胃癌组织中CXCR3表达与微血管形成的关系及其临床意义

目的探讨胃癌组织中CXCR3的表达和微血管形成的关系并分析其临床意义。方法采用免疫组化法检测169例胃癌组织中CXCR3蛋白表达和肿瘤间质微血管密度(microvascular density,MVD),分析其相关性及其与胃癌临床病理参数的关系。结果 CXCR3表达在分化程度高(P=0.025)、浸润程度浅(P=0.005)、TNM分期低(P=0.002)及无淋巴结转移(P=0.001)的胃癌患者中更高;MVD在胃癌分化程度低者中更高(P=0.001),与浸润深度、TNM分期及淋巴结转移无关(P0.05)。胃癌组织中CXCR3表达与MVD呈负相关(r=-0.151,P=0.049)。Kaplan-Meier分析发现高表达CXCR3的胃癌患者(P=0.015)和低MVD患者(P=0.047)的生存时间延长。结论胃癌中CXCR3的表达与MVD呈负相关,且与胃癌的浸润、转移相关。     

FAP在胃癌间质中的表达及其与微血管密度的关系

目的 探讨FAP在胃癌间质中的表达及其与微血管密度(microvessel density,MVD)的关系.方法 收集162例胃癌组织,同时建立人胃癌细胞系SGC-7901裸鼠皮下移植瘤模型,采用免疫组织化学染色法检测FAP和CD34的表达.结果 在人胃癌组织中,FAP表达于问质成纤维细胞,表达阳性率为90.74%(147例),而胃癌细胞和正常胃组织中无表达,且FAP表达和MVD分别与胃癌的分化程度(χ2=51.882,P<0.01;χ2=46.383,P<0.01)、侵袭深度(χ2=40.193,P<0.01;χ2=21.617,P<0.01)及淋巴结转移(χ2=24.232,P<0.01;χ2=13.393,P<0.01)有关.在15例裸鼠皮下移植瘤中,所有肿瘤中FAP均不同程度在间质成纤维细胞呈阳性表达.在人胃癌组织(χ2=97.710,P<0.01)和裸鼠皮下移植瘤组织(χ2=11.100,P<0.01)中,不同强度的FAP表达组间肿瘤间质MVD的差异具有统计学意义,且随着FAP表达水平的增高,MVD也随之增加.结论 FAP的表达与胃癌的分化程度、侵袭深度及淋巴结转移有关.FAP可能通过促进肿瘤的微血管生成,加快肿瘤的生长、侵袭和转移.     

直肠癌的血管生成和血管内皮生长因子表达的实验研究

目的探讨直肠癌组织微血管密度(MVD)和血管内皮生成因子(VEGF)表达与肿瘤浸润和转移的关系. 方法应用CD31抗体和VEGF抗体,采用免疫组化S-P法对141例手术切除的直肠癌患者进行血管标记和染色,并取10例直肠正常组织对照. 结果有淋巴转移组直肠癌MVD、VEGF表达强度与无淋巴结转移组、正常对照组间比较,均有显著性差异(p<0.01),且MVD与VEGF表达两者呈正相关(r=0.93). 结论直肠癌组织内微血管密度和VEGF表达强度与直肠癌的浸润深度及淋巴结转移密切相关,两者均可考虑作为预测直肠癌发生转移的指标.     

在宫颈癌间质中表达的FAP与MVD的相关性

目的 探讨成纤维细胞激活蛋白(fibroblast activation protein,FAP)在人宫颈癌间质中的表达及其与微血管密度(microvessel density,MVD)的关系.方法 应用免疫组织化学技术检测50例宫颈癌中FAP和CD34的表达.结果 在50例宫颈癌间质中FAP表达阳性率为88%(44例),而在正常宫颈组织中无表达,宫颈癌细胞少量表达.FAP表达与宫颈癌的临床分期有关(χ2=4.379,P＜0.05),与淋巴结转移和病理分级无关.间质中的MVD与宫颈癌的临床分期有关(χ2=13.116,P＜0.01),与淋巴结转移和病理分级无关.不同强度的FAP表达组间MVD的差异具有统计学意义(χ2=44.199,P＜0.01),且随着FAP表达水平的增高,MVD也随之增加.结论 人宫颈癌中FAP可能通过促进肿瘤的微血管生成而促进肿瘤的演进.     

直肠癌的血管生成和血管内皮生长因子表达的实验研究

目的　探讨直肠癌组织微血管密度 (MVD)和血管内皮生成因子 (VEGF)表达与肿瘤浸润和转移的关系 .方法　应用CD31抗体和VEGF抗体 ,采用免疫组化S -P法对 14 1例手术切除的直肠癌患者进行血管标记和染色 ,并取 10例直肠正常组织对照 .结果　有淋巴转移组直肠癌MVD、VEGF表达强度与无淋巴结转移组、正常对照组间比较 ,均有显著性差异 (p<0 .0 1) ,且MVD与VEGF表达两者呈正相关 (r=0 .93) .结论　直肠癌组织内微血管密度和VEGF表达强度与直肠癌的浸润深度及淋巴结转移密切相关 ,两者均可考虑作为预测直肠癌发生转移的指标 .     

胃癌组织中COX-2表达及其与微血管和微淋巴管密度的关系

目的 研究胃癌组织中COX-2表达的临床病理学意义,同时探讨COX-2与微血管密度(MVD)和微淋巴管密度(MLD)的关系.方法 采用免疫组化EnVision两步法,检测46例胃癌中COX-2的表达,同时标记CD34和D2-40,分别检测胃癌组织中微血管和微淋巴管密度.结果 46例胃癌中COX-2表达的阳性率为80.43%(37/46),COX-2的表达与患者性别、浸润深度无关(P>0.05),而与肿瘤大小、组织学分期、淋巴结转移和临床分期等临床病理参数密切相关(P<0.05);COX-2表达阳性组的平均生存时间明显低于表达阴性组(P<0.05);COX-2表达阳性组的MVD和MLD明显高于COX-2表达阴性组(P<0.05).结论COX-2可能通过促进肿瘤的血管和淋巴管形成而参与了胃癌细胞的浸润转移,导致胃癌患者预后不良.     

乳腺癌MMP-2表达与间质微血管密度和肿瘤转移的关系

目的 :研究乳腺癌组织中基质金属蛋白酶 2 (MMP 2 )的表达特点 ,探讨其与间质微血管密度及肿瘤转移的关系。方法 :应用免疫组化S P法 ,检测 49例乳腺癌、10例癌旁正常组织MMP 2的表达 ,并在CD34染色切片上检测间质微血管密度(MVD)。结果 :乳腺癌组织MMP 2的表达 (75 5 % )明显高于癌旁正常组织 (30 % ) ,二者之间差异有显著性 (P <0 0 1) ;MMP 2阳性组MVD均值 (5 4 93± 13 86 )高于MMP 2阴性组 (4 1 2 8± 11 6 9) ,MMP 2的表达与MVD呈正相关 (P <0 0 1)。此外 ,乳腺癌MMP 2的表达与组织学分级、淋巴结转移密切相关 (P <0 0 5 ) ,而与患者年龄、肿瘤大小、组织学分型、临床分期无关。结论 :MMP 2促进乳腺癌间质血管生成 ,促进肿瘤的侵袭和转移 ,有可能成为判定乳腺癌生物学行为和预后的重要指标     

胃癌微血管密度与增殖细胞核抗原的相关性研究

目的 探讨胃癌及其周边正常组织微血管密度（MVD）、增殖细胞核抗原（PCNA）的表达差异和癌组织中MVD和PCNA的相关性。方法应用免疫组化染色和图像分析方法对43例晚期胃癌的癌组织及其癌旁正常粘膜MVD、PCNA进行检测，同时检测其淋巴结转移组和非转移组该二项指标表达情况。结果 晚期胃癌组织微血管明显增生、PCNA活性明显增高，且在淋巴结转移组和非转移组之间差异显著。但肿瘤细胞内PCNA表达与MVD无直接因果关系。     

bFGF、VEGF和MVD在原发性输卵管癌中的表达(一)

目的　研究碱性成纤维细胞生长因子 (bFGF)、血管内皮生长因子 (VEGF)在原发性输卵管癌组织中的表达以及微血管密度 (MVD)与原发性输卵管癌的生长、浸润及转移的关系。方法　采用免疫组织化学方法 (二步法 )检测30例原发性输卵管癌和 8例对侧正常输卵管组织中bFGF、VEGF蛋白的表达 ,以CD34抗原作为血管内皮细胞标记 ,测定其微血管密度。结果　bFGF、VEGF在原发性输卵管癌和正常输卵管组织中的阳性表达率分别为 :10 0 % (30 /30 )、86 6 7% (2 6 /30 ) ;3/8、3/8。输卵管癌组与正常组相比差异有极显著性 (P <0 0 1)。MVD与bFGF、VEGF的表达有正相关性。在原发性输卵管癌的临床病理特征中 ,bFGF在临床分期Ⅲ期表达较Ⅰ期和Ⅱ期者高 (P <0 0 5 )。结论　bFGF、VEGF和MVD在原发性输卵管癌中的表达较强 ,bFGF、VEGF在原发性输卵管癌的发生发展中有促进血管形成的作用。     

层粘连蛋白受体、Ⅳ型胶原的表达及微血管密度与乳腺癌转移的关系

目的：探讨乳腺癌组织层粘连蛋白受体（LN－R）、Ⅳ型胶原（Col Ⅳ)、间质微血管密度与乳腺癌淋巴结转移的关系。方法：应用免疫组织化学S－P方法标记82例乳腺癌组织中LN－R、Col Ⅳ、FⅧRAg，并在第Ⅷ因子相关抗原（FⅧRAg)标记切片上计算微血管密度（MVD）。结果：LN－R表达强度及MVD的高低在乳腺癌有淋巴结转移组和无淋巴结转移组间有差异；ColⅣ在两组间无差异。结论：乳腺癌间质微血管密度增加及LN－R表达增强可作为预测肿瘤转移及判断预后的指标。     

Inhibition of bFGF gene expression and tumor angiogenesis of orth otopic implantation of human gastric carcinoma by N-desulfated heparin]

OBJECTIVE: To investigate the effect of N-desulfated heparin on tumor metastasis, tumor angiogenesis and basic fibroblast growth factor(bFGF) gene expression of orthotopically implanted human gastric carcinoma in NOD-SCID mice. METHODS: Human gastric cancer SGC-7901 tissues were orthotopically implanted into the stomach of the NOD-SCID mice. Twenty mice were randomly divided into two groups which received either intravenous injection of 0.9% NaCl solution(0.9%NaCl solution group) or 10 mg/kg N-desulfated heparin (N-desulfated heparin group) twice a week for three weeks. Mice were sacrificed six weeks after tumor implantation. Tissues from stomach and other organs were obtained for histopathological evaluation. The intratumoral microvessel density (MVD) in tumor was evaluated immunohistochemically. Real time PCR was used to detect bFGF mRNA expression. RESULTS: The tumor metastasis rates were 9/10 in 0.9% NaCl solution group and 2/10 in N-desulfated heparin group(P<0.05).MVD was 9.1+/-3.4 in 0.9% NaCl solution group and 4.7+/-1.8 in N-desulfated heparin group (t=3.617,P<0.05). bFGF mRNA expression was lower in N-desulfated heparin group(2.60+/-0.56%)than that in 0.9% NaCl solution group(30.65+/-6.84%). CONCLUSION: N-desulfated heparin can inhibit the metastasis of gastric cancer through inhibiting tumor bFGF gene expression and tumor angiogenesis with no obvious anticoagulant activity.     

Coexpression of heparanase, basic fibroblast growth factor and vascular endothelial growth factor in human esophageal carcinomas

Heparan sulfate (HS), which is degraded by heparanase, plays an important role in cell adhesion, insolubility of the extracellular matrix (ECM) and as a reservoir for various growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). In the present study, we examined the immunohistochemical expression of heparanase, bFGF and VEGF, and evaluated the correlation between their expression and microvessel density (MVD) in human esophageal carcinomas. Heparanase, bFGF and VEGF were immunolocalized predominantly to the carcinoma cells, but they were also localized to the endothelial cells of microvessels near the carcinoma cell nests. In carcinomas with invasion of the muscular layer or adventitia, heparanase staining was stronger at the invasive areas of carcinomas than the intraepithelial spread. Expression of heparanase and bFGF and the degree of MVD were associated with tumor invasion, lymph node metastasis and pathological stages. Cases with positive staining for heparanase, bFGF or VEGF tended to have a higher MVD than those without staining, and carcinomas with concomitant expression of heparanase, bFGF and VEGF showed the highest MVD. The level of heparanase mRNA expression was directly correlated with the MVD. In addition, heparanase-positive cases had a higher positive ratio of bFGF and VEGF compared with the heparanase-negative cases. These data suggest the possibility that heparanase may contribute to not only cancer cell invasion but also angiogenesis probably through degradation of HS in the ECM and release of bFGF and VEGF from the HS-containing ECM.     

肝素酶和碱性成纤维细胞生长因子与非小细胞肺癌转移和预后的关系

目的 探讨肝素酶(heparanase)和碱性成纤维细胞生长因子(bFGF)在人非小细胞肺癌(NSCLC)组织中表达的临床意义及其与肺癌转移和预后的关系。方法 采用免疫组织化学、原位杂交和Western blot方法,检测115例人NSCLC石蜡切片和45例新鲜肺癌及对应癌旁正常组织中肝素酶和bFGF的表达情况。采用χ^2检验、t检验、生存曲线和Cox比例风险回归等方法分析肝素酶和bFGF分别表达及共表达的意义。结果 免疫组织化学染色证实肝素酶(91／115)和bFGF(89／115)主要表达在癌细胞质和(或)细胞膜中,在正常肺泡上皮和支气管上皮中则呈阴性表达。Western blot也证实肝素酶在肺癌中的表达明显增高(P=0．041)。统计分析结果显示：肝素酶和bFGF的表达具有明显的一致性(P：0．0001),二者单独表达和共表达均与肺癌的分期、血管侵袭、淋巴结转移、微血管密度和预后有关,其中,二者共表达时与分期和微血管密度的相关性更显著;另外,bFGF还与肺癌的分化程度有关。多因素分析结果显示,肺癌的分化程度、血管浸润、淋巴结转移和bFGF的表达可以作为判断肺癌预后的危险因素,但肝素酶不是影响预后的独立因素。结论 肝素酶和bFGF均与肺癌的转移、血管生成和预后密切相关。     

胆囊癌组织P62蛋白的表达及其与血管生成关系

目的 :检测胆囊癌组织中P6 2蛋白、碱性成纤维细胞生长因子(bFGF)的表达和微血管密度 (MVD) ,探讨它们的相互关系 ,以及与胆囊癌临床病理特征的关系。方法 :4 1例胆囊癌和 2 2例慢性胆囊炎组织中 ,P6 2蛋白和bFGF的表达用SP免疫组化染色法进行检测。胆囊癌组织中MVD用抗CD34单抗 (mAb)做SP免疫组化染色进行检测。结果 :4 1例胆囊癌组织中 ,P6 2和bFGF表达阳性率分别为 6 3.4 %和 75 .6 % ,均高于 2 2例慢性胆囊炎组织 (P <0 .0 1)。P6 2的表达与胆囊癌淋巴结转移有关 (P <0 .0 5 ) ,与癌组织的分级、临床分期无显著关系。bFGF的表达与胆囊癌临床病理分期及组织学分级有关 (P <0 .0 5 ) ,而与淋巴结转移无显著关系。P6 2表达率与bFGF表达率呈正相关关系 (r=0 .5 2 1;P <0 .0 1)。两者的表达均与患者的年龄、性别、肿瘤的种类、是否伴有胆囊结石无关。胆囊癌组织中MVD明显高于慢性胆囊炎组织 (P <0 .0 1)。P6 2及bFGF表达阳性组织MVD高于表达阴性组织 (分别P <0 .0 5和P <0 .0 1)。MVD与胆囊癌的Nevin分期及淋巴结转移有关 (P<0 .0 1) ,与患者的年龄、性别、肿瘤种类、分化程度以及是否伴有胆囊结石无关。结论 :P6 2蛋白及bFGF的表达与胆囊癌组织中血管的生成相关 ,在胆囊癌的发生和发展过程中可能具有重     

血管内皮细胞生长因子和血管生成与胃癌发展的关系

目的探讨血管内皮细胞生长因子（ＶＥＧＦ）和血管生成与胃癌发展的关系。方法应用免疫组织化学和原位分子杂交技术,检测５６例人胃癌组织ＶＥＧＦ蛋白表达和微血管密度（ＭＶＤ）及部分胃癌ＶＥＧＦｍＲＮＡ表达,分析ＶＥＧＦ和ＭＶＤ、及其与胃癌组织学分型、浸润深度、生长方式、淋巴结转移、远处转移和预后的关系。结果ＶＥＧＦ阳性者ＭＶＤ值显著高于阴性者（Ｐ＜００１）,ＶＥＧＦ表达和ＭＶＤ与胃癌浸润深度（Ｐ＜００１）、淋巴结转移（Ｐ＜００５）和远处转移（Ｐ＜０．０５）密切相关,而与组织学分型和生长方式无关（Ｐ＞００５）;ＶＥＧＦ表达阳性或ＭＶＤ≥４３的胃癌患者５年生存率较低;ＶＥＧＦｍＲＮＡ表达与ＶＥＧＦ蛋白表达具有一致性,但其分布不同。结论ＶＥＧＦ与胃癌的血管生成密切相关,对胃癌的生长和浸润转移有促进作用,ＶＥＧＦ和ＭＶＤ可作为反映胃癌生物学行为的指标之一     

VEGF、ANG-1、ANG-2、TSP-1的表达与胆管细胞性肝癌血管生成和侵润转移的关系

目的：研究血管内皮生长因子（VEGF）、血管生成素-1（ANG-1）、血管生成素-2（ANG-2）、血小板反应蛋白-1（TSP-1）的表达与胆管细胞性肝癌(CCC)血管生成和侵润转移的关系。方法： 对33例手术切除的CCC标本进行CD34、VEGF、 ANG-1、 ANG-2 和TSP-1的免疫组化染色，研究VEGF、ANG-1、ANG-2、TSP-1的表达与胆管细胞性肝癌血管生成和肿瘤门静脉侵犯、肝内转移、淋巴结转移以及肿瘤分化水平之间的关系。 结果： 本组CCC的微血管密度（MVD）为(87.2±52.6)/mm2，VEGF、ANG-1、ANG-2 和TSP-1的阳性率分别为75.6%、36.0%、57.6%和45.5%。VEGF和ANG-2的阳性表达与高MVD相关，TSP-1则与MVD负相关（P<0.01,P<0.05,P<0.01）。阳性TSP-1与肝内转移正相关（46.7% vs 5.6%，P<0.05）。结论： CCC瘤内的血管新生活跃，VEGF和ANG-2的阳性表达与CCC血管生成正相关，TSP-1则与其负相关，TSP-1的阳性表达还与肝内转移相关，VEGF、ANG-1、ANG-2的表达与肿瘤的侵润转移未见显著相关。     

血小板反应素-4在胃癌中的表达及其临床意义

目的定量测定血小板反应素-4(TSP-4)基因在胃癌及癌旁组织中的表达,探讨其与胃癌临床病理学特征、微血管密度(MVD)和基质金属蛋白酶-9(MMP-9)表达水平的关系,评价其在胃癌发生和发展中的意义。方法采用RT-PCR技术检测82例配对的胃癌组织及癌旁组织TSP-4mRNA的表达,并分析其与临床病理学特征的关系;通过免疫组织化学检测肿瘤组织中CD34和MMP-9的表达,分析TSP-4mRNA的表达与肿瘤微血管密度、MMP-9表达的相关性。结果TSP-4mRNA在胃癌中的表达高于癌旁组织(P=0.03);胃癌组织中TSP-4mRNA的表达水平与肿瘤大小、组织分型、淋巴结转移、肿瘤微血管密度及MMP-9表达密切相关(P=0.002,P=0.031,P=0.014,r=0.67P0.01,P=0.008),但与性别、年龄及侵袭程度无关(P=0.53,P=0.57,P=0.15)。结论TSP-4可能通过调节胃癌新血管生成和MMP-9的表达,促进肿瘤生长与转移。     

Comparative evaluation of microvessel density determined by CD34 or CD105 in benign and malignant gastric lesions

Microvessel density (MVD) is regarded as a surrogate marker for angiogenesis and has been used for tumor prognosis. In this study, MVD was identified immunohistochemically by monoclonal antibodies against CD105 and CD34 in the tissues representing gastric carcinoma, chronic gastritis, and hyperplastic polyps, and the results were correlated with clinicopathologic features. The expression of CD105 in the microvessels within benign lesions was barely visible, and MVD was markedly lower than that determined by CD34. CD34 was strongly expressed in the microvessels within hyperplastic polyps and tissues with gastritis. In gastric carcinoma, CD105 expression in microvessels was as high as the MVD, compared with benign lesions. CD105 stained well-formed mature and newly formed immature vessels within the cancer mass. Correlation analysis showed that MVD determined by CD105 correlated with blood vessel invasion, distant metastasis, and formation of ascites. Survival analysis demonstrated an inverse correlation between MVD count and overall survival: patients with MVD counts of 32 or higher survived for a much shorter time than those with counts lower than 32. Multivariate analysis confirmed that MVD determined by CD105 was an independent prognostic factor for survival. Microvessel density determined by CD34 inversely correlated with overall survival, but it did not correlate with other clinicopathologic parameters except formation of ascites. In conclusion, CD34 was universally expressed in blood vessels within benign and malignant tissues, whereas CD105 expression was minimal in benign tissues but stronger in gastric carcinoma. These data suggest that both CD105 and CD34 could be used for quantification of angiogenesis, but preference should be given to CD105 in the evaluation of prognosis in gastric carcinoma.     

Hypercholesterolemia impairs angiogenesis in patients with breast carcinoma and, therefore, lowers the risk of metastases

Our aim was to study the effect of hypercholesterolemia on angiogenesis induced by breast carcinoma. Of 51 patients with invasive ductal carcinoma, 28 had hypercholesterolemia and 23 had normocholesterolemia. The intratumoral microvessel density (MVD) was evaluated by using anti-CD31 antibody. The expression of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on endothelial and tumor cells was examined and graded semiquantitatively. Patients with normocholesterolemia had a higher MVD (76.4 +/- 8.2) than those with hypercholesterolemia (54.6 +/- 5.1) (P < .01). The risks of recurrence and distant metastasis were higher in patients with normocholesterolemia than in patients with hypercholesterolemia (P < .01). Patients with hypercholesterolemia showed lower expression of endothelial VEGF and bFGF than patients with normocholesterolemia (P < .05 and P < .01, respectively). In addition, tumoral bFGF and VEGF expression showed negative correlation with the presence of hypercholesterolemia (P < .01). We suggest that hypercholesterolemia impairs angiogenesis by suppressing endothelial and tumoral bFGF and VEGF expression and, therefore, lowers the risk of metastases in cases of invasive breast carcinoma.