Association of vascular endothelial growth factor expression with angiogenesis and lymph node metastasis in nasopharyngeal carcinoma.

OBJECTIVE: Recent experimental evidence indicates that angiogenesis affects tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is considered to be an important regulator of tumor angiogenesis. The present study was designed to examine the role of VEGF on angiogenesis and lymph node metastasis in primary nasopharyngeal carcinomas (NPCs). STUDY DESIGN: Formalin-fixed paraffin-embedded biopsy specimens were obtained from 29 primary NPCs that consisted of 22 differentiated nonkeratinizing carcinomas and seven undifferentiated carcinomas. METHODS: Microvessels were highlighted by staining endothelial cells with von Willebrand factor (VWF) using immunohistochemical techniques, and were counted (per x 400 field) in the most active area of angiogenesis on light microscopy. The expression of VEGF was also studied with immunohistochemistry. Positive ratio for VEGF was graded on a scale of 1 and 2. Scale 1 represents patients with less than the mean value of the positive ratio, and scale 2 represents patients with more than the corresponding value. RESULTS: There was a significant correlation between increased microvessel count and the progression of regional lymph node involvement. The microvessel counts and the progression of N factor were significantly higher in scale 2 patients than in scale 1 patients. CONCLUSION: These results suggest that VEGF plays an important role in lymph node metastasis through induction of angiogenesis in NPCs.     

The clinical significance of coexpression of cyclooxygenases-2, vascular endothelial growth factors, and epidermal growth factor receptor in nasopharyngeal carcinoma

Objectives/Hypothesis: To investigate the inter‐relationship of the expressions of cyclooxygenases‐2 (COX‐2), vascular endothelial growth factors (VEGF), and epidermal growth factor receptor (EGFR) in nasopharyngeal cancer (NPC) cells, and their clinical significance in association with the extent of disease at diagnosis. Study Design: Prospective. Methods: Expressions of COX‐2, VEGF, and EGFR protein were detected using immunohistochemistry in 111 patients with pathologically confirmed stage II to IV nasopharyngeal carcinoma. The correlation between the expressions of the three tumor markers and the stages of disease at diagnosis were investigated. Results: COX‐2, VEGF, and EGFR were over‐expressed in 76.6, 66.7, and 73.9% of NPC cells, respectively. The staining patterns was cytoplasmic for VEGF, membranous for EGFR, and both cytoplasmic and membranous for COX‐2 in tumor cells. Linear associations were observed between the intensity of the expressions of COX‐2 vs. VEGF, COX‐2 vs. EGFR, or VEGF vs. EGFR. Furthermore, the intensity of the expressions of all three markers was significantly associated with the extent of the tumor measured by the Tumor, Node, Metastasis classification and staging grouping of the American Joint Committee on Cancer/International Union Against Cancer staging system. Conclusion: COX‐2, VEGF, and EGFR expressions in NPC cells were interrelated, and the intensity of the expressions of all three markers were significantly associated with the stage of the disease at diagnosis. Further investigation is needed to determine the clinical applications of COX‐2, VEGF, and EGFR in predicting the long‐term outcome of NPC after definitive therapy.     

血管内皮生长因子在鼻咽癌组织中的表达及其与淋巴转移的关系

目的 检测鼻咽癌中血管内皮生成因子C(VEGF-C)的表达及微淋巴管密度(microlymphatic vessel density,MLVD),探讨鼻咽癌淋巴管生成及淋巴转移之间的关系.方法 采用免疫组化SP法检测58例鼻咽癌和20例鼻咽部炎性反应组织中VEGF-C的表达情况,并用淋巴管内皮细胞特异性抗体LYVE-1行免疫组化染色,计数肿瘤内MLVD,并结合临床病理特征进行分析.结果 鼻咽癌组和炎性反应对照组VEGF-C的阳性表达率分别为84.5%(49/58)和15.0%(3/20),差异有统计学意义(X2=32.309,P＜0.01).鼻咽癌组织MLVD为(28.6±6.2)个/视野,鼻咽炎性反应组为(10.5 4±3.0)个/视野,两组差异有统计学意义(t=12.491,P＜0.01).鼻咽癌组织中,有淋巴转移组VEGF-C阳性表达率(87.8%)明显高于无淋巴转移组(76.5%);有淋巴转移组MLVD(30.2 4±6.4)个/视野高于无淋巴转移组(24.8±3.6)个/视野,经统计学分析,差异均有统计学意义(t=3.259,P＜0.01).VEGF-C的表达与MLVD(t=3.512,P＜0.01)、淋巴转移(X2=7.715,P＜0.01)、临床分期(X2=4.250,P＜0.05),与病理分化程度无关(X2=0.000,P＞0.05).VEGF-C的表达与MLVD(t=3.512,P＜0.01)、淋巴转移(X2=7.715,P＜0.01,r=0.712)、临床分期(X2=4.250,P＜0.05,r=0.481)相关,与病理分化程度无关(X2=0.000,P＞0.05).结论 在鼻咽癌组织中VEGF-C呈高表达,VEGF-C表达与鼻咽癌组织MLVD、淋巴转移、临床分期密切相关.VEGF-C可能参与了鼻咽癌发生、浸润和转移的过程.VEGF-C与肿瘤组织微淋巴管密切相关,在鼻咽癌发展过程中起重要作用,可能成为抗肿瘤治疗的潜在靶点.     

鼻咽癌中VEGF、bFGF的表达及其与颈淋巴结转移的关系

目的 探讨鼻咽癌中血管生长因子VEGF、bFGF的表达及其与颈淋巴结转移的关系。方法 采用免疫组化S－P法对35例鼻咽癌（其中15例同时取颈部转移癌组织）,20例鼻咽粘膜不典型增生组织和10例慢性炎症组织中VEGF、bFGF的表达进行了检测。结果（1）35例鼻咽癌中17例（48．6％）VEGF表达阳性,明显高于非癌对照组（6．7％,P＝0．000）,有颈淋巴结转移鼻咽癌中VEGF的表达（73．3％）明显高于无颈淋巴结转移者（30％,P＝0．018）;晚期（Ⅲ、Ⅳ期,70．6％）明显高于早期（Ⅰ、Ⅱ期,27．8％,P＝0．018）：但咽癌原发灶中VEGF的表达与颈部转移灶中的表达无相关性（P＞0．05）;（2）35例鼻咽癌中有8例（22．9％）bFGF表达阳性,明显高于非癌对照组（3．3％,P＝0．031）。但鼻咽癌中bFGF的表达与患者的年龄、性别、肿瘤的组织学类型和分期无关,也与肿瘤的N分期无关（P＞0．05）。结论 （1）VEGF与鼻咽癌的生长及颈淋巴结转移有关,它可能可以作为预测鼻咽癌颈淋巴结转移的的指标;（2）bFGF可能与鼻咽癌的生长有关系,但与肿瘤的颈淋巴结转移可能无关。     

Serum vascular endothelial growth factor in patients with head and neck squamous cell carcinoma

Vascular endothelial growth factor (VEGF) is a key pro-angiogenic cytokine expressed by most human tumours. Two isoforms, VEGF₁₂₁ and VEGF₁₆₅, are soluble and can be assayed in serum. Serum VEGF has been shown to be significantly raised in patients with solid tumours and shows some promise as a potentially useful tumour marker. Serum levels of VEGF were assayed in 52 patients with untreated head and neck squamous cell carcinoma (HNSCC) and 104 healthy controls. Serum VEGF is significantly raised in patients with HNSCC (P < 0.001), but there was no association with either tumour stage or specifically the presence of nodal metastases. Sixteen patients (31%) had a higher serum VEGF than 95th centile of controls, suggesting that serum VEGF measurement is of little practical use as an initial diagnostic tool. The finding that patients with HNSCC have significantly raised serum VEGF probably relates to enhanced platelet aggregation in these patients.     

鼻咽癌患者血清血管内皮生长因子检测及临床意义

目的 :探讨鼻咽癌患者放疗前后血清中血管内皮生长因子 (VEGF)的变化及临床意义。方法 :应用酶联免疫吸附法 (ELISA)对 4 6例鼻咽癌患者放疗前后血清中VEGF水平进行检测。结果 :鼻咽癌患者放疗前血清VEGF水平明显高于正常人 (P <0 .0 1) ,并随病情进展而升高 ;放疗后VEGF水平较放疗前明显降低 (P <0 .0 1)。VEGF水平 >15 0ng/L与 <15 0ng/L者的复发或转移率有明显差异 (P <0 .0 1)。结论 :VEGF不仅与鼻咽癌发生、发展有关 ,而且与其预后也密切相关 ,可望作为鼻咽癌患者预后的一个新的检测指标     

环氧化酶-2和血管内皮生长因子在鼻咽癌组织中的表达及相关性

目的:探讨环氧化酶-2(COX-2)、血管内皮生长因子(VEGF)在鼻咽癌组织中的表达及其相关性。方法:用免疫组织化学SP法检测58例鼻咽癌患者(鼻咽癌组)和38例鼻咽炎症患者(对照组)黏膜组织中COX-2、VEGF的表达。结果:COX-2、VEGF在鼻咽癌组中的表达均明显高于对照组(均P<0.05)。COX-2、VEGF的表达与鼻咽癌TNM分期有关,Ⅲ～Ⅳ期明显高于Ⅰ～Ⅱ期(P<0.05);与鼻咽癌的浸润和转移有关,有颈淋巴结转移者的表达率明显高于无颈淋巴结转移者(P<0.05)。鼻咽癌组织中COX-2、VEGF的表达呈正相关(r=0.302,P<0.05)。结论:COX-2、VEGF在鼻咽癌发生、发展中起重要作用,在鼻咽癌淋巴结转移中可能有协同效应。     

微血管密度与鼻咽癌生物学行为的相关性

探讨鼻咽癌血管生成与癌生物学行为的关系。方法采用免疫组织化学ＳＰ法检测了６５例ＮＰＣ、１５例鼻咽良性肿瘤、１５例无瘤者鼻咽部石蜡标本组织中的微血管密度及血管内皮细胞生长因子表达。     

Immunohistochemical demonstration of vascular endothelial growth factor in vestibular schwannomas correlates to tumor growth rate

OBJECTIVE: Vascular endothelial growth factor (VEGF) is one of the most potent mediators of angiogenesis, which is a mandatory process during tumor growth. The present objectives were to determine expression of VEGF in vestibular schwannomas by immunohistochemistry and to examine a possible correlation with symptom duration, tumor size, or growth rate. STUDY DESIGN: Retrospective patient file review; immunohistochemistry and light microscopy of vestibular schwannomas removed by surgery. METHODS: Vestibular schwannomas from 18 patients were immunolabelled using a polyclonal antibody against VEGF, followed by light microscopy and blinded semiquantitation of VEGF expression. Fifteen patients had a well-defined tumor growth rate defined by repeated preoperative magnetic resonance imaging scans. RESULTS: All tumors showed expression of VEGF in the Schwann cell cytoplasm, with a more intense staining of the perinuclear region of some cells. The staining intensity varied from tumor to tumor, and semiquantitation revealed a significant correlation between VEGF expression and tumor growth rate, but not symptom duration or tumor size. CONCLUSION: VEGF is expressed in vestibular schwannomas and the level of expression correlates positively with tumor growth rate, but not with tumor size and symptom duration. We conclude that VEGF seems to be a factor involved in the growth of vestibular schwannomas.     

鼻咽癌中VEGF的表达与树突状细胞含量的相关分析及临床意义

目的 探讨鼻咽癌组织中VEGF表达与树突状细胞含量的相关性。方法 选取鼻咽癌组织和鼻咽部淋巴组织各25例,采用ELISA方法检测组织中VEGF的表达,采用流式细胞仪检测组织中树突状细胞和调节性T细胞的含量并分析其相关性。结果 鼻咽癌组织中VEGF含量高于鼻咽部淋巴组织,组间差异具有统计学意义(t=12.324,P<0.01);鼻咽癌组织中CD4+淋巴细胞含量低于鼻咽部淋巴组织,组间差异具有统计学意义(t=14.304,P<0.01);而鼻咽癌组织中CD4+CD25+调节性T淋巴细胞含量高于鼻咽部淋巴组织,组间差异具有统计学意义(t=5.910,P<0.01);鼻咽癌组织中CD123+树突状细胞含量低于鼻咽部淋巴组织,组间差异具有统计学意义(t=7.866,P<0.01),鼻咽癌组织中CD11c+树突状细胞含量低于鼻咽部淋巴组织,组间差异具有统计学意义(t=3.411,P<0.01),鼻咽癌组织VEGF表达与CD4+CD25+淋巴细胞含量呈正相关(r=0.966 ,P<0.01),与CD123+树突状细胞含量呈负相关(r= -0.946,P<0.01),与CD11c+树突状细胞含量呈负相关(r= -0.954,P<0.01)。结论 鼻咽癌组织中VEGF表达与鼻咽癌组织中CD4+、CD25+调节性T细胞和树突状细胞的含量有关,可能参与鼻咽癌的免疫逃逸。     

喉癌组织血管内皮生长因子的表达与喉癌临床病理关系

目的 :探讨血管内皮生长因子 (VEGF)的表达与喉鳞状细胞癌的临床病理关系。方法 :采用SP免疫组织化学染色技术 ,评价 87例喉鳞癌患者的肿瘤组织中VEGF的表达和微血管计数 (MVC)。资料分析采用SAS软件。结果 :在喉鳞状细胞癌中 ,VEGF的免疫反应主要发生于肿瘤细胞的胞浆内 ,其阳性率为 77.0 %。肿瘤侵犯范围越广 ,VEGF的表达越强 ,肿瘤侵犯范围越小 ,VEGF的表达越弱 (P <0 .0 5 ) ;肿瘤分化越差 ,VEGF的表达越强 ,肿瘤分化越好 ,VEGF的表达越弱 (P <0 .0 5 ) ;VEGF的表达越强 ,MVC越多 ,二者呈明显的正相关(P <0 .0 1) ,且肿瘤组织中的平均MVC明显高于切缘组织中的平均MVC(P <0 .0 1)。结论 :在喉鳞状细胞癌中 ,VEGF的表达与肿瘤的临床分期和分化明显相关 ,与MVC存在着明显的正相关 ,提示VEGF在喉鳞状细胞癌的进展中具有重要的作用     

HIF-1a和VEGF在喉癌中的表达及其与血管生成的关系

目的：研究缺氧诱导因子-1a（HIF-1a）及血管内皮生长因子（VEGF）在喉癌组织中的表达程度及其与喉癌临床病理学特征之间的关系,并探讨HIF-1a及VEGF在肿瘤血管生成中的作用。为喉癌的发生机制提供理论基础,并为喉癌的早期诊断提供新思路。方法：试验分组：60例喉癌标本及20例癌旁正常组织。采用免疫组织化学方法检测HIF-1a及VEGF表达情况,并用CD105标记血管内皮细胞,计算微血管密度（MVD）。结果：60例喉癌组织中,HIF-1a、VEGF阳性表达率分别为71．67％（43／60）、65．00％（39／60）,MVD平均值为33．82±10．15;20例癌旁正常组织中,HIF-1a、VEGF阳性表达率分别为10％（2／20）、20％（4／20）,MVD平均值为21．48±6．84。喉癌组织中HIF-1a、VEGF阳性表达率显著高于正常喉组织。HIF-1a在喉癌组织中的阳性表达率与癌组织的临床分期、分化程度和淋巴结转移密切相关。VEGF阳性表达率与临床分期及有无淋巴结转移相关,而与组织分化程度无关。HIF-1a与VEGF表达一致符合率为56．67％（34／60）,两者表达呈明显正相关。HIF-1a、VEGF均阳性的喉癌组织MVD高于两者均为阴性者,差异有统计学意义（P〈0．01）。结论：喉癌组织中存在HIF-1a蛋白及VEGF的过表达,HIF-1a、VEGF与MVD在喉癌中的表达呈正相关,协同促进肿瘤新血管形成。     

The expression of vascular endothelial growth factor (VEGF) and VEGF‐C in early laryngeal cancer: relationship with radioresistance

The expression of vascular endothelial growth factor (VEGF) and VEGF‐C in early laryngeal cancer: relationship with radioresistance Angiogenesis is essential for tumour growth and invasion. Vascular endothelial growth factor (VEGF) is a prime mediator of tumour angiogenesis. VEGF‐C is a closely related protein that effects lymphatic endothelial cells and may be important in the process of lymphatic metastasis. The purpose of this study was to evaluate the expression of these cytokines in patients with T1 and T2a glottic, squamous cell carcinoma, in comparison with normal epithelial control tissue, to ascertain any association with radioresistance. Twenty‐two tumours treated by radiotherapy (13 radiosensitive, nine radioresistant) and seven normal control tissues were studied. The minimum follow‐up was 2 years after radiotherapy. Expression of VEGF and VEGF‐C was evaluated by immunohistochemistry of formalin‐fixed, paraffin‐embedded biopsy specimens. Analysis was carried out using a quantitative computer image analyser. Both VEGF and VEGF‐C were detectable in tumour and normal control specimens. There was increased expression in tumour specimens of both VEGF (P = 0.03) and VEGF‐C (P < 0.001). In addition, the expression of VEGF‐C was associated with tumours of higher histological grade (P = 0.021). There was, however, no difference in VEGF and VEGF‐C expression between radioresistant and radiosensitive tumours. The expression of VEGF and VEGF‐C is increased in early laryngeal squamous cell carcinoma (SCC). However, measuring the expression of these proteins cannot predict radioresistance in this tumour group.     

血管内皮生长因子及其受体对喉癌细胞生长的影响

为探讨血管内皮生长因子（ＶＥＧＦ）在喉癌中的作用及可能的作用方式，用抗ＶＥＧＦ抗体及其受体ｆｌｔ抗体通过微波处理暴露抗原后，进行标准化的ＥｌｉｔｅＡＢＣ染色；将不同浓度的抗ＶＥＧＦ及抗ｆｌｔ抗体分别加入ＨＥＰ－２细胞的培养液中，培养５ｄ后测ＨＥＰ－２细胞的活性（ＭＴＴ法）。结果：免疫组化染色显示ＶＥＧＦ及其受体ｆｌｔ主要在喉癌细胞和血管内皮细胞表达；不同浓度的ＶＥＧＦ抗体及抗ｆｌｔ抗体对ＨＥＰ－２     

鼻咽癌病人血清VEGF的表达及意义

目的探讨鼻咽癌病人血清中血管内皮生长因子(vascurar endothelial growth factor,VEGF)表达水平与鼻咽癌发生及复发之间的关系。方法应用酶联免疫吸附法(ELISA)定量检测35例鼻咽癌初发者、9例鼻咽癌复发者、7例完全缓解者、10例慢性鼻咽炎病人、10例正常健康人及鼻咽癌上皮细胞株(HNE-1)培养上清液中VEGF含量情况。结果35例鼻咽癌初发者、9例鼻咽癌复发者血清及HNE-1培养上清液中VEGF含量较正常健康人对照组显著增高(P<0.01);而完全缓解者组VEGF含量与正常对照组及慢性鼻咽炎病人比较无统计学意义(P>0.05);HNE-1培养上清液中VEGF含量与培养的鼻咽癌细胞数有一定相关性(P<0.05,r=0.657)。结论血清VEGF水平检测可作为诊断鼻咽癌发生、复发的观测指标之一。     

Serum levels of vascular endothelial growth factor in patients with head and neck cancer

Angiogenesis is now considered to be crucial for tumor growth and metastasis. In several tumors, microvascular density has been shown to be correlated with metastasis and aggressiveness. Vascular endothelial growth factor (VEGF) is a secreted endothelial cell-specific mitogen, which is induced by hypoxia and is angiogenic in vivo. VEGF has been identified in a wide variety of malignancies including head and neck squamous cell carcinomas (HNSCC). We investigated the circulating level of VEGF in sera from patients with various head and neck squamous cell carcinomas (n = 71) as well as from healthy normal controls (n = 47). Serum VEGF concentrations were determined as serum immunoreactivity by using a quantitative sandwich enzyme immunoassay technique. For statistical analysis, the Wilcoxon 2-sample test and Kruskal-Wallis test were performed. The majority of the patients with HNSCC were found to have high concentrations of serum VEGF. The levels of VEGF in the sera of patients with cancer ranged from below the detection limit to 937.1 pg/ml (mean, 144.5 pg/ml). In contrast, the VEGF serum levels in 47 healthy individuals ranged from below the detection limit to 168.1 pg/ml (mean, 32.7 pg/ml), VEGF serum concentration being significantly higher in HNSCC patients (P = < 0.001). These findings indicate that a positive angiogenesis regulator such as VEGF might function as an endocrine growth factor, particularly for solid HNSCC tumors and may be a useful marker for clinical monitoring. Received: 12 April 1999 / Accepted: 30 September 1999     

鼻咽癌组织中Shh与微血管密度的表达及其 和肿瘤转移的关系

目的分析鼻咽癌组织中Shh蛋白的表达以及与微血管密度分布的关系,探讨其与肿瘤淋巴结转移的关系。方法应用免疫组化Elivision PIus二步法,检测50例鼻咽癌和26例炎性鼻咽部黏膜组织间质微血管密度(micro vascular density,MVD)的分布,并检测Shh的表达。结果①Shh在鼻咽癌组织中较鼻咽慢性炎症组织明显呈高表达(P<0.05);②鼻咽癌中Shh阳性组MVD均值26.441±6.239,高于Shh阴性组15.667±4.899,两者之间差异有显著性(P<0.01);肿瘤细胞Shh表达与MVD相关,即MVD值随着Shh表达而增高;③鼻咽癌组织中Shh蛋白表达率与MVD均与临床分期,颈淋巴结转移有密切关系(P<0.05)。结论Shh可能促进鼻咽癌间质血管生成,促进肿瘤的侵袭和转移,Shh和MVD有可能成为判定鼻咽癌生物学行为和预后的重要指标。     

TrKB与VEGF在鼻咽癌组织中的表达及临床意义

目的探讨血管内皮生长因子(VEGF)、酪氨酸激酶B(TrKB)在鼻咽癌(NPC)组织中的表达并比较两者表达的相关性及分析与肿瘤临床特征的关系。方法采用免疫组化方法检测经活检确诊为NPC的患者55例及鼻咽炎组织30例中VEGF、TrKB蛋白表达水平,比较二两者表达差异。根据患者年龄和性别、肿瘤临床分型、原发灶大小、淋巴结转移和有无远处转移将病例分组,应用双变量相关Pearson检验分析研究VEGF、TrKB表达与肿瘤临床病理特征之间的关系。结果①VEGF蛋白于肿瘤细胞浆及血管内皮细胞浆中均表达,TrKB蛋白阳性表达绝大多数位于细胞浆内。在55例NPC患者中,45例TrKB阳性表达,阳性表达率为81.8%;47例VEGF阳性表达,阳性表达率为85.4%。30例鼻咽炎中,只有3例TrKB阳性表达,阳性表达率为10.0%;5例VEGF阳性表达,阳性表达率为16.7%。肿瘤组织中TrKB、VEGF阳性表达率明显高于鼻咽炎组织（P<0.05）,NPC组织中VEGF与TrKB表达有明显相关性（R=0.716,P<0.01）;②VEGF蛋白表达与NPC的临床分期(P=0.002)、肿瘤的直径大小(P=0.009)及有无淋巴结转移(P=0.001)明显相关,与患者性别、年龄、有无远处转移无关（P＞0.05）。TrKB蛋白表达与临床分期(P=0.00)、肿瘤的直径大小(P=0.00)、有无淋巴结转移（P=0.006）明显相关,与患者性别、年龄、有无远处转移无关（P＞0.05）。结论VEGF、TrKB在NPC组织中表达增加,可能与NPC的发生发展有关。TrKB可能与NPC血管形成有关。 （     

喉癌组织中P53和COX-2及VEGF与微血管密度相关性研究

目的探讨喉癌组织中P53、环氧合酶-2(cyclooxygenase-2,COX-2)及血管内皮生长因子(vascular endothelial growth factor,VEGF)与微血管密度(microvessel density,MVD)的关系。方法通过免疫组化S-P法对64例喉癌组织标本中P53、COX-2、VEGF及CD34抗体标记的MVD进行检测。结果喉癌组织中P53、COX-2、VEGF的阳性表达率分别为62.50%(40/64)、68.75%(44/64)和71.88%(4 6/6 4),MVD为3 5.8 7±9.3 8。P5 3、COX-2与VEGF之间呈正相关(r=0.3 8 3,P=0.0 0 2;r=0.305,P=0.014)。在有淋巴结转移的肿瘤中P53、COX-2及VEGF阳性表达率及MVD明显高于非转移组(P<0.05)。结论 P53、COX-2及VEGF表达可能共同参予喉癌的血管形成,且COX-2、VEGF的表达可能由P53调节,共同参与颈淋巴结转移的过程。