血管内皮生长因子在肾细胞癌中的表达及意义

研究肾细胞癌血管内皮生长因子（ＶＥＧＦ）的表达及其与肿瘤转移、分期、病理类型及预后的关系。采用抗ＶＥＧＦ的多克隆抗体免疫组织化学技术染色（ＬｓＡＢ法）研究６１例肾癌组织切片。结果显示：４５９％（２８／６１）的肾癌ＶＥＧＦ表达阳性，淋巴结和（或）血行转移的ＶＥＧＦ表达率（７７８％）明显高于非转移者（３２６％，Ｐ＜００１）；阳性表达者五年生存率（２９１％）明显低于阴性表达者（８４６％，Ｐ＜００１）；Ⅰ、Ⅱ期阳性表达低于Ⅲ、Ⅳ期（Ｐ＜００５）；但与性别、年龄及肿瘤的病理类型无关。ＶＥＧＦ除在癌细胞胞浆和胞膜表达外，尚表达于肿瘤基质血管和邻近肿瘤的正常肾小管胞浆、肾小球和血管内皮及血管平滑肌胞膜。认为ＶＥＧＦ除由肿瘤细胞合成外，可能尚表达于邻近肿瘤的正常肾小管胞浆，ＶＥＧＦ表达有助于肾癌预后判断及指导治疗，ＶＥＧＦ可能是肿瘤血管的良好标记物，设法抑制ＶＥＧＦ可望成为肾癌治疗的有效方法。     

膀胱移行细胞癌VEGF表达和MVD检测的临床意义

目的　探讨膀胱移行细胞癌组织中血管内皮细胞生长因子（ＶＥＧＦ） 的表达与肿瘤间质微血管密度（ＭＶＤ）检测的临床意义。　方法　采用免疫组化方法对７７ 例膀胱移行细胞癌及１０ 例正常膀胱组织进行ＶＥＧＦ多克隆抗体及第Ⅷ因子相关抗原（ＶＷＦ：Ａｇ） 单克隆抗体染色,观察膀胱移行细胞癌ＶＥＧＦ的表达与ＭＶＤ 之间的相关性。　结果　ＶＥＧＦ的表达与肿瘤间质微血管密度之间存在正相关性,二者均与膀胱移行细胞癌的病理分级显著相关,浸润性肿瘤明显高于浅表性肿瘤（Ｐ＜０ ．０５） ;术后随访６ 年,术后２ 年内复发组明显高于６ 年内未复发组（ Ｐ＜ ０ ．０５） ,但与肿瘤大小、性别、年龄无关。　结论　ＶＥＧＦ的表达为膀胱移行细胞癌的恶性表型,并与膀胱肿瘤间质微血管形成有关,上述二项指标对评估膀胱移行细胞癌的预后有重要意义。     

膀胱癌组织中血管内皮生长因子的表达及与血管生成的关系

目的 探讨血管内皮生长因子（ＶＥＧＦ）在原发性膀胱移行细胞癌中的表达及其与膀胱癌血管生成之间的关系。方法 免疫组织化学技术检测６８例原发性膀胱移行细胞癌和７例正常膀胱组织中血管内皮生长因子的表达,测定４０例浸润性膀胱癌的微血管密度,并分析ＶＥＧＦ和ＭＶＤ间以及它们与膀胱癌病理分级和临床分期间的关系。结果 ＶＥＧＦ在正常膀胱中不表达或低表达,而在膀胱表达较强;ＶＥＧＦ表达及ＭＶＤ值均与肿瘤的病理分级     

血管内皮细胞生长因子mRNA在肾细胞癌中的表达

用逆转录聚合酶链反应（ＲＴＰＣＲ）方法检测２０例肾细胞癌组织和癌周组织血管内皮细胞生长因子（ＶＥＧＦ）ｍＲＮＡ的表达，有１８例癌组织表达ＶＥＧＦｍＲＮＡ，表达率为９０％；２例无表达。癌周组织仅有３例表达ＶＥＧＦｍＲＮＡ，表达率为１５％，两组间有显著性差异（Ｐ＜０．０１）。结果表明，ＶＥＧＦ在肾细胞癌的生长和进展过程中起重要作用，通过诱导血管内皮细胞通透性和内皮细胞的增生，促进肿瘤生长。以ＶＥＧＦ作为靶分子的基因治疗将提高防治肾癌进展和转移的水平。     

乳腺癌血管生成与淋巴结转移的关系

为探讨乳腺癌血管生成与淋巴结转移的关系,作者采用免疫组织化学方法检测了１９８４年至１９８５年手术切除的７０例原发性乳腺癌石蜡标本组织中的微血管密度（ＭＶＤ）及血管内皮生长因子（ＶＥＧＦ）表达,其中有腋淋巴结转移（ＬＮ＋）者３１例,无腋淋巴结转移（ＬＮ－）者３９例。光镜下,２００倍视野计数ＭＶＤ,４００倍视野计数ＶＥＧＦ阳性细胞。结果显示：ＬＮ＋组的ＭＶＤ及ＶＥＧＦ表达显著高于ＬＮ－组;ＭＶＤ及ＶＥ     

肾癌发生发展过程中VHL基因与VEGF的作用

肿瘤生长与转移依赖于血管生长。肾癌（ＲＣＣ）以血管丰富为特性。血管生长因子直接或间接地刺激宿主的免疫细胞或基质细胞，促进内皮细胞的增殖与迁移，最终导致血管生长，尤其血管内皮生长因子（Ｖａｓｃｕｌａｒ　ｅｎｄｏｔｈｅｌｉａｌ　ｆａｃｔｏｒ ，ＶＥ ＧＦ）。而ＶＨＬ疾病为常染色体显性遗传家族性肿瘤综合征，ＴＨＬ基因失活是ＶＨＬ疾病发生的必要条件。其失活在散发性非遗传ＲＣＣ特别是肾透明细胞癌中具有较高的发生率，但在ＭＣ中ＶＨＬ与ＶＥＧＦ之间存在反向调节相关性，本文综述在ＲＣＣ发生发展过程中肿瘤抑制基因Ｖ…     

膀胱移行细胞癌VEGF表达及与血管形成定量的关系

为了探讨膀胱移行细胞癌中血管内皮生长因子（ＶＥＧＦ）表达及其与血管形成定量关系，应用免疫组织化学方法，对６２例原发性膀胱移行细胞癌及８例正常膀胱组织中ＶＥＧＦ进行检测，并对其在３０例浸润性膀胱癌组织中表达与血管形成定量关系进行了研究。结果发现正常膀胱组织均为阴性反应，膀胱癌组织中ＶＥＧＦ蛋白阳性表达率为５６％。低分化和浸润性癌中ＶＥＧＦ蛋白阳性表达率明显高于高分化和表浅性癌组（Ｐ＜００５），浸润性膀胱癌组织中血管形成定量与ＶＥＧＦ表达密切相关（Ｐ＜００１）。结果提示：ＶＥＧＦ表达对膀胱癌生物学行为有重要影响。ＶＥＧＦ是膀胱癌发生发展过程中一个主要血管生成因子，ＶＥＧＦ蛋白表达和血管形成定量有可能成为预测膀胱癌转移和预后的指标     

血管内皮细胞生长因子是预测肝细胞癌患者术后转移复发的潜在指标

目的　检测肝细胞癌（ＨＣＣ） 患者术前血清血管内皮细胞生长因子（ＶＥＧＦ）水平与ＨＣＣ切除术后转移复发的关系。方法　采用ＥＬＩＳＡ法检测ＨＣＣ患者血清ＶＥＧＦ水平,同时应用Ｗｅｓｔｅｒｎ Ｂｌｏｔ方法对２４ 例相应ＨＣＣ组织ＶＥＧＦ表达水平进行定量分析。结果　高转移复发倾向组ＨＣＣ 患者术前血清ＶＥＧＦ水平（２８３．３３±２６３ ．１５） ｎｇ／Ｌ显著高于低转移复发倾向组（１４７．０４ ±１３２ ．６８） ｎｇ／Ｌ（ Ｐ＜ ０ ．０５） 。Ｗｅｓｔｅｒｎ Ｂｌｏｔ 显示,ＨＣＣ患者血清ＶＥＧＦ水平变化与其对应肿瘤组织ＶＥＧＦ表达变化一致。结论　ＨＣＣ患者术前血清ＶＥＧＦ水平可作为预测ＨＣＣ切除术后转移复发的指标。ＨＣＣ患者血清ＶＥＧＦ水平升高是其对应肿瘤组织高表达的结果。     

肿瘤血管生成与大肠癌肝转移

目的分析大肠癌肿瘤血管生成与转移、预后的关系。方法用免疫组化法检测６１例大肠癌手术标本肿瘤组织微血管密度（ＭＶＤ）、血管内皮生长因子（ＶＥＧＦ）的表达。结果ＭＶＤ计数为（２７０±８４）、ＶＥＧＦ表达为（５９７５±１２３６）％,二者与肝、淋巴结转移明显相关（Ｐ＜００１、Ｐ＜００５）。ＭＶＤ计数与术后生存率明显相关（Ｐ＜００１）。结论ＭＶＤ计数与大肠癌肝转移、生存率明显相关,可作为一个新的具有参考意义的预后判断指标。     

膀胱移行细胞癌微血管密度与肿瘤复发的关系

目的：探讨肿瘤微血管形成能力与膀胱移行细胞癌复发的关系及其机制,方法：采用免疫组织化学方法对２５例膀胱移行细胞癌组织中ＶＩＩＩ因子相关抗原、碱性成纤维细胞生长因子（bFGF)及血管内皮细胞生长因子（ＶＥＧＦ）分别进行特异性染色,计数肿瘤内微血管密度（iWV),并观察bＦＧＦ、ＶＥＧＦ的表达,结果：ＶＥＧＦ和bFGＦ的阳性表达率分别为４８％和２８％,阳性表达组iMV显才高于阴性表达组（Ｐ＜０．０５）,术后复发组iMV显著高于未复发组（Ｐ＜０．０５）,且高iMV组复发率高于低iMV组（Ｐ＜０．０５）,结论：iMV与膀胱移行细胞癌复发有关,而促血管形成因子的异常表达是其微血管形成能力增高的重要因素。     

Angiogenesis in renal cell carcinoma: Evaluation of microvessel density, vascular endothelial growth factor and matrix metalloproteinases

BACKGROUND: Angiogenesis, the growth of new blood vessels, has a critical role in tumor growth and metastasis. The purpose of this study was to investigate the involvement of angiogenesis and angiogenic factors in the pathogenesis of renal cell carcinoma (RCC). METHODS: Formalin-fixed and paraffin-embedded tissue blocks from 70 patients with RCC were studied. The situations of tumor angiogenesis were evaluated by assessing microvessel density (MVD) through CD31 immunostaining. The expression of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) was detected immunohistochemically. RESULTS: The value of MVD ranged from 12.0 to 93.0 with a median of 39.91 in RCC. Of the 70 RCCs, the expression of VEGF was detected in 52 (74.3%), MMP-2 in 29 (41.4%) and MMP-9 in 19 (27.1%) cases. Statistical analysis revealed significant associations of the tumor stage with MVD, and the expression of VEGF and MMP-2 in RCC. Additionally, MVD was closely related to the expression of VEGF but was not related to the expression of MMP-2 and MMP-9 in RCC. CONCLUSION: The degree of angiogenesis may be closely related to the tumor progression of RCC. The expression of VEGF may be responsible for angiogenesis in RCC, and both VEGF and MMP-2 expression may function as tumor associated angiogenic factors in RCC.     

Expression of vascular endothelial growth factor protein in human renal cell carcinoma

OBJECTIVE: To evaluate the effect of vascular endothelial growth factor (VEGF, one of the most important angiogenetic factors) in renal cell carcinoma (RCC) by analysing many RCCs for the expression of immunohistochemical (IHC) VEGF-staining related to clinicopathological findings and survival. PATIENTS AND METHODS: VEGF immunostaining was examined with the tissue microarray (TMA) method on tumour samples from 229 patients and validated in 71 by ordinary tissue sections (TS). IHC VEGF expression was quantified by estimating the volume density and staining intensity on a three-grade scale. RESULTS: In most RCCs there was VEGF staining in the cell cytoplasm and membrane. In cell membranes the VEGF expression declined with storage time. IHC VEGF expression analysed by TMA and TS gave corresponding results. There was no difference in VEGF expression among conventional, papillary and chromophobe RCCs. There were significant correlations between VEGF expression and tumour size and stage. In univariate analysis VEGF expression correlated with survival, especially in conventional RCCs; this prognostic information was lost in multivariate analysis. The VEGF staining intensity correlated only with VEGF expression but not with any clinicopathological factors. CONCLUSIONS: VEGF protein was present in most RCC cells. There was no difference in VEGF expression among the different RCC types. The correlation between VEGF expression and tumour stage and with prognosis indicates the significance of VEGF within tumour growth and progression in RCC.     

肾细胞癌VEGF表达和MVD检测的临床意义

目的 探讨肾细胞癌（RCC）组织中血管内皮细胞生长因子（VEGF）的表达与肿瘤间质微血管密度（MVD）检测的临床意义。方法 采用免疫组化方法对65例肾细胞癌（RCC）及10例正常肾组织进行VEGF单克隆抗体及CD34单克隆抗体染色，观察RCC的VEGF表达与MVD之间的相关性。结果 VEGF的表达与肿瘤间质微血管密度之间存在正相关性，二者均与RCC的病理分级、临床分期及远处转移显著相关（P〈0.05，P〈O．001）。结论 VEGF与MVD可客观准确反映RCC的生物学行为，上述二项指标可作为评估RCC恶性程度、转移及预后的重要指标。     

Different isoform patterns for vascular endothelial growth factor between clear cell and papillary renal cell carcinoma

OBJECTIVE: To investigate the protein expression of vascular endothelial growth factor (VEGF) isoforms in relation to the clinical course in patients with different renal cell carcinoma (RCC) types, as angiogenesis is essential for tumour growth and metastasis. PATIENTS AND METHODS: Western blots were assayed of protein extracts from tumour and concomitant kidney cortex samples from 96 patients. The levels of VEGF189, VEGF165, and VEGF121 isoforms were correlated with clinicopathological characteristics and survival. RESULTS: VEGF189 levels were significantly higher in kidney cortex and chromophobe RCC than in papillary and conventional RCC. In papillary RCCs, VEGF189 levels correlated inversely with tumour stage and tumour size. VEGF165 levels were higher in kidney cortex than in RCC, but there was no difference among the RCC types. VEGF121 expression was associated with less advanced tumour stage in conventional RCC. Using multivariate analysis, VEGF189 remained as an independent prognostic factor for patients with papillary RCC. CONCLUSIONS: VEGF189 was associated with tumour progression; in papillary RCC, VEGF189 was a significant independent prognostic factor. VEGF protein isoform patterns differed among the specific RCC types. Additional knowledge is essential to design new anti-angiogenic therapies for all RCC types.     

Tumour vascular endothelial growth factor (VEGF) mRNA in relation to serum VEGF protein levels and tumour progression in human renal cell carcinoma

Angiogenesis is gaining interest because of its importance in tumour growth and metastasis. Renal cell carcinoma (RCC) is known to be a well-vascularized tumour. The aim of this study was to evaluate the expression of VEGF mRNA and receptor flt-1 mRNA (VEGF R1) in a clinical material of RCCs compared with clinicopathological variables and serum VEGF levels. Total RNA was extracted from snap-frozen tumour tissue obtained from 61 patients. Expression of mRNA for VEGF₁₂₁, VEGF₁₆₅ and flt-1 were analysed using quantitative RT-PCR. Relative VEGF mRNA levels, corrected for corresponding cyclophilin value, were related to stage, grade, RCC type and survival time. Serum VEGF₁₆₅ protein was analysed using a quantitative ELISA. Papillary RCC had significantly lower VEGF₁₂₁ and flt-1 mRNA levels compared with conventional RCC (p=0.001). VEGF₁₂₁ mRNA levels were significantly lower in locally advanced tumours in relation to tumours limited to the kidney and those with metastatic disease (p=0.047 and p=0.036). This statistical difference disappeared when only conventional RCCs were evaluated. No association was found between VEGF mRNA levels and nuclear grade. Patients with lower VEGF₁₂₁ mRNA levels had significantly longer survival time compared with those with higher levels (when adjusted to stage, p=0.0097, log rank test). There was an inverse relation between VEGF₁₆₅ mRNA and serum VEGF₁₆₅ levels. The trend to lower VEGF₁₂₁ mRNA levels in locally advanced RCC indicate that angiogenic activity and degradation might be up-regulated in tumours with a high ability to invade. The association with tumour progression shows that VEGF is a promising angiogenic factor especially important in conventional RCCs. VEGF expression might possibly be of help to identify RCCs susceptible for anti-angiogenic therapies.     

Associations of single nucleotide polymorphisms in the vascular endothelial growth factor gene with the characteristics and prognosis of renal cell carcinomas

OBJECTIVES: Vascular endothelial growth factor (VEGF) is considered to play critical roles in tumor development and progression, especially in renal cell carcinoma (RCC) via von Hippel-Lindau gene inactivation. Although VEGF -2578CC, -1154GG, and -634CC genotypes are reportedly correlated with higher levels of VEGF production, no previous studies have reported on the associations of these polymorphisms with RCCs. This study was aimed to clarify the effects of these functional polymorphisms on RCC progression and prognosis. METHODS: We investigated the associations of three polymorphisms (-2578C/A, -1154G/A, and -634C/G) in the VEGF gene with the clinicopathologic parameters and survival of 213 patients with RCC. The -2578C/A and -634C/G polymorphisms were genotyped using a polymerase chain reaction (PCR) restriction fragment length polymorphism technique and the -1154G/A polymorphism was genotyped by an amplification refractory mutation system PCR technique. RESULTS: The GA+AA genotypes of -1154G/A were weakly associated with smaller tumors, lower tumor stage, and lower stage grouping (p=0.028, p=0.012, and p=0.028, respectively). The CA and CA+AA genotypes of -2578C/A were weakly associated with less frequent lymph node metastasis (p=0.029 and p=0.034, respectively) and were significantly associated with favorable cancer-specific survival (p=0.047 and p=0.048, respectively). There was no apparent clinical effect of the -634C/G polymorphism. CONCLUSIONS: These results suggest that some VEGF genotypes may have effects on RCC progression or prognosis, possibly through altered VEGF expression. This finding might help in clarifying the mechanisms of RCC development and progression.     

基质金属蛋白酶-9及其抑制因子在肾细胞癌组织中的表达和意义

目的　探讨基质金属蛋白酶 9(MMP 9)和金属蛋白酶组织抑制因子 1(TIMP 1)在肾细胞癌中的表达及其与临床病理参数之间的关系。方法　采用免疫组织化学链霉菌抗生物素蛋白过氧化酶 (SP)法检测 5 5例肾细胞癌中MMP 9和TIMP 1的表达情况。结果　MMP 9、TIMP 1蛋白在肾细胞癌和正常肾组织中的阳性表达率各为 63 .63 %和 10 .0 0 % (P <0 .0 5 ) ;60 .0 0 %和10 .0 0 % (P <0 .0 5 )。在肾癌中 ,MMP 9蛋白表达与肿瘤Robson分期、肾包膜侵袭和淋巴结转移密切相关 (P <0 .0 5 ) ,而与组织学类型无关 (P >0 .0 5 ) ;TIMP 1蛋白表达与肾细胞癌的临床病理参数无关 (P >0 .0 5 )。结论　MMP 9蛋白高表达参与了肾癌的发展 ,MMP 9和TIMP 1的平衡失调可能在肾癌的侵袭转移中发挥重要作用。     

血管内皮生长因子mRNA表达在胃癌中的意义

目的:探讨血管内皮生长因子(VEGF)mRNA在胃癌中的表达及其与临床病理特征之间关系.方法:用原位杂交和免疫组织化学方法分别对28例胃癌组织中VEGF mRNA及其蛋白质表达、微血管数量(MVC)进行检测.结果:19/28(67.9%)胃癌病例呈VEGF mRNA阳性表达.VEGF mRNA主要见于恶性上皮而非正常胃粘膜,其表达在与坏死区邻接的肿瘤细胞中明显增加.MVC与VEGF mRNA表达有明显相关性(P<0.005);VEGF mRNA表达也与浆膜浸润、淋巴结转移及TNM分期有关(P分别<0.05).结论:通过刺激血管生成,VEGF mRNA表达与胃癌的浸润转移有关.