直肠腺癌VEGF-C及VEGFR-3的表达与淋巴转移的关系

目的为探讨癌细胞淋巴管转移机理,观察血管内皮生长因子-C(VEGF-C)和血管内皮生长因子受体-3(VEGFR-3)在直肠腺癌组织及淋巴管的表达。方法取人直肠腺癌手术材料30例,用免疫组化方法检测癌区和癌周正常区VEGF-C和VEGFR-3的表达情况。结果VEGF-C主要表达在直肠腺癌的癌细胞胞浆,VEGFR-3主要在淋巴管内皮细胞有阳性表达,两者在癌区的表达率均高于正常区直肠组织;癌区淋巴管的平均面密度(33.81±5.67)高于正常区平均面密度(20.13±3.27)。结论VEGF-C和VEGFR-3在人直肠腺癌中的过表达,可能与淋巴管增生和扩张,促进癌细胞的淋巴转移有关。     

腮腺癌中血管内皮生长因子和血管内皮生长因子受体3表达与淋巴结转移

目的:研究血管内皮生长因子C及受体3(VEGF-C、VEGFR-3)在腮腺癌中的表达及其与淋巴结转移的关系。方法:采用免疫组织化学SP法检测62例腮腺癌标本组织中VEGF-C、VEGFR-3的表达,并计算其阳性表达率。结果:VEGF-C、VEGFR-3在腮腺癌中显著表达,其阳性率分别是51.6%、48.4%,与淋巴结转移密切相关。结论:VEGF-C、VEGFR-3与淋巴结转移有相关性,为肿瘤细胞淋巴道转移提供了条件,可以作为判断腮腺癌患者预后的一个重要指标。     

VEGF-C及VEGFR-3在乳腺癌中的表达

目的探讨乳腺癌中血管内皮生长因子-C(VEGF-C)、血管内皮生长因子受体-3(VEGFR-3)的表达及与淋巴管生成的关系。方法采用免疫组化SP法检测57例乳腺癌组织中VEGF-C及VEGFR-3的表达,并在显微镜下记数VEGFR-3标记的脉管。结果淋巴结转移组VEGF-C的阳性率(90.48%)显著高于无淋巴结转移组(47.22%)(P<0.05);淋巴结转移组VEGFR-3阳性脉管数(7.62±1.18)显著高于无淋巴结转移组(5.27±0.96)(P<0.05);VEGF-C的阳性表达与VEGFR-3阳性脉管数呈正相关,相关系数为r为0.882(P<0.05)。结论 VEGF-C及VEGFR-3与乳腺癌的生长,淋巴管的生长及淋巴结的转移有关。     

The significance of VEGF-C/VEGFR-2 interaction in the neovascularization and prognosis of nephroblastoma (Wilms' tumour)

AIM: To investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF)-C and VEGFR-2 in nephroblastoma tissue and correlate their presence with the survival rate of children diagnosed with stage III Wilms' tumour. METHODS AND RESULTS: The material included nephroblastoma tissue obtained from 25 children hospitalized in the Department of Paediatric Oncology, Haematology and Transplantology between 1997 and 2003. VEGF-C and VEGFR-2 expression was evaluated by immunohistochemical assay. VEGF-C was expressed in all cells of the blastemal component and in 30% of tumour cells in the stromal part. It was absent from epithelial elements. VEGFR-2 expression was spread over the surface of numerous stromal cells as well as all the epithelial cells forming dysplastic tubules. The blastemal component of Wilms' tumour was VEGFR-2-negative. VEGF-C-immunopositive stromal cells were situated in the closest proximity to VEGF-C-immunonegative but VEGFR-2-immunoreactive tubules. VEGF-C expression was of prognostic value for both clinical progression (P = 0.0005) and tumour-related death (P = 0.0365). CONCLUSIONS: VEGF-C expression in Wilms' tumour constitutes a potent unfavourable risk factor and may direct future antiangiogenic treatment strategies. The proximity of VEGF-C and VEGFR-2 in the stromal and epithelial components of nephroblastoma could be the neoplastic equivalent of the binary VEGF-C function observed in epithelial and endothelial morphogenesis.     

甲状腺癌组织中VEGF和VEGF-C的表达及意义

目的　探讨血管内皮生长因子(VEGF)、VEGF- C在甲状腺癌中的表达及其意义。方法　应用免疫组化S P法检测44例甲状腺癌中VEGF、VEGF C的表达情况,并以17例癌旁正常甲状腺组织作对照。结果　VEGF、VEGF- C在甲状腺癌中呈高水平表达(88. 6%、81. 8% )。VEGF表达随癌组织分化程度的减低而增高, 9例死亡病例均为阳性表达;VEGF- C表达随癌组织分化程度的减低而减低,乳头状癌阳性表达(88 .9% )高于其它类型,VEGF- C阳性率在有淋巴结转移组(92. 0% )明显高于无淋巴结转移组(68. 4% ) (P<0. 05)。9例死亡病例中7例为阳性表达,且7例同时VEGF呈阳性表达。结论　VEGF、VEGF- C表达与甲状腺癌病理分型及预后可能有一定关系,VEGF- C与甲状腺癌淋巴结转移密切相关。     

Expression and localization of placenta growth factor and PlGF receptors in human meningiomas

It has previously been suggested that in human brain tumours, endothelial cell proliferation during angiogenesis is regulated by a paracrine mechanism involving vascular endothelial growth factor (VEGF) and its receptors (VEGF receptor 1 and VEGF receptor 2). The mechanism of growth factor up-regulation is based on hypoxic activation of mRNA expression and mRNA stabilization and genetic events, leading to an increase of growth factor gene expression. The role of the other newly discovered VEGF family members with a high specificity for endothelial cells in the pathogenesis of glial neoplasms is unknown. To investigate which other members of the VEGF family are overexpressed in human brain tumours, the mRNA levels of placenta growth factor (PlGF), VEGF-A, and VEGF-B genes were determined by northern blot analysis in surgically obtained human meningiomas. In the 16 meningiomas examined, the mRNA for PlGF was highly expressed in four tumours and VEGF-A mRNA was highly abundant in three tumour samples. There was no close correlation between PlGF mRNA levels and VEGF-A expression levels. VEGF-B mRNA was abundantly expressed in all tumour samples at uniform levels. In a PlGF-positive tumour sample, immunoreactive VEGFR-1 and VEGFR-2 were detected in endothelial cells of the blood vessels. PlGF protein was detectable in most but not all capillaries of the tumour. PlGF is thus highly up-regulated in a subset of human meningiomas and may therefore have functions, in some tumour vessels, connected to endothelial cell maturation and tube formation. These findings suggest that PlGF, in addition to VEGF-A, may be another positive factor in tumour angiogenesis in human meningiomas. Copyright © 1999 John Wiley & Sons, Ltd.     

阻断VEGFR-3表达对肿瘤细胞诱导的淋巴管内皮细胞增殖的影响

目的观察阻断VEGFR-3(F lt 4)表达对肿瘤细胞(前列腺癌细胞株PC3)诱导的淋巴管内皮细胞增殖的影响。方法实验分4组,第1组为对照组。每组有6孔,每孔具有相同细胞数2×105/m l,实验组每孔各加入试剂100 m l/L。第1组(对照组)加入淋巴管内皮细胞完全条件培养液(LEC)1 m l,第2组加入LEC 1 m l+兔血清100μl,第3组加入LEC 1 m l+PC3细胞上清100μl。第4组加入LEC+抗F lt 4抗体100μl。并于24、48、72、96 h观察各组淋巴管内皮细胞生长情况。各时间段计数第1~3组细胞数,第4组于72 h计数后,去除抗体,重新加入LEC+PC3细胞上清继续培养至120 h;除96 h外,其余各时间段均计数细胞数。比较各组细胞增殖情况。结果第1、2组淋巴管内皮细胞在加试剂后各时间段两组细胞数及形态无明显差别,第3组加入PC3细胞上清后,细胞数明显多于第1、2组。第4组加试剂后24、48、72 h细胞计数均少于前24 h。清除抗体后加入PC3细胞上清48 h计数细胞,细胞数仅略见增加。结论VEGF-C高表达的PC3细胞上清能显著刺激淋巴管内皮细胞增殖,阻断F lt4表达,可在一定程度上阻断PC3细胞上清促淋巴管内皮细胞增殖作用。     

VEGF-C、VEGFR-3和iNOS在人乳腺癌淋巴管的表达

目的检测乳腺癌组织血管内皮生长因子-C(VEGF-C)及其受体(VEGFR-3)、iNOS基因表达的相关性及这三个基因mRNA表达水平与淋巴管密度(LVD)的相关性,为阐明乳腺癌淋巴管生成的分子机理提供实验依据。方法RT-PCR检测乳腺癌组织及正常乳腺组织VEGF-C、VEGFR-3、iNOSmRNA的表达水平;免疫组织化学染色法检测淋巴管内皮细胞上VEGFR-3的表达,测定淋巴管密度。结果乳腺癌LVD为20.35±4.23,显著高于正常对照组(P<0.05);乳腺癌组织VEGF-C、VEGFR-3、iNOSmRNA三者的表达率分别为74.0%、84.0%、82.0%,显著高于正常对照组(P<0.05);VEGF-C、VEGFR-3、iNOS阳性组中LVD分别为21.34±3.45、18.54±4.68、17.43±4.76,显著高于对照组(P<0.05)。结论VEGF-C、VEGFR-3、iNOSmRNA表达与淋巴管密度之间呈正相关,并且3者之间的表达亦具有相关性,这些基因的表达增高可能在乳腺癌淋巴管生成过程中具有重要作用。     

Immunohistochemical expression and distribution of VEGFR-3 in malignant mesothelioma

Homogeneity of mesothelial and lymphatic endothelial cells, express some markers that are presumed to be exclusive of the endothelium was recently reported. This similarity is important to improve the diagnosis and prognosis of malignant mesothelioma (MM). Additionally, some of these markers provide the rationale for specific molecular-targeted novel therapies aimed at MM, an aggressive malignant neoplasm, with an usually dismal prognosis. The goal of our study was to determine the prevalence and expression pattern of VEGF receptor-3 (VEGFR-3) immunoreactivity in MM and whether this immunoreactivity occurs in different phenotypes of this neoplasm. Formalin-fixed and paraffin-embedded samples from 29 MM cases and 5 metastatic carcinomas were immuno-stained for VEGFR-3 according to the streptavidin-biotin-peroxidase complex technique using a primary antibody (Zymed Laboratories, CA, USA) diluted at 1:200. Lymphatic vessels (LV) were outlined mainly in the peripheral area surrounding the neoplasms. Blood vessels were only rarely positive for VEGFR-3 in a pattern easily distinguishable from LV. In 25 out of 29 cases (86.2%) LV were strongly positive for VEGFR-3: 14 cases (48.2%) exhibited positive VEGFR-3 reactivity in malignant cells. Epitheliod MM showed a moderate to intense VEGFR-3 positive reaction in LV from 8 out of 19 cases. Among the other histological subtypes, a positive VEGFR-3 reaction was noted in malignant cells from two cases of transitional and one case of pleomorphic MM. Malignant cells from two out of three biphasic and one out of three sarcomatoid MM were also positive for VEGFR-3. Interestingly, one case of the multicystic subtype was negative for VEGFR-3 in malignant cells and faintly positive in an occasional LV. All cases of metastatic carcinoma were negative for VEGFR-3 in the neoplastic cells. In conclusion, VEGFR-3 was expressed in malignant cells from different subtypes of MM, reinforcing the putative role of this marker as a potential therapeutic target in this group of neoplasia.     

血管内皮生长因子C及其受体在MNNG诱发的大鼠大肠癌细胞及淋巴管的表达

目的 观察大鼠大肠癌组织内血管内皮生长因子-C(VEGF-C)及其受体3(VEGFR-3)的表达情况,探讨VEGF-C及其受体VEGFR-3在肿瘤淋巴转移中的作用.方法 采用甲基硝基亚硝基胍(MNNG)诱发的大鼠大肠癌模型,应用免疫组织化学(SABC法)技术检测29例大鼠原发性大肠癌组织中VEGF-C及VEGFR-3蛋白,观察VEGF-C及VEGFR-3在大肠癌组织内的表达.结果 正常大肠组织内未见VEGF-C阳性表达,但可见淋巴管内皮细胞VEGFR-3阳性表达.在大肠癌组织内,VEGF-C蛋白表达于癌细胞,早期和中晚期癌的阳性表达率分别是75%和100%,(P＜0.05).VEGFR-3主要表达于淋巴管内皮细胞,早期和中晚期癌组织内淋巴管的阳性表达率分别是58.33%和94.12%(P＜0.05).结论 大鼠大肠癌VEGF-C的表达与肿瘤进展有关,推测VEGF-C通过受体VEGFR-3诱导淋巴管生成:VEGFR-3在淋巴管的阳性表达均随肿瘤进展增高,可能与大肠癌淋巴转移有关.     

喉癌组织中VEGF—C和VEGF-D的研究新进展

目的：探讨喉癌中VEGF—C与VEGF—D的表达及其与淋巴转移的关系。方法：搜集整理新近发表的相关文献,进行归纳总结。结果：VEGF—C及VEGF—D在各种肿瘤组织中的表达均显著增高。喉癌中二者的表达高于癌周及正常组织,且有淋巴转移组的表达高于无淋巴转移组。结论：喉癌的淋巴转移和VEGF-C及VEGF-D的表达相关,阻断VEGF—C／VEGF-D／VEGFR-3通路的表达有望成为抗肿瘤淋巴转移的新手段。     

胃癌不同部位血管内皮生长因子C及其受体的表达和淋巴管计数

目的观察胃癌原发灶、淋巴结转移灶及癌旁组织中血管内皮生长因子C(VEGF-C)及其受体(VEGFR-3)表达水平和淋巴管(LV)计数,探讨3者的相互关系及其临床病理意义。方法49例胃癌手术切除原发灶、36例淋巴结转移灶标本和20例癌旁组织常规制作石蜡包埋切片,VEGF-C、VEGFR-3和LV染色方法均为SP免疫组化法。结果胃癌原发灶组织VEGF-C、VEGFR-3阳性表达率及LV计数明显高于癌旁组织[(61.2%比25.0%,P<0.01;57.1%比25.0%,P<0.05;(13.8±5.2)个/HP比(6.8±3.2)个/HP,P<0.01]。胃癌淋巴结转移灶组织VEGF-C、VEGFR-3表达阳性率及LV计数亦明显高于癌旁组织[61.1%比25.0%,P<0.01;58.3%比25.0%,P<0.05;(11.2±4.9)个/HP比(6.8±3.2)个/HP,P<0.01]。组织学分级Ⅱ级、侵袭深度T1～T2、无区域淋巴结转移、N1站淋巴结转移及无远处转移胃癌VEGF-C、VEGFR-3表达阳性率及LV计数均明显低于组织学分级Ⅲ～Ⅳ级、侵袭深度T3～T4、区域淋巴结转移、N2～N3站淋巴结转移及远处转移病例(P<0.05或P<0.01)。VEGF-C、VEGFR-3表达呈高度一致性(P<0.01)。胃癌原发灶及淋巴结转移灶中VEGF-C、VEGFR-3阳性病例LV计数明显高于阴性病例(P<0.01)。结论VEGF-C、VEGFR-3和LV可能是反映胃癌发生发展、侵袭潜力、转移发生及预后的重要生物学标记物。VEGF-C通过与VEGFR-3结合具有促胃癌淋巴管生成作用。     

Expression of vascular Notch ligands Delta-like 4 and Jagged-1 in glioblastoma

Jubb A M, Browning L, Campo L, Turley H, Steers G, Thurston G, Harris A L & Ansorge O
(2012) Histopathology  60, 740–747
Expression of vascular Notch ligands Delta‐like 4 and Jagged‐1 in glioblastoma Aims: The coordinated expression of the Notch ligands Delta‐like 4 (Dll4) and Jagged (Jag)1 is believed to define appropriate endothelial sensitivity to vascular endothelial growth factor (VEGF). Preclinical data suggest that Dll4‐Notch signalling may confer resistance to anti‐VEGF therapy with bevacizumab, and Jag1 may antagonize Dll4–Notch. The aims of this study were to characterize the expression of Dll4 and Jag1 in primary glioblastomas. Methods and results: Immunohistochemistry was performed on 40 glioblastomas and normal brain using validated antibodies against Dll4 and Jag1. In‐situ hybridization for Dll4 was performed on serial sections and compared with protein expression. Dll4 expression was localized to the cytoplasm and membrane of endothelial cells in all glioblastomas; it was weak or absent in normal brain. Jag1 expression was observed in the cytoplasm and membrane of glomeruloid and non‐glomeruloid endothelial cells from 76% and 67% of glioblastomas, respectively. However, endothelial Jag1 expression was less intense and less prevalent than Dll4. There was no association between Dll4 and Jag1 expression. Conclusions: In summary, Dll4 and Jag1 are expressed in glioblastoma vasculature. These data may define subsets of glioblastoma that might be sensitive (Dll4⁺/Jag1⁺) or resistant (Dll4⁺/Jag1^–) to bevacizumab. Our data also suggest that anti‐Dll4 therapy should be evaluated experimentally in glioblastoma.     

VEGF在自发性高血压大鼠肾小球内的表达

目的研究血管内皮生长因子（VEGF）在幼年及成年自发性高血压大鼠（SHR）肾小球内的表达,探讨它在高血压病肾损害中的作用。方法6周龄SHR和WKY大鼠各10只,15月龄SHR和WKY大鼠各20只,将肾组织进行常规病理和免疫组化染色（SP法）,利用计算机图像分析定量肾组织内的微血管数和VEGF的表达。结果VEGF蛋白主要分布于肾小球内的足细胞和球内系膜细胞,15月龄SHR组的阳性反应程度显著高于其余3组（P〈0．05）,而其他各组间无显著差异。结论推测VEGF可能参与高血压肾损害的发病过程。     

小儿肾病患者治疗前后VEGF检测的临床意义

目的 :探讨了小儿肾病患者血管内皮生长因子的水平。方法 :应用酶联双抗体夹心法测定了 31例小儿肾病患者血管内皮生长因子的含量 ,并以 35名正常健康人作比较。结果 :小儿肾病患者血浆中血管内皮生长因子水平非常显著地高于正常人组 (P <0 0 1) ,经治疗一个月后与正常人比较仍有差异 (P <0 0 5 )。结论 :小儿肾病的发生、发展与血管内皮生长因子水平密切相关。     

VEGF-C及其受体Flt4在乳腺癌转移中的作用

目的　探讨VEGF C/VEGFR 3(Flt4)在乳腺癌转移中的作用和意义。方法　采用免疫组化S P法检测 10 1例乳腺癌组织中VEGF C、Flt4的表达。结果　 10 1例乳腺癌组织VEGF C阳性率为 93 1%(94/10 1) ,Flt4阳性率为 86 1%(87/10 1) ,且VEGF C与Flt4表达呈正相关。VEGF C阳性指数在转移组 (6 1 89± 17 79)高于未转移组 (44 2 8± 17 87) (P <0 0 5 )。随着癌细胞VEGF C表达强度增强 ,Flt4阳性脉管数也随之增加 ,各组间差异均有显著性 (P <0 0 1)。乳腺癌中Flt4阳性脉管数在淋巴结转移组 (15 5 5± 3 6 3)高于未转移组 (10 71± 2 90 ) (P <0 0 5 )。结论　乳腺癌细胞高水平表达VEGF C、Flt4,两者表达呈正相关。Flt4阳性脉管数与淋巴结转移密切相关。     

Immunohistochemical localization of endothelial cell markers in solitary fibrous tumor

Solitary fibrous tumor (SFT) is an uncommon tumor first reported in the pleura, but recently described in other tissues. CD34, which is expressed in hematopoietic stem cells, endothelial progenitor cells and vascular endothelial cells, is observed in most SFT and some investigators believe that its expression is a definitive marker of this tumor. In the present study, the expression of vascular endothelial cell markers, such as vascular endothelial growth factor receptor (VEGFR)-1 (flt-1), VEGFR-2 (flk-1/KDR), Tie-2 and c-Met, was examined in SFT to clarify the relationship between SFT and endothelial cells. By immunohistochemical staining of tumor cells from 26 patients, VEGFR-1 was detected in 24 (92%), VEGFR-2 in five (19%), Tie-2 in 14 (54%), and c-Met, a specific receptor of hepatocyte growth factor (HGF) in 23 patients (88%). Furthermore, VEGFR-3 (flt-4) immunoreactivity was detected in eight of 26 patients (31%). In contrast, VEGF, VEGF-C and HGF, which are ligands for the receptors, were not localized in the SFT cells. These findings indicate that most SFT may closely relate to vascular or lymphatic endothelial cells and the endothelial growth factors may contribute to the growth of SFT in a paracrine manner.     

小儿隐睾症手术治疗前后VEGF检测的临床意义

目的:探讨了小儿隐睾症患者血管内皮生长因子水平。方法:应用酶联双抗体夹心法测定了30例小儿隐睾症患者血管内皮生长因子的含量,并以35名正常健康儿童作比较。结果:小儿隐睾症患者血浆中血管内皮生长因子水平非常显著地高于正常人组(P<0.01),经手术治疗3个月后与正常人比较无显著性差异(P>0.05)。结论:小儿隐睾症的发生、发展与血管内皮生长因子水平密切相关。     

Smad4和VEGF-C在喉癌中的表达及其与淋巴管生成之间的关系

目的观察Smad4与VEGF-C在喉癌组织内的表达情况,分析Smad4和VEGF-C的表达与喉癌组织内淋巴管生成及淋巴结转移之间的关系。方法取喉癌病例58例,其中淋巴结转移组34例,无淋巴结转移组24例。应用免疫组化法和Western blot技术观察Smad4和VEGF-C在喉癌组织内的表达。以D2-40特异性标检测喉癌组织内淋巴管生成情况。结果 Smad4在无淋巴结转移的喉癌组织内的表达率明显高于其在有淋巴结转移组的表达率。Smad4表达阳性组的淋巴管数密度(LVD)明显低于Smad4表达阴性组的LVD。VEGF-C在淋巴结转移组的表达率明显高于其在无淋巴结转移组的表达率。Smad4的表达与VEGF-C的表达呈显著的负相关性(r=-0.391)。结论 VEGF-C在喉癌淋巴管的发生及淋巴结转移中发挥重要作用。Smad4与VEGF-C的表达呈负相关,Smad4可能有抑制喉癌淋巴管生成和淋巴道转移的作用。