VEGF-C和VEGF-D在胰腺癌淋巴转移中的意义

目的 分析胰腺癌肿瘤中心和肿瘤周边组织中血管内皮生长因子(VEGF)-C、VEGF-D与微血管密度(MVD)、微淋巴管密度(MLVD)的关系,探讨VEGF-C、VEGF-D在胰腺癌淋巴结转移及发展中的意义.方法 免疫组织化学法检测30例胰腺癌组织中VEGF-C、VEGF-D、VEGF受体(VEGFR)-3、CDM蛋白的表达情况.结果 30例胰腺癌中肿瘤周边部位VEGF-C、VEGF-D蛋白阳性率分别为73.3%和56.7%,显著高于肿瘤中心部位(30.0%和16.7%,P<0.01).VEGF-C、VEGF-D高表达的肿瘤周边部位淋巴结转移、淋巴管和血管浸润显著增加(P<0.01).VEGF-C蛋白阳性组MVD高于阴性组,MLVD显著高于阴性组(P<0.01),淋巴结转移增多;VEGF-D蛋白阳性组与阴性组相比MVD无变化(P=0.07),MLVD高于阴性组(P<0.01),淋巴结转移增加.结论 胰腺癌中肿瘤周边区域中VEGF-C、VEGF-D的表达与患者淋巴结转移显著相关,并介导其淋巴管生成;而VEGF-C可能主要参与胰腺癌的血管生成和淋巴管生成的调节,VEGF-D可能仅参与其淋巴管生成的调节.     

VEGF-C和VEGF-D在胃癌及相关淋巴结组织中表达和临床意义的研究

目的：比较血管内皮生长因子C（vascular endothelial growth factor C,VEGF-C）和血管内皮生长因子D（vascular endothelial growth factor D,VEGF-D）在胃癌和相关淋巴结的表达,并评价其预后意义.方法：采用原位杂交技术检测45例胃癌患者原发病灶和转移淋巴结中VEGF-C和VEGF-D mRNA的表达水平;并检测转移及非转移淋巴结中VEGF-C和VEGF-D mRNA表达差异.结果：71%和62.2%的胃癌原发病灶可见VEGF-C和VEGF-D mRNA表达,原发病灶阳性者,相应的淋巴结转移病灶都可见VEGF-C和VEGF-D mRNA表达,55.6%和51.1%的胃癌患者淋巴结转移病灶VEGF-C和VEGF-D mRNA表达水平高于原发病灶,原发病灶和转移病灶淋巴管生成表达水平的差异与胃癌的预后密切相关（P＜0.05）.结论：胃癌癌细胞转移至淋巴结后淋巴管生成因子表达可能进一步提高,以进一步增强转移能力.     

大肠癌组织淋巴管生成与淋巴转移相关性的研究

目的：探讨大肠癌组织中血管内皮生长因子-C（vascular endothelial growth factorC，VEGF：C）和-D（vascular endothelial growth factor D，VEGF—D）、癌旁淋巴管密度（lymphatic microvessel density，LMVD）的表达及其与临床病理参数的关系。方法：应用5’-Nase-酶组织化学技术及免疫组化SP法检测对50例大肠癌组织、正常肠组织测定中VEGF-C、VEGF-D和癌旁LMVD。结果：癌旁LMVD与VEGF-C、VEGF-D的表达呈正相关，大肠癌旁LMVD与VEGF-C、VEGF-D的表达与淋巴转移、Duke分期相关。结论：VEGF-C、VEGF-D／VEGFR-3信号传导机制促进淋巴管生成，导致癌旁LMVD的升高，进而促进大肠癌淋巴转移。     

胰腺癌VEGF-C的表达与淋巴管生成的关系及意义

目的探讨血管内皮生长因子C(vascular endothelial growth factor C,VEGF-C)在胰腺癌淋巴管生成及其与淋巴结转移中的作用。方法采用免疫组织化学染色法,检测42例胰腺癌组织标本和10例正常胰腺组织标本的VEGF-C表达;应用酶组织化学方法检测癌周微淋巴管密度(microlymphatic vessel density,MLVD)。结果胰腺癌VEGF-C的阳性表达率为64．3％,显著高于正常对照组的20％(P<0．05);胰腺癌MLVD为21．93±6．39,显著高于正常对照组的4．40±2．07(P<0．001),VEGF-C表达与肿瘤组织MLVD及淋巴结转移呈正相关(P<0．05)。结论VEGF-C在胰腺癌淋巴管生成及其淋巴结转移中具有重要作用。     

胆囊癌组织中血管内皮生长因子C和D的表达及其与淋巴管和血管生成的关系

目的 探讨胆囊癌组织中血管内皮生长因子C(VEGF-C)和VEGF-D的表达及其与淋巴管和血管生成的关系.方法 采用免疫组化法检测50例胆囊癌组织中VEGF-C、VEGF-D、D2-40和CD31的表达,以10例癌旁正常胆囊组织和19例慢性胆囊炎作为对照,并分析其与临床病理诸因素的关系.结果 50例胆囊癌组织中,32例VEGF-C表达阳性,阳性率为64.0%,31例VEGF-D表达阳性,阳性率为62.0%,均高于癌旁正常组织(P<0.05),但与慢性胆囊炎差异无统计学意义(P>0.05).VEGF-C的表达与胆囊癌患者的年龄和淋巴结转移有关,VEGF-D的表达仅与胆囊癌患者的淋巴结转移有关.50例胆囊癌组织的微淋巴管密度(MLVD)和微血管密度(MVD)分别为6.94±3.6和36.1±12.8.VEGF-C阳性组和VEGF-D阳性组的MLVD和MVD均高于阴性组.MLVD与淋巴结转移有关,MVD与淋巴结转移、分化程度有关.VEGF-C与VEGF-D的表达呈正相关(r=0.498,P<0.01).结论 在胆囊癌中,VEGF-C和VEGF-D参与胆囊癌的淋巴生成和血管生成的调节,通过增加瘤周淋巴管的密度促进肿瘤细胞的淋巴结转移.     

肾癌的淋巴管新生研究进展

肾癌是泌尿系统常见的恶性肿瘤,占成人恶性肿瘤的2%~3%。淋巴管生成可能是肾癌淋巴结转移的重要因素,在肿瘤转移过程中,血管内皮生长因子及其受体家族发挥了重要的作用。血管内皮生长因子-C（vascular endothelial growth fac? tor-C,VEGF-C）与其特异性的受体血管内皮生长因子受体-3（vascular endothelial growth factor receptor-3,VEGFR-3）结合可促进淋巴管生成,并促进肿瘤淋巴结转移。肿瘤的淋巴管新生是当前肿瘤研究的热点,并有可能成为治疗肿瘤淋巴结转移的靶点。近年来对于肾癌淋巴管的研究正在展开,本文对肾癌淋巴管新生的最新研究进展及此项研究的临床意义进行综述。      

食管鳞癌组织VEGF-C和VEGF-D表达及其与淋巴管生成和转移关系的探讨

目的:探讨食管鳞癌组织中血管内皮生长因子C(vascular endothelial growth factor-C,VEGF-C)、血管内皮生长因子D(vascular endothelial growth factor D,VEGF-D)的表达及与淋巴管生成和淋巴结转移的关系.方法:采用免疫组化法检测64例食管癌和14例癌旁正常食管黏膜中VEGF-C、VEGF-D和D2-40的表达,并分析其与临床病理诸因素的关系.结果:VEGF-C在淋巴结转移组和无淋巴结转移组的阳性率分别为73.08%(19/26)和34.21%(13/38),VEGF-D的阳性率分别为53.85%(14/26)和28.95%(11/38),差异有统计学意义,x2值分别为9.328和4.021,P值分别为0.002和0.045.VEGF-C和VEGF-D之间的表达差异无统计学意义,x2=1.641,P=0.20.癌组织和癌旁正常食管黏膜中D2-40阳性表达的淋巴管密度(lymphatic-vessel density, LVD)差异有统计学意义,P=0.000;VEGF-C阳性组与阴性组中D2-40阳性表达的LVD差异有统计学意义,P=0.010,而VEGF-D阳性组与阴性组中差异无统计学意义.P=0.543.结论:在食管癌中存在VEGF-C、VEGF-D的表达,VEGF-C通过增加癌周LVD促进肿瘤细胞的淋巴结转移,与VEGF-D各自参与淋巴结转移的作用.两者的表达预示淋巴结转移的增加,对食管癌预后估计有指导意义.     

非小细胞肺癌VEGF-C VEGF-D VEGFR-3表达与淋巴转移关系的研究

目的:探讨血管内皮生长因子(vascular endothelial growthfactor,VEGF)-C-、-D及其受体3(vascular en-dothelial growthfactor receptor-3,VEGFR-3)在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达规律、与微淋巴管密度(microlymphatic vessel density,MLVD)、淋巴转移之间的关系及其在NSCLC发生发展、预后中的意义.方法:以40例经病理确诊的NSCLC组织、146枚淋巴结为实验组,以11例肺良性病变组织为对照组,采用免疫组织化学染色法(immunohistochemistry,IHC)对上述组织中VEGF-C、VEGF-D、VEGFR-3、淋巴管内皮透明质酸受体-1(1ymphatic vegscl endothelial hyaluronan receptor-1,LYVE-1)蛋白的表达进行分析,并计数微淋巴管密度.结果:[1]NSCLC组织中VEGF-C、VEGF-D及VEGFR-3蛋白的阳性率分别为77.50%(31/40例)、67.50%(27/40例)、62.50%(25/40例),明显高于肿瘤周边组织(距肿瘤边缘100μm区域内)及肺良性病变组织(P=0.003,P=0.007,P=0.002;P=0.009,P=0.003,P=0.009).②VEGF-C、VEGF-D及VEGFR-3蛋白的表达与NSCLC患者的性别、年龄、肿瘤的大小、组织学类型、分化程度无关,但与肿瘤的淋巴结转移(P=0.044,P=0.027,P=0.001)、PTNM分期(P=0.018,P=0.033,P=0.007)显著相关.③VEGF-C与VEGFR-3蛋白表达(r=0.409,P=0.005),VEGF-D与VEGFR-3蛋白表达(r=0.492,P=0.000)均存在相关性;而VEGF-C与VEGF-D蛋白表达无相关性(r=0.256,P=0.093).④146枚淋巴结中35枚有转移,有转移的淋巴结组织中VEGF-C、VEGF-D及VEGFR-3蛋白的阳性率分别为74.29%(26/35例)、65.71%(23/35例)、54.29%(19/35例),明显高于无转移的淋巴结组织(P=0.000,P=-0.001,P=0.006).⑤NSCLC肿瘤中心组织中LYVE-1标记的MLVD为4.22 ±1.25,明显低于肺良性病变组织(P=0.000),而NSCLC肿瘤周边部位的MLVD显著高于肿瘤中心部位及肺良性病变组织(P=0.000).VEGF-C、VEGF-D、VEGFR-3表达阳性的组织中,MLVD显著高于阴性组织(P<0.05).MLVD与肿瘤的淋巴结转移(P=0.000)、PTNM分期(P=0.000)显著相关.结论:淋巴管生成因子VEGF-C、VEGF-D及其受体VEGFR-3蛋白在NSCLC中表达显著增高,并且通过VEGF-C、VEGF-D/VEGFR-3信号通路诱导淋巴管内皮细胞新生和淋巴管生成,从而促进淋巴结转移和肿瘤生长;VEGF-C、VEGF-D及其受体VEGFR-3可能成为检测NSCLC淋巴转移和评估预后的重要分子指标;淋巴管内皮细胞特异性标志物LYVE一1可以较严格地区分血管和淋巴管内皮,相对精确地评价肿瘤的脉管系统.     

血管内皮生长因子C的研究进展

区域淋巴结转移是大多数肿瘤的重要愈后因素,抗淋巴管转移的治疗是目前的研究热点之一,但迄今为止人们对淋巴转移机制了解甚少.血管内皮生长因子C（vascular endothelial growth factor-C,VEGF-C）是第一个被发现的促淋巴管生成因子,已证实VEGF-C及其受体VEGFR-3 （vascular endothelial growth factor receptor-3）在通过诱导肿瘤淋巴管的生成进而促进区域淋巴结转移中可能起重要作用.因此,VEGF-C/ VEGFR-3信号通路可能在肿瘤的抗淋巴管生成治疗中提供一个新靶区.且在恶性肿瘤中,VEGF-C可能通过结合VEGFR-2和VEGFR-3共同促进肿瘤血管生成.对近年来关于VEGF-C与肿瘤淋巴管、血管转移的关系及抗淋巴管生成治疗的研究进行综述.     

VEGF在恶性肿瘤中的研究进展

肿瘤的生长依赖肿瘤新生血管的形成，血管内皮生长因子（VEGF）及其家族是重要的血管生成正性调节因子，VEGF家族包括VEGF-A﹑VEGF-B ﹑VEGF-C﹑ VEGF-D ﹑VEGF-E和胎盘生长因子，本文旨在对VEGF家族的结构、功能、调控等方面的研究作一综述。     

血管内皮生长因子受体在恶性肿瘤中的研究进展

血管内皮生长因子受体（VEGFR）是血管内皮生长因子的特异性受体，包括VEGFR-1、VEGFR-2、VEGFR-3、神经纤维因子-1及神经纤维因子-2。前三者是酪氨酸激酶亚家族的成员之一，具有特征性的胞外区和酪氨酸激酶区，通过与相应的VEGF结合刺激血管内皮细胞增殖、迁移、促进新生血管的生成，与机体多种常见肿瘤的发病和转移有着密切的关系。本文就VEGFR家族成员、基因结构及其与肿瘤的关系做一系统综述。     

Vascular permeability factor (VPF,VEGF) in tumor biology

Summary Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a multifunctional cytokine expressed and secreted at high levels by many tumor cells of animal and human origin. As secreted by tumor cells, VPF/VEGF is a 34–42 kDa heparin-binding, dimeric, disulfide-bonded glycoprotein that acts directly on endothelial cells (EC) by way of specific receptors to activate phospholipase C and induce [Ca²⁺]i transients. Two high affinity VPF/VEGF receptors, both tyrosine kinases, have thus far been described. VPF/VEGF is likely to have a number of important roles in tumor biology related, but not limited to, the process of tumor angiogenesis. As a potent permeability factor, VPF/VEGF promotes extravasation of plasma fibrinogen, leading to fibrin deposition which alters the tumor extracellular matrix. This matrix promotes the ingrowth of macrophages, fibroblasts, and endothelial cells. Moreover, VPF/VEGF is a selective endothelial cell (EC) growth factorin vitro, and it presumably stimulates EC proliferationin vivo. Furthermore, VPF/VEGF has been found in animal and human tumor effusions by immunoassay and by functional assays and very likely accounts for the induction of malignant ascites. In addition to its role in tumors, VPF/VEGF has recently been found to have a role in wound healing and its expression by activated macrophages suggests that it probably also participates in certain types of chronic inflammation. VPF/VEGF is expressed in normal development and in certain normal adult organs, notably kidney, heart, adrenal gland and lung. Its functions in normal adult tissues are under investigation.     

Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

Vascular endothelial growth factor (VEGF) receptors consist of three cell-membrane type receptors (VEGFR-1, VEGFR-2 and VEGFR-3), and soluble form of VEGFR-1 (sVEGFR-1), an intrinsic negative counterpart of the VEGF. In this study, we measured intratumoral protein levels of free and total VEGF, VEGFR-2 and sVEGFR-1 from 202 primary breast cancer tissues and examined their prognostic values. A significant inverse correlation was found between free or total VEGF and oestrogen receptor (ER) status (P=0.042 and 0.032, respectively). A univariate analysis showed that low sVEGFR-1 and high total VEGF were significantly associated with poor prognosis in disease-free survival (DFS) and overall survival (OS). The ratio of sVEGFR-1 to total VEGF was a strong prognostic indicator (DFS: P=0.008; OS: P=0.0002). A multivariate analysis confirmed the independent prognostic values of total VEGF and the ratio of sVEGFR-1 to total VEGF. In subgroup analysis, total VEGF was a significant prognostic indicator for ER-positive tumours but not for ER-negative tumours, whereas sVEGFR-1 was significant for ER-negative tumours but not for ER-positive tumours. In conclusion, the intratumoral sVEGFR-1 level, VEGF level and the ratio of sVEGFR-1 to total VEGF are potent prognostic indicators of primary breast cancer, and might be relevant to ER status.     

Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer

Angiogenesis, the formation of new blood vessels, is controlled by a balance between positive and negative endothelial regulatory factors. Soluble vascular endothelial growth factor receptor-1 (sVEGFR1), a naturally occurring soluble form of VEGFR1, is a negative counterpart of the vascular endothelial growth factor (VEGF) signaling pathway, which has been characterized as one of the most important endothelial regulators in human tumor angiogenesis. In our study, we examined the expression of sVEGFR1 in 110 primary breast carcinomas, and assessed its clinical significance. Ninety-four of 110 tumors showed > or = 0.1 ng/mg protein of sVEGFR1 (range:0. 1-6.9 ng/mg protein; median: 1.03 ng/mg protein) as determined by a specific enzyme-linked immunosorbent assay (ELISA). Immunoblot analysis confirmed the presence of sVEGFR1 in breast tumor tissues. The levels of sVEGFR1 were correlated significantly with the levels of VEGF. There was no significant correlation between the levels of sVEGFR1 and any clinico-pathological factors including age, menopause, nodal involvement and hormone receptor status. A univariate prognosis analysis showed that the intratumoral VEGF status, as determined by ELISA, was a significant prognostic indicator, but sVEGFR1 status was not. In the combined analysis, however, the ratio of sVEGFR1 and VEGF levels provided more statistically significant prognostic value than VEGF status alone. Tumors in which the sVEGFR1 levels exceeded VEGF levels 10-fold had a markedly favorable prognosis. Multivariate analysis also demonstrated that the ratio of sVEGFR1 and VEGF was an independent prognostic indicator after nodal status. In conclusion, sVEGFR1, an intrinsic inhibitor of VEGF, frequently co-expressed with VEGF in primary breast cancer tissues. The intratumoral balance between sVEGFR1 and VEGF levels might be crucial for the progression of breast cancer.     

淋巴管生成因子在肿瘤转移中的作用

肿瘤转移是恶性肿瘤高死亡率的主要原因，淋巴管系统是肿瘤转移的一个重要途径。长期以来，由于缺乏淋巴管内皮细胞特异性标志，我们对淋巴管系统及其在肿瘤转移中的作用知之甚少。目前，淋巴管生成因子和淋巴管内皮细胞特异性标志的相继发现大大促进了淋巴系统这一领域的研究。大量动物实验以及临床病理研究结果显示，淋巴管生成因子与肿瘤中淋巴管生成和淋巴结转移显著相关，这使得淋巴管生成因子成为肿瘤淋巴道转移机制和抗肿瘤研究的新热点。     

血管内皮生长因子D及其受体3在乳腺癌淋巴转移中作用的研究进展

乳腺癌是女性最常见的恶性肿瘤。乳腺癌淋巴转移与患者的预后密切相关。最近研究表明淋巴管生成可能会主动促进淋巴转移的发生,而血管内皮生长因子家族的部分成员在这一过程中发挥了重要作用,如血管内皮生长因子C、血管内皮生长因子D及其受体3等。但是,对乳腺癌中血管内皮生长因子D的作用及其预后价值、血管内皮生长因子受体3与乳腺癌淋巴管生成的关系等问题仍有争议。本文对近年国内外有关血管内皮生长因子D及其受体3在乳腺癌淋巴转移中作用的研究进展作一综述。     

宫颈癌中VEGF-C及其受体mRNA的表达及其临床意义

背景与目的：血管内皮生长因子C（vascular endothelial growth factor C，VEGF-C）是一个较为特异的淋巴内皮细胞生长刺激因子，通过其受体VEGFR-2（KDR）及受体VEGFR-3（Flt-4）分别作用于血管和淋巴管上皮促进肿瘤的生长和转移。研究宫颈癌组织及癌旁组织中血管内皮生长因子C及其受体mRNA的表达情况，分析其在肿瘤转移中的作用。方法：采用RT-PCR法分析48例新鲜宫颈癌组织及癌旁组织标本中VEGF-C／KDR／Flt-4mRNA的表达情况，并分析其与各临床病理参数之间的关系。结果：48例宫颈癌组织与瘤旁组织中的VEGF-C及其受体mRNA表达率明显高于正常宫颈组织，肿瘤组织中VEGF-C mRNA表达与flt-4 mRNA的表达呈显著正相关，癌旁组织（PT）中VEGF-C mRNA表达与KDR mRNA的表达显著相关（P〈0．001）。宫颈癌组织的VEGF-C、KDR或Flt-4 mRNA表达与肿瘤的病理类型及临床病理分期无明屁的相关；而与肿瘤的病理分化程度、淋巴结转移、肿瘤直径、深肌层浸润间差异有显著性（P〈0．05）。结论：VEGF-C可能在宫颈癌转移尤其是淋巴转移中起重要作用，是一个反映患者淋巴转移和预后的良好指标。     

VEGF 与 EGFR 在胸腔积液鉴别中的意义

近年来发现VEGF及EGFR在不同疾病致胸腔积液的形成过程中发挥了重要作用，本文旨在探讨以血管内皮生长因子（VEGF）及表皮生长因子受体（EGFR）为指标判断胸液良恶性的作用。     

The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer

A positive association between vascular endothelial growth factor-C (VEGF-C) expression and lymph node metastasis has been reported in several cancers. However, the relationship of VEGF-C and lymph node metastasis in some cancers, including non-small cell lung cancer (NSCLC), is controversial. We evaluated the VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression in NSCLC samples from patients who had undergone surgery between 1998 and 2002 using real-time quantitative RT-PCR and immunohistochemical staining. We failed to find a positive association between VEGF-C and VEGFR-3 mRNA expression and lymph node metastasis in NSCLC. An immunohistological study demonstrated that VEGF-C was expressed not only in cancer cells, but also in macrophages in NSCLC, and that VEGFR-3 was expressed in cancer cells, macrophages, type II pneumocytes and lymph vessels. The VEGF-C/VEGFR-3 ratio of the node-positive group was significantly higher than that of the node-negative group. Immunohistochemical staining showed that VEGFR-3 was mainly expressed in cancer cells. The immunoreactivity of VEGF-C and VEGFR-3 was roughly correlated to the mRNA levels of VEGF-C and VEGFR-3 in real-time PCR. VEGF-C mRNA alone has no positive association with lymph node metastasis in NSCLC. The VEGF-C/VEGFR-3 ratio was positively associated with lymph node metastasis in NSCLC. This suggests that VEGF-C promotes lymph node metastasis while being influenced by the strength of the VEGF-C autocrine loop, and the VEGF-C/VEGFR-3 ratio can be a useful predictor of lymph node metastasis in NSCLC.