISA)测定血浆Ang2的水平.同时测定血浆冯·维勒布兰德因子(Von Willebrand factor,vWF)、血栓调节蛋白(thrembomodulin,TM)的水平.统计数据用均数±标准差(-x±s)表示,所有数据采用SPSS 13.0统计软件进行统计分析.应用单因素方差分析和两两比较的Q检验(Newman-Keuls法)比较分析各组Ang2的水平差异.采用成组资料t检验比较分析死亡和生存患者Ang2的水平.采用pearson相关分析法分析Ang2水平与血浆vWF,TM的相关性.以P<0.05为差异具有统计学意义.结果 重伤组(ISS≥16分)血浆Ang2水平明显高于轻伤组(ISS<16分)(P<0.05),两组均明显高于正常对照组(P<0.05).死亡组血浆Ang2水平明显高于生存组(P<0.05).创伤后Ang2水平变化与血浆vWF,TM水平均有明显相关性(P<0.05).结论 血浆Ang2水平在多发伤早期明显增高,和创伤严重程度相关,和创伤后内皮损伤相关,其对预后有重要的预测价值.

Abstract：

Objective To investigate the early changes of plasma levels of angiopoietin2 in patients with multiple trauma and the relationship between plasma levels of angiopoietin2 (Ang2) and endothelial injury as well as prognosis of patients in order to determine their clinical significance. Methods Patients with multiple trauma admitted to emergency department from January 2008 to January 2010 were enrolled. A total of 59 casualties met the criteria(admission within 1 h after trauma and age > 18 years), and were eligible for enrollment. Patients with heart, brain, liver, kidney and other organic diseases, diabetes, hypertension, tumor, acute and chronic infectious diseases , severe brain injury (CCS < 12 points) , anticoagulant and thrombolytic medicine used two weeks before trauma were excluded. Among 59 patients, 36 were males and 23 females. The average age was(32.3 ±11.5) years. Patients were divided into severe trauma group (ISS ≥16 points,n =29) , moderate trauma group (ISS < 16 points, n =30 ) judged by using injury severity score (1SS). Thirty healthy subjects were selected as controls, 19 male and 11 female, with age > 18 years and an average age of(33.5 ±10.6) years. All groups had comparable gender proportion and average age. The 10 mL peripheral blood sanple was collected within 10 minutes after arrival of patients to emergency department and the plasma was separated from blood. Enzyme-linked immunosorbent assay (ELISA) was used to detect the plasma levels of angiopoietin2, and the plasma levels of von Willebrand factor (vWF) and thrombomodulin (TM) were also detected. Data were expressed as mean ± standard deviation and were statistically analyzed by using SPSS version 13.0 statistical software. The differences in plasma levels of angiopoietin2 of patients in each group were analyzed by ANOVA and Newman-Keuls test. Levels of angiopoietin2 in fatal patients and survival patients were also compared by using t test. The relationships between angiopoietin2 and plasma levels of vWF as well as levels of TM were analyzed by Pearson correlation analysis. Changes were considered as statistically significant if P value was less than 0.05. Results The plasma levels of angiopoietin2 in severe trauma group (ISS scored 16 points) were significantly higher than those in moderate trauma group (ISS < 16 points) ( P < 0.05 ), and those in trauma patients of the two groups were both significantly higher than those in control group (P < 0.05). The plasma levels of angiopoietin2 in fatal patients were significantly higher than those in survivors (P < 0.05). Plasma levels of angiopoietin2 were significantly correlated with plasma levels of vWF and TM (P < 0.05). Conclusions The plasma levels of angiopoietin-2 significantly increase after multiple trauma, and correlate with the degree of trauma severity. The plasma levels of angiopoietin2 correlate with endothelial injury after multiple trauma, having important prognosis value in patients with multiple trauma.     

Antisense angiopoietin-1 inhibits tumorigenesis and angiogenesis of gastric cancer

AIM: To investigate the effect of angiopoietin-1 (Ang-1) on biological behaviors in vitro and tumorigenesis and angiogenesis in vitro of human gastric cancer cells. METHODS: Human full-length Ang-1 gene was cloned from human placental tissues by RT-PCR method. Recombinant human Ang-1 antisense eukaryotic expression vector was constructed by directional cloning, and transfected by lipofectin method into human gastric cancer line SGC7901 with high Ang-1 expression level. Inhibition efficiency was confirmed by semi- quantitive PCR and Western blot method. Cell growth curve and cell cycle were observed with MTT assays and flow cytometry, respectively. Nude mice tumorigenicity test was employed to compare in vitro tumorigenesis of cells with Ang-1 suppression. Microvessel density (MVD) of implanted tumor tissues was analyzed by immunohistochemistry for factorⅧstaining. RESULTS: Full-length Ang-1 gene was successfully cloned and stable transfectants were established, namely 7Angl- for antisense, and 7901P for empty vector transfected. 7Angl- cells showed down-regulated Ang-1 expression, while its in vitro proliferation and cell cycle distribution were not significantly changed. In contrast, xenograft of 7Angl- cells in nude mice had lower volume and weight than those of 7901P after 30 days' implantation (p<0.01, 293.00±95.54 mg vs. 624.00±77.78 mg) accompanied with less vessel formation with MVD 6.00±1.73 compared to 7901P group 8.44±1.33(p<0.01). CONCLUSION: Ang-1 may play an important role in tumorigenesis and angiogenesis of gastric cancer, and targeting its expression may be beneficial for the therapy of gastric cancer.     

The Tie2 Receptor Antagonist Angiopoietin-2 in Systemic Lupus Erythematosus: Its Correlation with Various Disease Activity Parameters

Background: Systemic lupus erythematosus is one of the autoimmune diseases characterized by multisystem involvement associated with autoantibody and immune complex vasculitis along with endothelial cell damage. Objective: to study the possible role of Angiopoietin- 2 (Ang-2) as a recently highlighted inflammatory and angiogenic mediator in the pathogenesis of SLE and its correlation with the state of another inflammatory marker, P-Selectin, as well as with various markers of the disease activity. Patients and methods: The present study included 3 main groups: active SLE patients (group I), inactive SLE patients (group II) and healthy normal control subjects (group III). Groups I and II were subjected to disease activity assessment using the SLEDAI scoring system and measurement of plasma Ang-2 and P-Selectin by ELISA in addition to various laboratory investigations to assess disease activity as: Complete blood count, ESR, serum creatinine, C3, C4 and 24-h urinary proteins. Results: The mean level of Plasma Ang-2 and P-selectin showed a high significant increase in active group compared to inactive SLE patients and control subjects (p < 0.001).There was a significant positive correlation between Ang-2, P-Selectin, and each of SLEDAI score and 24-h urinary proteins in all SLE patients as well as in the active group, and Ang-2 was a significant independent marker for proteinuria. A significant negative correlation was found between Ang-2, P-Selectin and each of C3, C4. Ang-2 and P-Selectin showed a high sensitivity and specificity in the patients with SLE. Conclusion: Our study suggests that Ang-2 may be a more useful marker than P-Selectin, C3 and C4 in the assessment of disease activity.     

慢性肝炎和原发性肝癌患者血管生成素的表达比较及其与血管生成之间的关系

目的探讨原发性肝癌和慢性肝炎组织中血管生成素-1（Ang-1）、血管生成素-2（Ang-2）的表达与血管生成间的关系。方法应用免疫组织化学方法对26例原发性肝癌组织以及58例慢性肝炎组织中Ang-1、Ang-2及CD34标记的微血管密度（MVD）进行检测。结果原发性肝癌组织中Ang-2表达明显高于慢性肝炎组织,差异有显著性（P〈0．05）;而Ang-1在两组间比较无显著性差异（P〉0．05）。原发性肝癌组织中MVD水平明显高于慢性肝炎组织,两组比较差异有显著性（P〈0．05）。相关性分析表明,Ang-2与原发性肝癌肿瘤大小、分级、有无转移、MVD水平相关。慢性肝炎组织中Ang-1、Ang-2表达随着炎症程度分级和纤维化程度分期越高表达越强,但将各分期合并为不同的组合后,各组间比较无显著性差异（P〉0．05）。结论血管生成在慢性肝炎发展到肝癌中起重要作用,但Ang-1、Ang-2作为一种重要的血管生成因子,其在促进慢性肝炎发展到肝癌中的证据还不是很充分,机制还有待进一步研究。     

Vascular characterization of clear cell sarcoma of the kidney in a child: a case report and review

Clear cell sarcoma of the kidney (CCSK) is uncommon pediatric renal tumor and can present a significant therapeutic challenge in those patients whose tumors spread beyond the kidney. Thus, identifying potential novel targets for treatment may be clinically important. Clear cell sarcoma of the kidney is characterized by a unique vascular pattern, in which nests of tumor cells are separated by regularly-spaced, fine fibrovascular septa. This distinctive histopathology raises the possibility that understanding the factors which drive angiogenesis in CCSK tumors may suggest new therapeutic targets. Here, we describe a case of CCSK and present immunohistochemical studies of its vasculature.