胰腺癌组织中淋巴管生成的机制及意义

目的：探讨胰腺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）与微淋巴管密度（microvessel vessd density,MLVD）、微血管密度（microvessel density,MVD）及淋巴结转移之间的相关关系,阐明癌周淋巴管增生的机制及意义.方法：免疫组化检测30例胰腺癌组织中VEGF-C、VEGF- D、血管内皮生长因子受体3（vascular endothelial growth factor receptor-3, VEGFR-3）（MLVD）以及CD34（MVD）蛋白的表达,RT-PCR检测VEGF-A、VEGF-C、VEGF-D mRNA在30例胰腺癌新鲜组织中的表达.结果： VEGF-C、VEGF-D蛋白阳性率分别为73%（22/30）和57%（17/30）,肿瘤周边部位显著高于肿瘤中心部位,差异有统计学意义,P ＜0.05; 其表达与肿瘤的部位、分化程度以及组织学类型无关,而与肿瘤的TNM分期有关,Ⅲ、Ⅳ期显著高于Ⅰ、Ⅱ期.在VEGF-C蛋白阳性组,MVD高于阴性组, P=0.047 2,MLVD亦高于阴性组,P＜0.01,淋巴结转移增多,P=0.031 8;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,P=0.017 9.结论： VEGF-C参与胰腺癌血管生成和淋巴管生成的调控,VEGF-D只参与淋巴管生成的调控.VEGF-C和VEGF-D诱导胰腺癌淋巴管生成,促进肿瘤细胞淋巴道转移.     

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.     

胃癌细胞间黏附分子-1与VEGF-D的关系及意义

目的:研究细胞间黏附分子-1(intercellular adhesion molecule-1, ICAM-1)与血管内皮生长因子受体-3 (vascular endothelial growth factor receptor-3 , VEGFR-3)信号通路的关系,从而揭示胃癌淋巴管转移的部分机制.方法:选择胃癌患者100例 ,其中早期胃癌13例,进展期胃癌87例(无淋巴结转移者37例,有淋巴结转移者50例);取距胃癌病灶＞5 cm处的正常胃黏膜标本30例为对照组.利用免疫组织化学法检测对照组和胃癌组织中血管内皮生长因子-C(vascular endothelial growth factor-C,VEGF-C) 、VEGF-D、VEGFR-3、ICAM-1和肿瘤新生淋巴管密度.观察胃癌组织中淋巴管、血管受侵情况.结果:ICAM-1阳性表达随肿瘤浸润深度增加而增加,对照组、早期胃癌和进展期胃癌的ICAM-1阳性表达率分别是0%、7.7%和31.0%( P ＜ 0.05);ICAM-1阳性表达与淋巴结转移、淋巴管受侵、VEGF-C和VEGF-D阳性表达有关(分别为 P ＜0.005, P ＜0.025, P ＜ 0.025, P ＜0.005).Logistic回归分析显示,ICAM-1阳性表达与淋巴结转移和VEGF-D阳性表达相关( P =0.001 2, P =0.023 7 ).结论:ICAM-1阳性表达与VEGF-D阳性表达呈正相关,其机制可能是VEGF-D通过VEGFR-2信号途径调节ICAM-1表达,从而在胃癌淋巴管转移中发挥作用.     

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。     

血管内皮生长因子C、D在鼻咽癌组织中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)和D(vascular endothelial growth factor-D,VEGF-D)是目前已鉴定出的淋巴管生长因子,有研究表明肿瘤组织中VECF-C或VEGF-D过表达与淋巴转移有关.本研究旨在探讨鼻咽癌组织中VEGF-C和VEGF-D的表达情况及其临床意义.方法:采用免疫组化SP法检测66例鼻咽癌组织中VEGF-C和VEGF-D的表达情况,同时检测血管内皮生长因子受体3(vascular endotheliaI growth factor receptor-3,VEGFR-3)和CD34染色情况并计数微淋巴管密度(lymphatic microvessel density,LMVD)和微血管密度(microvessel density,MVD).结果:VEGF-C高表达率在鼻咽癌组织中(54.5%)较鼻咽非肿瘤组织中(26.3%)高(P＜0.05);鼻咽癌伴区域淋巴结转移或T分期晚者,VEGF-C高表达率增高,单因素及多因素Logistic回归分析均表明区域淋巴结转移与VEGF-C高表达相关(P＜0.05),但VEGF-C高表达与性别、年龄、5年生存率、LMVD、MVD等因素无关(P＞0.05).VEGF-D阳性表达率在鼻咽癌组织中(69.7%)较鼻咽非肿瘤组织中(42.1%)高(P＜0.05);鼻咽癌中VEGF-D阳性表达与性别、年龄、T分期、区域淋巴结转移、LMVD、MVD等因素无关(P＞0.05),但与VEGF-C高表达显著正相关(P＜0.01),VEGF-D阳性表达者5年生存率(50.0%)显著低于VEGF-D不表达者(85.0%)(P＜0.01).结论:鼻咽癌中VEGF-C高表达与区域淋巴结转移密切相关;VEGF-D阳性表达与区域淋巴结转移无关,但与VEGF-C高表达正相关,且与5年生存率密切相关.     

血管及淋巴管生成相关基因表达与肿瘤转移率和转移途径的比较分析

目的:研究促进血管及淋巴管生成因子--血管内皮生长因子(vascular endothelial growth factor,VEGF)-A、-C、-D表达水平与肿瘤转移率及转移途径的关系,探讨其在肿瘤转移方面所起的作用,以及是否可作为判断肿瘤转移和预后的指标.方法:建立2种小鼠和4种人的肿瘤动物模型,观察肺、肝及腹股沟、腋下、髂血管和腹主动脉旁淋巴结大小及肿瘤转移情况.实时荧光定量-PCR(real-time fluorogentie quantitative PCR,RFQ-PCR)检测体外培养的肿瘤细胞及小鼠体内生长的肿瘤组织内VEGF-A、-C、-D及血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)-2、-3和淋巴管内皮细胞标志物--淋巴内皮细胞透明质酸受体-1(lymphatic vessel endothelial HA receptor-1,LYVE-1)的表达水平.结果:2种小鼠和4种人的肿瘤动物模型中61%～100%出现了肺转移,16%～100%出现了肝转移,2种小鼠肿瘤动物模型中26%～100%出现了淋巴结转移.结果表明,VEGF-A在肿瘤组织中表达量的增加将伴随着更高的肝、肺转移率.肿瘤组织中VEGF-C的表达水平与肿瘤的淋巴转移存在相关性,但VEGF-D表达水平增加与肿瘤淋巴结转移的发生率并不平行.结论:VEGF-A表达水平与肿瘤血道转移关系密切,VEGF-C在肿瘤淋巴结转移中起重要作用.     

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。      

胃癌组织中血管内皮生长因子的表达对血管和淋巴管生成的影响及其预后意义

目的 研究胃痛组织中血管内皮生成因子(VEGF)-A、VEGF-C和VEGF-D的表达对血管和淋巴管生成的影响及其预后意义.方法 采用免疫组化法检测123例原发性胃癌组织中VEGF-A、VEGF-C和VEGF-D的表达,采用D2-40和CD34免疫组化双染法分别标记淋巴管和血管,并测定淋巴管密度(LVD)和血管密度(MVD).采用单因素分析VEGF-A、VEGF-C和VEGF-D表达与胃癌临床病理特征的关系;采用Kaplan-Meier法和Log rank检验评价VEGF-A、VEGF-C和VEGF-D表达与胃癌患者预后的关系,并用Cox比例风险模型进行多因素分析.结果 123例胃癌组织中,VEGF-A、VEGF-C和VEGF-D的高表达率分别为64.2%、65.9%和41.5%.VEGF-A、VEGF-C或VEGF-D高表达及两两高表达均与LVD有关(均P＜0.05);VEGF-A和VEGF-C高表达还与浸润深度、淋巴管浸润、静脉浸润、淋巴结转移和MVD有关(均P＜0.05);VEGF-C和VEGF-D高表达均与淋巴管浸润和淋巴结转移有关(均P＜0.05).VEGF-A、VEGF-C或VEGF-D高表达者的生存时间均明显短于其低表达者(均P＜0.05),其中VEGF-A和VEGF-C均高表达者的生存时间最短(56个月).VEGF-A的表达水平、MVD、淋巴结转移及浸润深度是影响胃癌患者预后的独立因素.结论 VEGF-A和VEGFC均高表达的胃癌有更强的促进血管和淋巴管生成的能力,并可促进肿瘤转移和影响患者预后;VEGF-C和VEGF-D可共同介导淋巴管生成,促进淋巴结转移;但仅VEGF-A高表达是影响患者预后的独立危险因素.     

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.     

Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes

The spread of tumor cells to regional lymph nodes is an early event of gastric cancer metastasis. In our study, we assessed the expression of lymphangiogenic factors and lymphatic endothelial markers in gastric carcinoma tissues and compared expression levels with the status of lymph node metastasis. We also examined the correlation between lymphatic vessel density (LVD) in primary tumors and lymph node metastasis. Paired biopsy samples (tumor and corresponding normal mucosa) of gastric tissue were obtained from 39 patients with gastric carcinoma. The expression of VEGF-C, VEGF-D, VEGFR-3 and podoplanin mRNAs was assessed by real-time quantitative PCR. The expression of VEGF-C (but not of VEGF-D) was significantly greater in patients with lymph node metastasis than in those without metastasis. The expression of lymphatic endothelial markers VEGFR-3 and podoplanin was also significantly greater in the node-positive group. LVD, as assessed by immunohistochemistry for podoplanin, was correlated with lymph node metastasis. These results indicate that quantitative analysis of lymphangiogenic markers in gastric biopsy specimens may be useful in predicting metastasis of gastric cancer to regional lymph nodes.     

血管内皮生长因子-D在胃癌中表达的意义

Objective： To investigate the expression of vascular endothelial growth factor D （VEGF-D） in gastric cancer and its relationship with lymph node metastasis. Methods： 100 cases of gastric carcinoma tissues （50 cases with lymph node metastasis, 50 cases negative） and 30 cases of normal gastric tissues were gathered to detect the expressions of VEGF-C and D proteins by immunohistochemistry. Results： VEGF-C and D were revealed in cytoplasm of gastric carcinoma tissues and normal gastric tissues. The positive rates of VEGF-C and D expressions were significantly higher in gastric cancer tissues than those in the normal ones （51%, 60% vs 10%, 20% respectively; both P 〈 0.05）. There were significant correlations between the positive expression of VEGF-D and lymph node metastasis, lymphatic invasion, positive expression of VEG F-C, but not with tumour size, tissue differentiation, and venous invasion. Conclusion： The expression of VEGF-D is closely related to lymph node metastasis in gastric carcinoma.     

Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer

In gastric cancer, lymph node metastasis is one of the major prognostic factors and forms the basis for surgical removal of local lymph nodes. Recently, several studies have demonstrated that overexpression of lymphangiogenic growth factor VEGF-C or VEGF-D induces tumor lymphangiogenesis and promotes lymphatic metastasis in mouse tumor models. We examined whether these processes could be inhibited in naturally metastatic tumors by blocking of their cognate receptor VEGFR-3 signaling pathway. Using a mouse orthotopic gastric cancer model which has a high frequency of lymph node metastasis, we estimated lymphatic vessels in gastric cancers by immunostaining for VEGFR-3 and other specific lymphatic markers, LYVE-1 and prox-1. Then we systemically administered anti-VEGFR-3 blocking antibodies. This treatment resulted in the inhibition of regional lymph node metastasis and reduction of lymphatic vessel density in the primary tumors. In addition, increased density of LYVE-1-positive lymphatic vessels of primary tumors was closely correlated with lymph node metastasis in human samples of gastric cancer. Antilymphangiogenesis by inhibiting VEGFR-3 signaling could provide a potential strategy for the prevention of lymph node metastasis in gastric cancer.     

人胃癌VEGF-C、VEGF-D的表达与淋巴结转移的关系

目的 通过从蛋白水平检测VEGF-C、VEGF-D在正常胃黏膜及胃癌中的表达情况,探讨胃癌发生淋巴结转移的机制.方法 应用免疫组化SABC法检测VEGF-C、VEGF-D在正常胃黏膜及胃癌组织中的表达情况.结果 VEGF-C在正常胃黏膜中阴性表达,在胃癌组织中有选择性的表达,阳性率为44.4%,胃癌组与正常胃黏膜组比较差异有统计学意义(P＜0.01).VEGF-D在正常胃黏膜中无表达,在胃癌组织中阳性率为41.3%,胃癌组与正常胃黏膜组比较差异有统计学意义(P＜0.01).在有淋巴结转移组和无淋巴结转移组,VEGF-C的阳性表达率分别为64.5%和25.0%,两组间比较差异有统计学意义(P＜0.05).VEGF-D在这两组中的阳性表达率分别为61.3%和21.9%,两组间比较差异有统计学意义(P＜0.05).且VEGF-C、VEGF-D的阳性表达与胃癌的组织学分级、浸润深度密切相关.结论 VEGF-C、VEGF-D的过表达可能参与了胃癌的淋巴结转移.     

Vascular endothelial growth factors C and D and lymphangiogenesis in gastrointestinal tract malignancy

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are members of the VEGF family of cytokines and have angiogenic and lymphangiogenic actions. In gastric adenocarcinoma, VEGF-C mRNA and tissue protein expression correlate with lymphatic invasion, lymph node metastasis and in some reports, venous invasion and reduced 5-year survival. Patients with gastric adenocarcinomas containing high levels of VEGF-C expression have significantly reduced 5-year survival rates, and VEGF-C expression is an independent prognostic risk factor for death. The role of VEGF-C in oesophageal squamous and colorectal cancer and VEGF-D in colorectal cancer is not clear, with conflicting reports in the published literature. In order to exploit potential therapeutic applications, further research is necessary to define the precise roles of these cytokines in health and disease.     

Vascular endothelial growth factors and receptors in colorectal cancer: implications for anti-angiogenic therapy

There are conflicting associations between growth factor expression and clinicopathological variables in colorectal cancer. This study aimed to define the expression of members of the VEGF family and the receptor, VEGFR2, in primary and metastatic sites of colorectal cancer and their relationship to metastatic potential. Thirty colorectal cancers, 12 lymph node metastases and 9 liver metastases were immunostained for VEGF-A, VEGF-C, VEGF-D and VEGFR2. VEGFR2 was expressed by endothelial cells and by the malignant epithelium. VEGF-C and VEGFR2 were co-expressed in the same territory and correlated throughout the primary tumour and in metastatic lymph nodes, but not in liver metastases. Their expression at the invasive tumour edge correlated with expression in metastatic nodes. The benefit of anti-VEGF antibodies might be increased by directing additional therapies against VEGF-C or against the kinase receptors to target redundancy in the system. A component of the therapeutic benefit might be due to a direct anti-tumour effect as well as an anti-angiogenic effect.     

Expression analysis of vascular endothelial growth factors and their relationships to lymph node metastasis in human colorectal cancer

This study was undertaken to determine whether expressions of the vascular endothelial growth factor (VEGF) family (VEGF-A, VEGF-B, VEGF-C, and VEGF-D) are correlated with clinicopathological parameters, with particular reference to lymph node metastasis in colorectal cancer. Total RNA was isolated from 82 surgical specimens of colorectal cancer and matched to normal mucosa with (n = 41) or without (n = 41) lymph node metastasis. The mRNA expression of each VEGF family member was quantified by real-time quantitative (RTQ) RT-PCR assay. VEGF-B and VEGF-C mRNA were significantly higher both in the tumors with lymph node metastasis (p = 0.027 and p = 0.024, respectively) and in tumors with lymphatic invasion (p = 0.042 and p = 0.005, respectively). In contrast, VEGF-D mRNA was down-regulated in tumors with lymphatic involvement (p = 0.047). Among the other clinicopathological factors, we noted that VEGF-A mRNA was higher in tumors with liver metastasis than in those without (p = 0.018) and was higher in tumors with venous invasion than in those without (p = 0.007). The results of this study demonstrate that high levels of VEGF-B, C and low levels of VEGF-D mRNA expression are associated with lymph node metastasis and lymphatic involvement. These results suggest that a balance among VEGF-B, VEGF-C, and VEGF-D might contribute to the lymphangiogenic process and metastasis in colorectal cancer.     

Expression of vascular endothelial growth factor C and D (VEGF-C and -D) is an important risk factor for lymphatic metastasis in undifferentiated early gastric carcinoma

BACKGROUND: Vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are considered to be potentially lymphangiogenic and can selectively induce hyperplasia of the lymphatic vasculature. In this study, we aimed to clarify the relation between expression of VEGF-C and -D and lymphatic metastasis in early gastric cancers. METHODS: Using the specific antibodies, we classified 105 cases which were treated as gastrectomy with standard lymphadenectomy at the First Department of Surgery, Tokyo University Hospital, between 1994 and 2001, into three groups (diffuse type, focal type and negative type) for VEGF-C and two groups (positive and negative) for VEGF-D. RESULTS: There was a significant correlation between the expression of VEGF-C and -D and lymphatic invasion but not with venous invasion. All of the 22 cases that were negative for VEGF-C and -D were histologically classified as adenocarcinoma of undifferentiated type and showed negative lymph node metastasis and also negative lymphatic invasion. VEGF-C was positive in all tumors of differentiated type, while its expression varied in tumors of undifferentiated type. The VEGF-D positive rate is much lower than that of VEGF-C. In undifferentiated tumors in particular, VEGF-D was positive only in 4/64 (6%) and three of these four had nodal metastasis. Therefore, in tumors of differentiated type, expression of VEGF-C and -D had no clinical relevance. In tumors of undifferentiated type, the negative expression of VEGF-C suggests lack of nodal metastasis, while the positive expression of VEGF-D suggests nodal metastasis. The lymph node metastasis was significantly related to the expression of VEGF-C and -D in adenocarcinomas of undifferentiated type but not in those of differentiated tumors. CONCLUSIONS: In early gastric cancers of histologically undifferentiated type with negative expression of VEGF-C and -D, limited surgery might be safely applied because the possibility of nodal metastasis is very low. These observations are based only on retrospective analysis of a small case series and further evaluation with a larger number of cases is necessary.