贲门腺癌中VEGF-C、VEGF-D和D2-40的表达及意义

目的 以一种新的淋巴管特异标记物D2-40标记贲门腺癌(gastric cardiac adenocarcinoma, GCA)及癌周组织淋巴管,并进行淋巴管计数,研究其与VEGF-C 、VEGF-D表达的关系及其临床病理意义.方法应用免疫组化SP法检测贲门癌、癌旁及正常黏膜组织中VEGF-C、VEGF-D、D2-40的表达情况.结果 癌及癌旁组中淋巴管密度(lymphatic vessel density,LVD)明显高于正常组(P<0.05),而癌组与癌旁组间LVD统计学无明显差异.癌组织中LVD与淋巴结转移、TNM分期及肿瘤浸润深度呈正相关(P<0.01),而与分化程度无关;VEGF-C、VEGF-D在贲门癌中的表达明显高于癌旁组和正常组(P<0.01);癌组织中LVD在VEGF-C和VEGF-D表达阳性组中高于阴性组(P<0.05);LVD与VEGF-C、VEGF-D的表达呈正相关(P<0.05).结论 贲门癌及癌周间质中D2-40标记的LVD升高可能增加了贲门癌淋巴结转移的风险;D2-40、 VEGF-C、VEGF-D的联合检测可作为评估贲门癌淋巴结转移潜能的标志物,并且对其预后评估有一定的价值.     

血管内皮生长因子-A与血管内皮生长因子-C在非小细胞肺癌中表达及与淋巴结转移的相关性

目的 探讨血管内皮生长因子(vascular endothelial growth factor,VEGF)-A和VEGF-C在非小细胞肺癌(non-small lung cancer,NSCLC)中的表达及与淋巴管生成、转移的关系.方法 以60例肺癌组织作为实验组,20例肺正常组织作为参考组,采用免疫组织化学方法检测其中的VEGF-A和VEGF-C两种蛋白表达,以D2-40 及CD34分别标记组织淋巴管和血管中的内皮细胞,并记录淋巴管的密度,血管作为对比,结合NSCLC临床、病理参数系统分析.结果 ①肺癌组织内VEGF-A蛋白阳性的表达率为73.33%(44/60)明显高于肺正常组织25.00%(5/20)(χ2=14.7641,P=0.0001),VEGF-C蛋白的阳性表达率为83.33%(50/60) 明显高于肺正常组织30.00%(6/20)(χ2=20.3175,P =0.0001).②肺癌组织VEGF-A蛋白阳性的表达高于癌旁周围组织(χ2=4.4815,P=0.0343),癌组织内VEGF-C蛋白阳性的表达高于癌旁周围组织(χ2=8.5333,P=0.0035).③VEGF-A与VEGF-C蛋白的表达和患者的性别、年龄大小、分化的程度、肿瘤大小、组织学无关,但淋巴结转移与PTNM分期呈显著相关(χ2=6.3736,P=0.0116)和(χ2=6.6516,P=0.0099).④VEGF-A蛋白阳性组织中微淋巴管密度(microlymphatic vessel density,MLVD)显著高于阴性组织(t=-7.2735,P<0.005),VEGF-C蛋白阳性的组织中MLVD 显著高于阴性组织(t=6.9338,P<0.005).MLVD与淋巴结转移和PTNM分期显著相关(t=-12.1146,P<0.05).结论 NSCLC组织中VEGF-A与VEGF-C二者蛋白的表达可能通过促进增加淋巴管生成从而促进淋巴结的转移.因此,在NSCLC中VEGF-A和VEGF-C蛋白可作为评估淋巴结转移的重要标记因子.     

喉鳞状细胞癌中BRAP和VEGF-C的表达及其与淋巴管生成的关系

目的探讨BRAP和VEGF-C在喉鳞状细胞癌(laryngeal squamous cell carcinoma, LSCC)组织中的表达及其与组织内淋巴管生成及淋巴结转移的关系。方法采用免疫组化PV 6000法检测84例LSCC组织及15例癌旁组织中BRAP、VEGF-C的表达,并用D2-40免疫组化染色标记检测微淋巴管生成情况。分析BRAP、VEGF-C蛋白表达与淋巴管生成及淋巴结转移的关系。结果 LSCC中BRAP、VEGF-C的高表达率分别为65.5%和53.6%,均高于癌旁组织(P0.05)。BRAP、VEGF-C在淋巴结转移组的表达均高于无淋巴结转移组(P0.05),两者的表达有相关性(P0.01)。淋巴结转移组的微淋巴管密度(micro-lymphatic vessel density, MLVD)高于无淋巴结转移组(P0.01),BRAP、VEGF-C高表达组的MLVD值比其低表达组均增高(P0.01)。结论 BRAP和VEGF-C在LSCC中呈高表达,BRAP可能通过上调VEGF-C促进肿瘤淋巴管的生成及淋巴结转移。     

VEGF-C表达与胰腺癌淋巴结转移及预后的关系

目的 观察血管内皮生长因子(VEGF)-C在胰腺癌组织内的表达情况,分析VEGF-C的表达与胰腺癌淋巴结转移和预后之间的关系。方法 取胰腺癌病例52例,其中,伴淋巴结转移组36例,无淋巴结转移组16例。应用免疫组化法和Western blot技术观察VEGF-C在胰腺癌组织内的表达。以D2-40作为淋巴管内皮特异性标记物,观察胰腺癌组织内淋巴管生成的情况。采用Kaplan-Meier法绘制生存曲线判断VEGF-C的表达对胰腺癌预后的影响。结果 Western blot和免疫组化法检测结果表明,VEGF-C主要表达于胰腺癌细胞浆内,淋巴结转移组阳性表达量明显高于无淋巴结转移组(p<0.05)。D2-40表达于胰腺癌组织内淋巴管内皮细胞,VEGF-C阳性组淋巴管数密度明显高于VEGF-C阴性组(p<0.05),表明VEGF-C的表达与胰腺癌淋巴管生成密切相关。Kaplan-Meier生存分析表明VEGF-C表达阴性患者的生存率均高于VEGF-C表达阳性患者,VEGF-C的表达影响患者的预后。结论 VEGF-C在胰腺癌的淋巴管生成和淋巴结转移过程中发挥重要作用,VEGF-C的表达是影响胰腺癌患者预后的主要因素之一。     

血管内皮生长因子C、D和受体3在人胰腺癌组织中的表达

目的:通过观察不同临床指标的人胰腺癌组织VEGF-C、VEGF-D、VEGFR-3的表达,来探讨VEGF-C和VEGF-D对人胰腺癌转移的影响,为癌组织中淋巴管的生成机制以及癌的淋巴道转移机制提供理论依据。方法:取人胰腺癌标本33例及癌旁正常胰腺组织15例,用免疫组化的方法观察VEGF-C、VEGF-D及VEGFR-3在人胰腺癌和癌旁正常胰腺组织中的表达。结果:VEGF-C、VEGF-D和VEGFR-3在胰腺癌组织中的表达比例较在癌旁正常胰腺组织中的表达比例明显增高,并且VEGFR-3的表达与VEGF-D的表达具有显著相关性(P<0.01),与VEGF-C的表达不具有相关性(P>0.05)。胰腺癌组织中VEGF-C和VEGF-D的表达与患者的年龄、性别、远处转移无关(P>0.05)。结论:VEGF-C、VEGF-D在胰腺癌组织中的表达明显增高,并有可能通过与VEGFR-3的结合促进了癌组织中淋巴管的生成,从而对癌的淋巴道转移起促进作用。     

Smad4的表达与胰腺癌淋巴管生成之间的关系

目的观察血管内皮生长因子(VEGF)-C和Smad 4在胰腺癌组织内的表达情况,分析VEGF-C和Smad 4的表达与胰腺癌淋巴管生成及淋巴结转移之间的关系。方法取胰腺癌病例52例,其中,无淋巴结转移组12例,淋巴结转移组40例。应用免疫组化和Western blot技术检测VEGF-C和Smad4在胰腺癌组织内的表达情况。以D2-40作为淋巴管内皮标记物,观察胰腺癌组织内淋巴管生成情况。结果 VEGF-C主要表达于胰腺癌细胞胞质内,在淋巴结转移组的表达水平明显高于无淋巴结转移组。Smad4表达于胰腺癌细胞胞质和胞核内,在无淋巴结转移组的表达水平明显高于淋巴结转移组,Smad4表达阳性组淋巴管数密度明显低于Smad4表达阴性组(=0.02)。Smad4的表达与VEGF-C的表达呈显著的负相关性。结论 VEGF-C在胰腺癌淋巴管的发生及淋巴结转移中发挥重要作用,Smad4可能通过调节VEGF-C蛋白的表达抑制胰腺癌淋巴管生成和淋巴结转移。     

血管内皮生长因子D和血管内皮生长因子受体3在人结肠癌中的表达及淋巴道转移中的作用

目的 观察血管内皮生长因子D(VEGF-D)和血管内皮生长因子受体3(VEGFR-3)在人结肠癌组织中的表达,检测结肠癌组织中的微淋巴管密度(LMVD),探讨VEGF-D和VEGFR-3在淋巴管生成以及结肠癌淋巴道转移中的作用.方法 选择55例不同时期,不同分化程度的人结肠癌组织样本,应用免疫组织化学染色的方法,观察VEGF-D和VEGFR-3在人结肠癌组织中的表达,应用Podoplanin标记淋巴管,检测结肠癌组织中的淋巴管密度.结果 在55例结肠癌组织中,VEGF-D的阳性表达率为54.5%,明显高于在癌周正常组织内的表达(P＜0.05);结肠癌组织中VEGFR-3表达的阳性率为69.1%,明显高于在癌周正常组织内的表达(P＜0.01);并且VEGFR-3的表达与VEGF-D的表达具有显著相关性(P＜0.01).在结肠癌组织中,淋巴结转移阳性组,浸润深度超过肌层组,DukeC、D期的VEGF-D的表达水平和LMVD明显高于淋巴结转移阴性组,浸润深度未超过肌层组,Duke A、B期(P＜0.01),经计数淋巴管数量,癌组织中的LMVD明显高于癌周正常组织(P＜0.01),并且LMVD与VEGF-D的表达显著相关(P＜0.01).结论 结肠癌组织中VEGF-D的表达水平随着癌的浸润和转移程度的增强而增高,并且通过上调其受体VEGFR-3的表达而促进癌组织中淋巴管的生成,从而促进癌的浸润和转移.     

甲状腺乳头状癌中VEGF-C和VEGF-D的表达及相关性及与临床病理特征的关系

目的探讨淋巴管生成因子VEGF-C、VEGF-D在甲状腺乳头状癌(papillary thyroid carcinoma,PTC)的蛋白表达及与临床病理特征的关系及表达相关性。方法对105例PTC进行VEGF-C和VEGF-D的免疫组化检测,以相应的癌旁正常甲状腺组织相对照,原位观察两者在甲状腺乳头状癌的蛋白表达,分析两者与临床病理特征的关系及两者表达的相关性。结果 (1)甲状腺乳头状癌中瘤组织VEGF-C和VEGF-D蛋白均高表达,表达率分别达54.3%(57/105)和74.3%(78/105)。(2)PTC中VEGF-C、VEGF-D蛋白表达在淋巴结转移阳性组较阴性组明显增强,差异具有统计学意义(P0.05)。(3)PTC中VEGF-C、VEGF-D两者蛋白表达呈正相关(r=0.466,P0.01)。结论甲状腺乳头状癌的瘤细胞VEGF-C、VEGF-D蛋白高表达在淋巴道转移中可能发挥了重要的作用。两者蛋白表达呈正相关,提示两者可能具有相似的诱发因素或彼此之间有协同作用。     

抑癌基因PTEN和血管内皮生长因子-C表达与乳腺癌淋巴管密度的相关性及其临床意义

目的:研究乳腺癌中抑癌基因PTEN和血管内皮生长因子-C(VEGF-C)表达与肿瘤间质淋巴管密度(LVD)的相关性及其临床意义。方法:应用EliVision免疫组化法检测90例乳腺浸润性导管癌组织和30例乳腺纤维腺瘤组织中PTEN、VEGF-C和淋巴管内皮细胞透明质酸受体1(LYVE-1)的表达,计算LYVE-1标记的乳腺癌间质淋巴管的密度,分析PTEN和VEGF-C与LVD的关系。结果:PTEN和VEGF-C在乳腺癌中的表达阳性率分别为48.9%、47.8%,LVD为(8.03±2.26)个/HPF,与良性对照组比较均有显著差异(P<0.01)。PTEN阳性率随乳腺癌淋巴结转移的出现和临床分期的升高而降低(P<0.05),乳腺癌VEGF-C阳性率随淋巴结转移的出现和临床分期的升高而增加(P<0.05),PTEN阳性组乳腺癌的LVD水平低于PTEN阴性组(P<0.05),VEGF-C阳性组乳腺癌的LVD水平高于VEGF-C阴性组(P<0.01),PTEN阳性组乳腺癌的VEGF-C阳性率低于PTEN阴性组(P<0.05)。结论:PTEN和VEGF-C的异常表达与乳腺癌间质淋巴管密度密切相关,在乳腺癌的淋巴管生成及侵袭转移过程中具有重要作用。     

血管内皮生长因子D的表达与乳腺癌淋巴管生成及淋巴结转移的相关性

目的 探讨乳腺癌患者不同区域淋巴管生成、淋巴管浸润特点以及与血管内皮生长因子D(VEGF-D)的表达关系,并结合腋淋巴结转移状态进行分析. 方法 选取乳腺癌根治术石蜡标本79例,分4个区域(肿瘤区、癌周区、近癌区、远癌区)取材.切片行免疫组织化学染色,采用D2-40对淋巴管进行标记,检测各区域淋巴管密度(LVD)、淋巴管浸润(LVI)及VEGF-D表达情况. 结果 癌周区LVD最高(20.25±2.03),肿瘤区VEGF-D和LVI阳性率最高,分别为87.34%和63.29%.肿瘤区VEGF-D表达与LVD之间、LVD与LVI之间、VEGF-D表达与LVI之间差异无统计学意义(P>0.05),但在其他各区域它们之间差异有统计学意义(P<0.05),且呈正相关.癌周区LVD与腋淋巴结转移状态有关(P<0.05);癌周区和近癌区的VEGF-D表达及LVI与腋淋巴结转移之间差异有统计学意义(P<0.05),但在其他区域差异无统计学意义(P>0.05). 结论 VEGF-D可能促进乳腺癌淋巴管生成,增加淋巴管浸润机会.LVD的增高易致淋巴管浸润,促进腋淋巴结转移.癌周区和近癌区在乳腺癌淋巴道转移以及评估腋淋巴结转移状态的研究中可能更具有意义.     

VEGF-D in association with VEGFR-3 promotes nodal metastasis in human invasive lobular breast cancer

We assessed the expression of vascular endothelial growth factors (VEGF-C and VEGF-D) in breast cancer cells and the density of lymph vessels and VEGF receptor-3 (VEGFR-3)-positive vessels in and around the tumor in invasive lobular breast cancer. We found significant correlation between peritumoral lymph vessel density and presence of lymph node metastases (P=.001) and the number of metastatic lymph nodes (P<.001). A significant correlation was detected between tumor cell VEGF-D expression and lymph node status (P=.001) and density of lymphatic vessel endothelial receptor (LYVE)-1-positive vessels (P=.035). VEGFR-3+/VEGF-D+ and VEGFR-3+/VEGF-C+ tumors had a significantly higher number of metastatic lymph nodes than tumors with other staining patterns (P<.001). Tumors positive for neither VEGF-D nor VEGFR-3 had a lower density of LYVE-1+ vessels than tumors with other staining patterns (P=.033). Our results indicate that peritumoral lymph vessel density is associated with lymph node metastases in invasive lobular breast cancer and that invasive lobular cancer producing VEGF-D, surrounded by VEGFR-3+ vessels, has a significantly higher peritumoral lymph vessel density and a higher number of metastatic lymph nodes.     

Lymphatic vessel density in pulmonary adenocarcinoma immunohistochemically evaluated with anti-podoplanin or anti-D2-40 antibody is correlated with lymphatic invasion or lymph node metastases

In lung cancers, lymph node metastasis of cancer cells is one of the most important prognostic factors, and lymphatic vessel invasion (LVI) is very important in the stage preceding lymph node metastases. Recently, it has been reported that lymphatic vessel density (LVD) is associated with lymph node metastasis. The aim of the present study was to evaluate the relationship between LVD and LVI based on the immunohistochemical expression of podoplanin or D2-40, which are new specific markers for lymphatic endothelium. Using 76 cases of pulmonary adenocarcinoma, the relationship between LVD and LVI, lymph node metastases, vascular endothelial growth factor C (VEGF-C), VEGF-D or hepatocyte growth factor (HGF) expression was investigated. LVD was significantly associated with LVI, lymph node metastases and VEGF-D expression. LVI was also associated with lymph node metastases, histological subtype, VEGF-C or VEGF-D expression. High LVD, induced by VEGF-C or VEGF-D expression of cancer cells, is a good indicator of lymphatic metastases and LVI in pulmonary adenocarcinoma.     

小细胞肺癌中CD24的表达及与微血管密度关系

目的检测CD24在小细胞肺癌(small cell lung cancer,SCLC)原发灶、淋巴结转移灶中的表达,探讨其与SCLC临床参数、侵袭转移及微血管密度(micro-vascular density,MVD)关系。方法应用免疫组化检测45例SCLC原发灶、33例区域淋巴结转移灶CD24表达及CD34-MVD。结果 SCLC原发灶、淋巴结转移灶CD24阳性率分别为53.3%(24/45)和60.6%(20/33),CD24阳性癌细胞常在癌巢周围密集分布,多见于侵袭边缘。CD34主要表达于血管内皮细胞胞膜,呈条索状甚至形成小管腔,主要位于癌巢边缘或癌细胞密集区;CD24、MVD与患者性别、年龄、肿瘤直径无关,而与淋巴结转移及胸膜侵袭有关(P<0.05);SCLC原发灶和淋巴结转移灶CD24阳性组MVD(33.44±8.51、47.65±14.31)均高于CD24阴性组(20.40±6.44、30.64±10.20)(P<0.05)。结论 CD24表达与SCLC侵袭转移行为和MVD有关。     

Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis

In many human carcinomas, expression of the lymphangiogenic factor vascular endothelial growth factor-D (VEGF-D) correlates with up-regulated lymphangiogenesis and regional lymph node metastasis. Here, we have used the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis to investigate the functional role of VEGF-D in the induction of lymphangiogenesis and tumor progression. Expression of VEGF-D in beta cells of single-transgenic Rip1VEGF-D mice resulted in the formation of peri-insular lymphatic lacunae, often containing leukocyte accumulations and blood hemorrhages. When these mice were crossed to Rip1Tag2 mice, VEGF-D-expressing tumors also exhibited peritumoral lymphangiogenesis with lymphocyte accumulations and hemorrhages, and they frequently developed lymph node and lung metastases. Notably, tumor outgrowth and blood microvessel density were significantly reduced in VEGF-D-expressing tumors. Our results demonstrate that VEGF-D induces lymphangiogenesis, promotes metastasis to lymph nodes and lungs, and yet represses hemangiogenesis and tumor outgrowth. Because a comparable transgenic expression of vascular endothelial growth factor-C (VEGF-C) in Rip1Tag2 has been shown previously to provoke lymphangiogenesis and lymph node metastasis in the absence of any distant metastasis, leukocyte infiltration, or angiogenesis-suppressing effects, these results reveal further functional differences between VEGF-D and VEGF-C.     

HIF-1α和VEGF-C在胃癌中的表达及意义

目的 探讨胃癌中缺氧诱导因子-1α(HIF-1α)和血管内皮生长因子-C(VEGF-C)在胃癌中的表达及其临床意义.方法 应用SP免疫组织化学技术检测44例胃癌和20例胃正常组织标本中HIF-1α和VEGF-C的表达,并分析其与胃癌临床病理学特征的关系.结果 HIF-1α在胃癌中的阳性表达率为59.09%(26/44),正常胃黏膜组织中的阳性表达率为25.00%(5/20),两者比较差异有统计学意义(x2=6.59,P＜0.05);其中淋巴结转移阳性组的阳性表达率为72.41%(21/29),淋巴结转移阴性组的阳性表达率为33.33%(5/15)(x2=6.25,P＜0.05),提示HIF-1α与胃癌转移相关.VEGF-C在胃癌中的阳性表达率为52.27%(23/44),正常胃黏膜组织中的阳性表达率为20.00%(4/20),两者比较差异显著(x2=4.73,P＜0.05);其中淋巴结转移阳性组的阳性表达率为65.52%(19/29),淋巴结转移阴性组的阳性表达率为26.67%(4/15),两者比较有统计学意义(x2=4.53,P＜0.05).胃癌中HIF-1α和VEGF-C的表达与肿瘤淋巴结转移和浸润深度有关,而与肿瘤部位、患者性别、年龄无关.HIF-1α与VEGF-C在胃癌组织中的表达呈正相关.结论 胃癌中HIF-1α和VEGF-C的表达上调且二者的表达均与淋巴结转移相关,有望成为胃癌治疗及判断预后的重要指标.     

血管内皮生长因子-D、 微血管密度及微淋巴管密度的表达与乳腺癌临床病理特征的相关性

目的 探讨乳腺癌中血管内皮生长因子D(vascular endothelial growth factor-D,VEGF-D)及微血管密度(microvessel density,MVD)、微淋巴管密度(Lymphatic vessel density,MLD)表达情况及意义.方法 收集2009年1月至2016年5月在临沂市肿瘤医院病理科存档病例,其中乳腺癌61例,乳腺增生症23例.采用免疫组化法检测各组织VEGF-D、MVD和MLD表达.结果 乳腺癌组织中VEGF-D蛋白阳性率为62.30%,明显高于乳腺增生组织,差异有统计学意义(χ2=16.215,P<0.05);乳腺癌组织中MVD和MLD分别为(17.70±7.10)和(2.41±0.85),明显高于乳腺增生组织,差异有统计学意义(t=10.900、t=8.795,P<0.05);VEGF-D表达与乳腺癌患者年龄、肿瘤大小以及淋巴结转移无明显关系(χ2=0.394、0.032、0.244,P>0.05);MVD和MLD密度与乳腺癌患者年龄和肿瘤大小无明显差异(χ2=0.081,0.126,0.219,0.196,P>0.05);VEGF-D、MVD和MLD密度与乳腺癌组织学分级相关(χ2=13.076、23.892、10.082,P<0.05),随着组织学分级递增,VEGF-D、MVD和MLD密度明显增高;MVD和MLD在乳腺癌伴淋巴结转移中密度明显高于无淋巴结转移(t=2.481、5.791,P<0.05).结论 VEGF-D在乳腺癌组织中呈高表达,可能在乳腺癌的发生发展中起重要作用,而MVD和MLD与乳腺癌肿瘤分化、转移有一定的关系.     

Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression.

Angiogenesis and lymphangiogenesis are essential for breast cancer progression and are regulated by vascular endothelial growth factors (VEGF). To determine clinical and molecular correlates of these processes, we measured blood and lymphatic vascular microvessel density in 29 invasive carcinomas (22 ductal, six lobular, one papillary), using the vascular marker CD31 and the novel lymphatic marker D2-40. Microvessel density was assessed microscopically and by image cytometry, and was compared with tumor histology, grade, stage, lymph node metastasis, hormone receptors, HER2/neu status, and expression of VEGF, VEGF-C and VEGF-D by immunohistochemistry or quantitative RT-PCR. Strong correlation was observed between visual and image cytometric microvessel density using D2-40 but not CD31 (P=0.016 and 0.1521, respectively). Image cytometric CD31 microvessel density correlated with tumor size, grade, stage and lymph node metastasis (P=0.0001, 0.0107, 0.0035 and 0.0395, respectively). D2-40 microvessel density correlated with tumor stage (P=0.0123 by image cytometry) and lymph node metastasis (P=0.0558 by microscopy). Immunohistochemical VEGF signal in peritumoral blood vessels correlated with image cytometric CD31 and D2-40 microvessel density (P=0.022 and 0.0012, respectively), consistent with the role of VEGF in blood and lymphatic vascular growth. Intratumoral VEGF-C and VEGF-D expression by quantitative RT-PCR correlated with D2-40 (P=0.0291 by image cytometry) but not with CD31 microvessel density, which could suggest a selective role of VEGF-C and VEGF-D in lymphangiogenesis. CD31 and D2-40 microvessel density correlated significantly with several prognostic factors, including lymph node metastasis. Thus, measurements of angiogenesis and lymphangiogenesis may have utility for breast cancer pathology, particularly for estimation of metastatic risk.