血管内皮生长因子在肺癌组织中表达的研究

目的　观察血管内皮生长因子 (VEGF)表达、肺癌组织微血管密度 (MVD)和肺癌临床病理指标及预后的关系 ,探讨VEGF的作用机制。　方法　应用免疫组化方法检测 6 0例肺癌患者肺癌组织标本MVD及VEGF的表达。　结果　①VEGF在肿瘤细胞、肺癌组织内巨噬细胞呈阳性 ,部分血管内皮细胞及成纤维细胞也呈弱阳性。②肺癌组织MVD计数在肺癌各项临床病理指标中无显著性差异 ,P >0 0 5 ;VEGF表达在不同N分期 (淋巴结转移 )及临床分期之间存在显著性差异 ( P <0 0 1,P <0 0 5 ) ,并随淋巴结转移及临床分期的进展而有逐渐增强的趋势。③血管高密度组VEGF表达阳性率为 77 4 %,明显高于血管低密度组 ( 44 8%) ,P <0 0 1。④CoxRegression风险比例模型分析 ,肺癌临床分期及VEGF表达可作为判断肺癌患者预后的独立指标。　结论　①VEGF可由肿瘤细胞、巨噬细胞及部分血管内皮细胞及成纤维细胞等多种细胞产生 ,通过旁分泌作用促进肿瘤血管生成。②VEGF在肺癌淋巴结转移及临床分期中起重要作用 ,并可作为判断肺癌患者预后的参考指标之一。     

血管瘤中血管内皮生长因子及其受体KDR的表达和血管生成的研究

目的 探讨血管内皮生长因子(VEGF)及其受体KDR在血管瘤中的表达以及其与微血管密度(MVD)的关系.方法 采用免疫组化SP法检测35例婴幼儿血管瘤VEGF及KDR的表达和MVD.结果 35例血管瘤中VEGF、KDR的蛋白表达阳性率分别是66.5%,73.4%.其中增生期和消退期VEGF阳性率分别为92.1%、31.4%(P<0.01),KDR阳性率分别为89.3%、42.5%(P<0.01);MVD分别为75.7±13.71、28.9±8.5(P<0.01).KDR的表达与VEGF成正相关(P<0.01),KDR和VEGF与MVD都成正相关(P<0.01).结论 血管瘤增生期血管内皮细胞存在着血管内皮细胞生长因子及其受体KDR的相互作用,促进了新生微血管生成.     

大肠癌组织血管内皮生长因子及其受体的表达与肿瘤血管生成的关系

目的探讨血管内皮生长因子(VEGF)及其受体(KDR)的表达与人大肠癌组织血管生成的关系.方法采用免疫组织化学SABC法观察了68例人大肠癌组织中的VEGF及KDR的定位与分布,并对血管进行染色及计数.结果68例大肠癌组织中VEGF表达阳性率为55.9%(38/68),阳性物质主要位于肿瘤细胞膜及胞浆KDR表达阳性率为45.6%(31/68),既可位于癌组织及癌组织旁的血管内皮细胞,又可位于肿瘤细胞胞膜及胞浆.VEGF表达与大肠Dukes分期密切相关.VEGF表达阳性大肠癌组织的微血管密度(MVD)(31.2±12.6)显著高于VEGF表达阴性(12.7±6.3)(P＜0.01),而且随着VEGF表达强度的增强,癌组织内微血管密度明显增加(P＜0.01).结论大肠癌细胞分泌的VEGF既可以旁分泌的形式促进肿瘤血管的生成,也可能存在着自分泌形式,VEGF与大肠癌的生长、浸泣和转移密切相关,是大肠癌主要的血管新生诱导因子之一,可促进大肠癌的血管生成.     

颌面部血管瘤VEGF及其受体的表达及意义

为探讨血管内皮生长因子（VEGF）及其受体（VEGFR／KDR）在颌面部血管瘤发生、发展中的作用，采用二步En Vision免疫组织化学方法，分别检测11例血管瘤（HA）和8例血管畸形（VM）组织中VEGF和VEGFR／KDR的表达；同时采用原位杂交Gene Point法检测VEGF mRNA的表达。结果显示，VEGF和VEGFR／KDR在HA中高表达，而在VM中低表达，两者差异有显著性（P＜0.01）；VEGF和VEGF mRNA在血管瘤细胞及周围间质细胞明显表达，VEGF／KDR主要表达于HA中内皮细胞膜上。提示VEGF可通过自分泌和旁分泌的形式影响HA内皮细胞的增殖，可能与HA发生、发展和退化密切相关。     

肺癌中血管内皮生长因子的表达及其与血管密度的关系

目的 研究各种类型肺癌中血管内皮生长因子（VEGF）的表达和病灶局部微血管密度（MVD）. 方法应用免疫组化法对非小细胞肺癌、小细胞肺癌及其癌旁组织和正常肺组织进行VEGF和MVD（Ⅷ因子）的检测.结果 VEGF在鳞癌、腺癌、小细胞癌和癌旁肺组织中均有不同程度的表达,VEGF在中、低分化程度肺癌中的表达程度高于高分化肺癌,在伴有淋巴结转移的肺癌组织中的表达较强.不同分化程度的肺癌组织中MVD呈上升趋势,分化程度低,血管密度高;伴有淋巴结转移,血管密度高.VEGF表达强度与肺癌的 MVD值密切相关,随VEGF表达强度增高,MVD值亦显著增高.结论 VEGF 在不同类型肺癌中有表达,与MVD和肺癌的发生、发展、转移关系密切,可作为肺癌的预后指标.     

肺癌中瘦素受体的表达及其在血管生成中的作用

目的研究瘦素受体（OB-R）、血管内皮生长因子（VEGF）和微血管密度（MVD）在肺癌组织中的表达,探讨瘦素受体在肺癌血管生成中的作用和机制。方法免疫组化法检测40例肺癌组织和正常对照组织中OB-R、MVD、VEGF的表达。结果肺癌及正常肺组织瘦素受体的阳性表达率分别为67．50％、37．50％,两组比较差异有统计学意义（P〈0．05）。瘦素受体的表达与性别年龄,肿物大小,病理类型无关（P〉0．05）,而与MVD,淋巴转移有关（P〈0．05）,肺癌组织中OB—R阳性组的MVD较阴性组高。VEGF阳性组的MVD明显高于阴性组。OB—R与VEGF表达部位一致,呈正相关（P〈0．05）。结论肺癌组织中OB-R表达增多对肺癌血管成生成促进作用,并且该作用可能与VEGF的上调有关。     

舒拉明体外对肺癌血管新生的抑制效应

为探讨舒拉明对血管内皮生长因子 (VEGF)及其受体 1(Flt 1)和受体 2 (KDR)作用的特点 ,我们采用四唑盐比色法(MTT)测定药物对肺癌细胞、上皮细胞的敏感性 ,用免疫细胞化学方法检测对VEGF及受体表达程度的影响 ,以期为抗肺癌血管新生治疗提供新的思路。材料与方法　舒拉明钠系德国拜耳公司产品 ,实验用A5 4 9肺腺癌细胞系和ECV 30 4上皮细胞系均由中国医学科学院血液学研究所药物室传代培养。舒拉明药物敏感性试验 :采用MTT法测定舒拉明对 2种细胞系的半数抑制浓度 (IC50 )。舒拉明对 2种细胞VEGF、Flt 1和KDR的影响 :将细胞浓…     

内皮素-1在肺癌中的表达及其与血管生成的关系

目的了解内皮素-1（ET-1）在肺癌组织标本中的表达并定量分析其与肺癌分型、分级的关系，观察ET—1的表达与肿瘤微血管密度（MVD）及血管内皮生长因子（VEGF）表达的关系，探讨ET—1在肿瘤血管生成中的作用。方法用免疫组织化学SABC染色方法检测ET—1及VEGF在肺癌中的表达、MVD的计数，并用图像分析技术测定ET—1的含量。结果ET-1主要分布在肿瘤细胞的胞浆中，在鳞癌、腺癌等非小细胞肺癌中高表达，而在小细胞肺癌中的阳性表达率低。图像分析表明，鳞癌、腺癌的分化程度越低ET—1含量越高，分化程度越高ET—1含量越低。ET—1表达阳性组中MVD显著增高，且ET—1的表达与VEGF有关。结论ET-1存在于肺癌细胞中，在腺癌和鳞癌组织中高表达，且ET—1含量与肿瘤分化程度有一定关系。ET-1可能作为一种血管生成促进因子参与肺癌的血管形成。     

大鼠肝脏癌变过程中环氧合酶-2表达与肿瘤血管生成的关系

目的 探讨环氧合酶2（COX-2）表达与肝癌血管生成之间的关系。方法 将40只Wistar大鼠分为模型组（30只）和正常对照组（10只），用0．01％二乙基亚硝胺（DEN）诱发大鼠实验性肝癌，于诱癌第6、12、18周分批处死实验大鼠，常规制作肝脏病理切片。用免疫组织化学法检测大鼠肝脏癌变过程中不同时期的COX-2、血管内皮生长因子（VEGF）及其受体2（VEGFR2／KDR）、基质金属蛋白酶-2（MMP-2）和微血管密度（MVD）的表达情况。结果 实验第6、12、18周，模型组大鼠肝脏呈现典型的脂肪变性炎性细胞浸润、肝硬化、肝癌的病理变化；肝脏COX-2、VEGF、KDR、MMP-2在大鼠肝脏癌变过程中表达明显增强；MVD值在肝癌期明显升高，MVD与VEGF、KDR、MMP-2之间存在着显著的正相关（r值分别0．858、0．788、0．684，P值均〈0．01），COX-2表达与VEGF、KDR、MMP2及MVD值之间也均具有显著的正相关性（r值分别为0．771、0．599、0．690、0．788，P值均〈0．01）。结论 COX-2在大鼠肝脏癌变过程中具有促进肿瘤血管生成的作用，这可能是COX-2导致肿瘤发生与发展的重要机制之一。     

Ang-2在食管鳞癌血管生成中的作用

应用免疫组化SP法检测食管鳞癌及食管断端正常鳞状上皮中促血管生成素（Ang）-2、血管内皮生长因子（VEGF）的表达，以及CD105标记的微血管密度（MVD）。结果显示，Ang-2蛋白表达主要定位于肿瘤细胞的胞质和胞膜，尤其是癌灶边缘血管重建区。食管鳞癌组织中Ang-2和VEGF蛋白表达显著高于食管断端正常鳞状上皮（P〈0．01），癌组织中Ang-2表达程度与VEGF表达程度及MVD呈明显正相关（P〈0．01，〈0．05）。提示食管鳞癌组织中Ang-2高水平表达可能促进肿瘤新生血管形成．促进食管鳞癌的发生发展。     

Prevention of thecal angiogenesis,antral follicular growth,and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2

This study was designed to investigate the effects of inhibition of thecal angiogenesis on follicular development in the marmoset monkey (Callithrix jacchus). To inhibit vascular endothelial growth factor (VEGF), a soluble combined truncated form of the fms-like tyrosine kinase (Flt) and kinase insert domain-containing receptor (KDR) receptor fused to IgG (VEGF Trap R1R2) was administered for 10 d during the follicular phase of the cycle. Changes in angiogenesis and follicular cell proliferation were quantified using immunocytochemistry for bromodeoxyuridine to obtain a proliferation index, CD31 to visualize endothelial cell area, and dual staining to distinguish thecal endothelial cell proliferation. The effects of the treatment on follicular development were assessed by morphometric analyses by measuring follicle diameter, thecal thickness, and a proliferation index for granulosa cells. Follicular atresia was detected and quantified using the terminal deoxynucleotidyltransferase-UTP nick end labeling method. Effects on gene expression of VEGF and its receptors, Flt and KDR, were studied by in situ hybridization. VEGF Trap R1R2 treatment resulted in a significant decrease in thecal proliferation and endothelial cell area, demonstrating the suppression of thecal angiogenesis. The absence of a normal thecal vasculature was associated with a significantly reduced thecal thickness. Antral follicular development was severely compromised, as indicated by decreased granulosa cell proliferation, decreased follicular diameter, and lack of development of ovulatory follicles. Furthermore, the rate of atresia was significantly increased. VEGF expression in granulosa and thecal cells increased after treatment, whereas Flt and KDR expressions in thecal endothelial cells were markedly decreased. These results show that VEGF Trap treatment is associated with the suppression of follicular angiogenesis, which results in the inhibition of antral follicular development and ovulation.     

Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4.

The tyrosine kinases Flt4, Flt1, and Flk1 (or KDR) constitute a family of endothelial cell-specific receptors with seven immunoglobulin-like domains and a split kinase domain. Flt1 and Flk1 have been shown to play key roles in vascular development; these two receptors bind and are activated by vascular endothelial growth factor (VEGF). No ligand has been identified for Flt4, whose expression becomes restricted during development to the lymphatic endothelium. We have identified cDNA clones from a human glioma cell line that encode a secreted protein with 32% amino acid identity to VEGF. This protein, designated VEGF-related protein (VRP), specifically binds to the extracellular domain of Flt4, stimulates the tyrosine phosphorylation of Flt4 expressed in mammalian cells, and promotes the mitogenesis of human lung endothelial cells. VRP fails to bind appreciably to the extracellular domain of Flt1 or Flk1. The protein contains a C-terminal, cysteine-rich region of about 180 amino acids that is not found in VEGF. A 2.4-kb VRP mRNA is found in several human tissues including adult heart, placenta, ovary, and small intestine and in fetal lung and kidney.     

KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells.

Vascular endothelial growth factor (VEGF), which is one of the most potent angiogenic factors, has been shown to play a pivotal role in tumor angiogenesis, including hepatocellular carcinoma (HCC). The effects of VEGF are mediated mainly through two distinct receptors, flt-1 and KDR/Flk-1. It has been suggested that KDR/Flk-1 plays an important role in tumor development. However, the role of KDR/Flk-1 in HCC has not been examined. We previously reported that VEGF tightly regulated murine HCC development, based on the results of a study using a retroviral tetracycline-regulated (Retro-Tet) gene expression system. This system allows VEGF gene expression to be manipulated in vivo by providing tetracycline in the drinking water. In the present study, we combined the KDR/Flk-1-specific neutralizing monoclonal antibody (KDR/Flk-1mAb) and the Retro-Tet system to elucidate the role of KDR/Flk-1 in VEGF-induced tumor development and angiogenesis in a murine HCC experimental model. In a xenograft study, tumor augmentation induced by VEGF overexpression was almost abolished by means of KDR/Flk-1mAb treatment, with accompanying inhibition of angiogenesis, KDR/Flk-1 autophosphorylation, but not interference of flt-1 activation. This inhibitory effect was achieved even on established tumors and regardless of whether the tumor size was small or large. On the contrary, KDR/Flk-1mAb treatment significantly increased the apoptosis in the tumor. With orthotopic transplantation, KDR/Flk-1mAb also inhibited HCC development in the liver. These results suggest that KDR/Flk-1 is a major regulator of VEGF-mediated HCC development and angiogenesis not only at the initial stage, but also after the tumor has fully developed.     

Histochemical study of angiogenesis in basaloid squamous carcinoma of the esophagus

Angiogenesis of esophageal basaloid squamous carcinoma (BSC) was studied immunohistochemically and compared with that of squamous cell carcinoma (SCC). In tissues taken from six patients with esophageal BSC and 35 with esophageal SCC, angiogenesis was evaluated by measuring microvessel density (MVD), defined as the microvessel count determined using factor VIII-related antigen immunostaining, and by measuring immunoreactivity of vascular endothelial growth factor (VEGF) and thymidine phosphorylase (dThdPase). Three of the six patients with BSC had distant metastases. There was no difference of MVD between BSC and SCC (22.0 +/- 4.6 vs. 27.6 +/- 9.4). VEGF expression tended to be more frequently observed in BSC than in SCC (100% vs. 60.0%; p = 0.066). Strong expression of VEGF was detected in three BSC with distant metastases; however, there was no difference in the rate of strong VEGF expression between BSC and SCC. The MVD in the cases of BSC with strong VEGF expression, i.e. in the cases with distant metastases, was higher than that in the cases of BSC with weak VEGF expression (p=0.049). There was no difference in dThdPase expression of the cancer cells between BSC and SCC (50.0% vs. 54.3%), whereas the infiltrating stromal cells of all the BSC expressed dThdPase. Strong dThdPase expression in the cancer cells or in the infiltrating stromal cells was observed in two and three BSC, respectively. However, there were no differences in the rate of cancer cells or stromal cells with strong dThdPase expression between BSC and SCC. In one BSC with high MVD and distant metastases, VEGF and dThdPase were both strongly expressed. The vascularity of esophageal BSC was not different from that of SCC. VEGF may participate in angiogenesis of esophageal BSC and may influence the rate of metastasis in esophageal BSC patients. dThdPase may play a partial rule in angiogenesis and metastasis in some cases of BSC.     

Vascular endothelial growth factor and microvascular density in esophageal and gastric carcinomas

AIM: To observe the relationship between the expression of vascular endothelial growth factor (VEGF), microvascular density (MVD) and the pathological characteristics of esophageal and gastric carcinomas. METHODS: S-P immunohistochemical staining was used to investigate the expression of VEGF in all the specimens. The antibody against factor VⅢ-related antigen was used to display vascular end othelial cells, and MVD was examined by counting the factor VⅢ-positive vascular endothelial cells. RESULTS: The positive rates of VEGF expression in esophageal carcinoma and gastric carcinoma were 81.36 % and 67.5 % resbectbely, and the MVD averaged 41.81&#177;8.44 and 34.36&#177;9.67 respectively, which were higher than those in benign diseases. The expression of VEGF and MVD were closely correlated with the degree of differentiation, Iyrnphatic metastasis, but not related to depth of cancer invasion. In early stage gastric carcinoma, the rate of expression of VEGF and MVD was lower than that in progressive gastric carcinomas.CONCLUSION: The expression of VEGF is correlated with tumor angiogenesis, and VEGF plays an important role in new blood vessels formation, the expression of VEGF and MVD play an important role in tumor growth and metastasis.MVD and the expression of VEGF may be two important indexes for patients‘‘ prognosis.     

A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma

BACKGROUND AND OBJECTIVES: In tumors, vascular endothelial growth factor-A (VEGF-A) stimulates angiogenesis and vascular permeability by activating the tyrosine kinase receptor-2 (VEGFR-2 or KDR/Flk-1) and-1 (VEGFR-1 or Flt-1). DESIGN AND METHODS: The distribution and function of VEGF homologs and their receptors on bone marrow plasma cells, endothelial cells, and other stromal cells (residual stromal cells) were examined in patients with multiple myeloma (MM). RESULTS. Plasma cells secrete VEGF-A (and VEGF-B, VEGF-C and VEGF-D, albeit marginally) into their conditioned medium (CM). CM VEGF-A stimulates proliferation and chemotaxis in endothelial cells (both being mandatory for angiogenesis) via VEGF receptor-2 (VEGFR-2), and in residual stromal cells via the VEGFR-1. Residual stromal cells secrete VEGF-C and VEGF-D, but little of the other homologs. Their CM VEGF-C and VEGF-D increase in response to plasma cell CM and trigger plasma cell proliferation via VEGFR-3. Proliferation in all cell types parallels VEGFR and extracellular signal-regulated protein kinase-2 (ERK-2) phosphorylation. The homologs and receptors are weakly or inconstantly expressed in patients with monoclonal gammopathies of undetermined significance or vitamin B12/iron deficiency anemias. INTERPRETATION AND CONCLUSIONS: This study shows that the VEGF pathway is directly involved in tumor angiogenesis and growth in MM. A paracrine VEGF loop for MM progression is suggested. This, in turn, provides a further indication that the VEGF pathway and its signaling proteins may be appropriate targets in the management of MM.     

胃、肠息肉中VEGF、KDR及MVD的表达及相关性

目的探讨胃、肠息肉中血管内皮生成因子(VEGF)、激酶插入嵌合受体/胎肝激酶-1(KDR)、微血管密度(MVD)的表达及相关性。方法采用免疫组织化学方法检测VEGF及KDR在胃、肠息肉组织中的表达水平,计数微血管密度(MVD)。结果胃、肠息肉组织中VEGF、KDR及MVD的表达显著低于胃、肠癌(P0.05),显著高于正常胃、肠黏膜(P0.05),且胃、肠息肉中VEGF、KDR的表达呈正相关(P0.01);直径2.0 cm息肉中VEGF、KDR的表达显著高于直径1.0 cm者,且在年龄50岁患者中表达增高;肠息肉中VEGF、KDR在绒毛状腺瘤、表面呈分叶状者中表达量高,差异有统计学意义(P0.05);肠息肉中VEGF、KDR的表达显著高于胃息肉(P0.01)。结论直径2.0 cm、年龄50岁的患者癌变概率高,肠息肉中腺瘤性息肉、分叶状息肉癌变率高;肠息肉癌变率高于胃息肉,VEGF、KDR、MVD及其相互作用对促进息肉血管生成及癌变的过程可能起到重要作用。     

Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma

PURPOSE: Tumor angiogenesis is crucial for both the growth of the primary tumor and the development of metastases. Among the factors causing tumor angiogenesis, vascular endothelial growth factor (VEGF) is considered as a leading candidate. We aimed to assess the prognostic significance of VEGF and tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a retrospective study of 69 patients with HNSCC, in order to investigate whether VEGF immunohistochemical expression and tumor angiogenesis correlate with clinicopathological parameters and outcome. Tumor angiogenesis was estimated by determining microvessel density (MVD), and VEGF expression was assessed quantitatively. RESULTS: Vascular endothelial growth factor and MVD correlated statistically significant with the clinical stage, but not with the presence of lymph node metastasis at the time of diagnosis. Tumors located in the oral cavity and larynx more often expressed high VEGF immunostaining compared with tumors located in the lower lip. High VEGF expression was associated with higher clinical stage and worse overall survival in this cohort of patients. CONCLUSIONS: Vascular endothelial growth factor expression may have prognostic significance for patients with HNSCC.