Notch1在食管鳞癌中的表达及其与毛细血管新生的关系

目的 研究Notch1在食管鳞癌中的表达与临床病理特征的关系及其与食管鳞癌新生毛细血管的关系.方法 通过免疫组化方法检测40例食管鳞癌和8例正常食管组织的Notch1和血管内皮生长因子(VEGF)、毛细血管密度(MVD)的表达情况并行相关性分析.结果 Notch1在食管鳞癌组织中表达明显低于正常对照组(P<0.05),在不同的分化程度中有差异(P<0.05),但在肿瘤浸润深度和淋巴结转移与否中无明显差异(P>0.05).VEGF和MVD在食管鳞癌组织中表达明显高于正常对照组(P<0.05),在不同分化程度、浸润深度和淋巴结转移与否中各组间均有显著性差异(P<0.05).相关性分析显示Notch1与VEGF为负相关关系.结论 Notch1在食管鳞癌中可能为抑癌基因;在早中期食管鳞癌中可能是主要影响肿瘤细胞的分化;其的异常低表达可能是引起VEGF和MVD异常高表达的原因之一.Notch信号通路在食管鳞癌新生毛细血管中可能有关键作用.

Abstract：

Objective To observe Notch1 expression in esophageal squamous cell carcinoma (ESCC) and investigate its relation with microvascular angiogenesis in the tumor. Methods Tissue slices of 40 cases ESCC (cancer group) and 8 cases normal esophagus tissues (normal group) were obtained to analyze the expression of Notch 1 and vascular endothelial growth factor (VEGF) using immunohistochemistry and estimate the micro vessel density (MVD) in the tumor. Results Notch 1 expression was significantly lower in the cancer group than in the normal group (P<0.05). In the cancer group, Notch 1 expression was higher in highly differentiated than in poorly differentiated tumors (P<0.05) regardless of tumor infiltration or lymph nodes metastasis (P>0.05). VEGF expression and MVD were significantly higher in cancer group than in normal group, and showed significant differences between tumors with different differentiation degrees, infiltration and lymph node metastasis (P<0.05). Correlation analysis showed that Notchl expression was inversely correlated to VEGF expression. Conclusion Notch1 may be an anti-oncogene in ESCC and affects cell differentiation in early stage of the malignancy. Abnormally low expression of Notchl in ESCC may be one of the upstream factors to induce high expression of VEGF and increased MVD. The Notchl pathway might play a key role in microvascular angiogenesis in ESCC.     

Exploration on Effect and Mechanism of Suiqing Pill (髓清丸) on Tumor Angiogenesis in Nude Mouse B16 Melanoma Model

Objective: To study the effect of Suiqing Pill (SQP, 髓清丸),a TCM compound drug that can activate blood circulation and get rid of blood stasis, on angiogenesis in tumor and its possible mechanism. Method: BALB/c nude mice were inoculated with melanoma cell line B16 at right armpit subcutaneously to establish cancer spontaneous metastasis model. Levels of microvessel density (MVD), vascular endothelial growth factor (VEGF) and protein expression of matrix metalloproteinase-2 (MMP-2) in tumor tissues were observed and compared. Results: Strong expression of anti-Factor Ⅷ (FⅧ) related antigen and plentiful tumor angiogenesis were seen in model control animals, while in the high-dose and low-dose SQP treated model mice, MVD was inhibited by 33. 5% and 22. 6% respectively ( P<0. 01, P<0. 05). The strong positive protein expression of VEGF and MMP-2 in model control also reduced in the SQP treated groups. Conclusion: SQP could inhibit tumor angiogenesis, protein expression of VEGF and MMP-2 in nude mice B     

Exploration on Effect and Mechanism of Suiqing Pill (髓清丸) on Tumor Angiogenesis in Nude Mouse B16 Melanoma Model

Objective: To study the effect of Suiqing Pill (SQP, 髓清丸), a TCM compound drug that can activate blood circulation and get rid of blood stasis, on angiogenesis in tumor and its possible mechanism.Method: BALB/c nude mice were inoculated with melanoma cell line R16 at right armpit subcutaneously to establish cancer spontaneous metastasis model. Levels of microvessel density (MVD), vascular endothelial growth factor (VEGF) and protein expression of matrix metalloproteinase-2 (MMP-2) in tumor tissues were observed and compared. Results: Strong expression of anti-Factor Ⅷ (FⅧ) related antigen and plentiful tumor angiogenesis were seen in model control animals, while in the high-dose and low-dose SQP treated model mice, MVD was inhibited by 33.5 % and 22.6 % respectively ( P＜0.01, P＜0.05). The strong positive protein expression of VEGF and MMP-2 in model control also reduced in the SQP treated groups. Conclusion: SQP could inhibit tumor angiogenesis, protein expression of VEGF and MMP-2 in nude mice B16 melanoma models.     

VEGF-targeted RNA interference suppresses angiogenesis and tumor growth of retinoblastoma

Vascular endothelial growth factor （VEGF） is one of the most important angiogenic growth factors for tumor angiogenesis which has been verified to be involved in neovascularization of retinoblastoma. Here, we sought to explore whether RNA interference （RNAi） targeting VEGF could inhibit retinoblastoma angiogenesis and tumor growth. Stable transfection of the two human retinoblastoma cell lines SO-RB50 and HXO-RB44 with VEGF-targeted small interfering RNA （siRNA） expression plasmid significantly inhibited VEGF expression determined by real-time polymerase chain reaction （PCR） , enzyme-linked immunosorbent assay and Western blot, whereas the control transfection showed no effects. The chemically synthesized VEGF siRNA dramatically suppressed tumor angiogenesis （CD34 immunohistochemistry） and tumor growth in the SO-RB50 subcutaneous xenograft model. Significant downregulation of VEGF expression both on messenger RNA and protein levels in VEGF-siRNA-treated SO-RB50 subcutaneous xenograft was confirmed by real-time PCR and Western blot compared to control. Our data demonstrate the suppression function on angiogenesis and tumor growth of retinoblastoma by VEGF-targeted RNAi. This novel therapeutic strategy promises to play a part in the clinical management of retinoblastoma.     

Correlation of vascular endothelial growth factor and CD105-microvascular density in primary pterygium

The relationship between the expression of vascular endothelial growth factor(VEGF) and microvascular density(MVD) marked by CD105(CD105-MVD),and that between CD105-MVD and the clinicopathological characteristics of primary pterygium were investigated.The streptavidin-biotin complex(SABC) immunohistochemical staining in paraffin-embedded tissues was used to detect the expression of VEGF in 23 cases of primary pterygia and 7 normal conjunctival specimens.The antibody against CD105 was used to display vascular endothelial cells,and MVD was examined by counting the CD105-positive vascular endothelial cells.The correlations of VEGF and CD105-MVD,and those of CD105-MVD and clinicopathological data were analyzed by using SPSS 12.0.The expression of VEGF was significantly increased in epithelia(P=0.000),endothelia and stroma cells(P=0.005) in primary pterygia as compared with normal conjunctivae.The CD105-MVD in pterygia(mean 19.22±6.68) was higher than that in normal conjunctivae(mean 4.00±2.15,P=0.000).MVD in pterygia was significantly associated with the Tan classification(P=0.000) and the VEGF expression level in the stroma(P=0.020),but not with sex(P=0.61),age(P=0.150) or the VEGF expression level in the epithelia(P=0.518).Our results suggest that over-expression of VEGF and high CD105-MVD in primary pterygium may contribute to the progression by increasing angiogenesis and growth of primary pterygium.     

VEGF stimulates lymphangiogenesis in colorectal cancer and the treatment via anti-lymphangiogenesis

Lymph node metastasis is the most common and basic way in the extending of colorectal tumor. It is an important reason for the difficulty of curing the tumor and the tumor's high mortality. And it is also an important factor that effects surgery treatment. Vascular endothelial growth factor( VEGF) family is a group of factors which specificly act on endothelial cell. VEGF has been shown to be an important regulator of tumour angiogenesis.but its effect on lymphan-giogenesis is not so clear. In this review, we discussed VEGF's effect on lymphangiogenesis, the colorectal microenviron-ment's effect on the factors expression and the therapeutics via antilymphangiogenesis by inhibiting VEGFR-3 signaling.     

VEGF and Angiogenesis in Renal Cell Carcinoma： A Minireview

Across a wide range of human tumors and/or cell lines, expression of VEGF has been shown to lead to the development and maintenance of a vascular network that promotes tumor growth and metastasis. Moreover, a large and growing body of evidence indicates that both VEGF gene expression and VEGF production are associated closely with poor prognosis. This review explores the implications of VEGF activity in renal cell carcinoma （RCC）.     

Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptor-1 in Human Meningiomas

The expression of basic fibroblast growth factor (bFGF) and fibroblast growth factor receptor-1 (FGFR-1) in human meningiomas and the relationships between their expression and the tumors‘ histological features and angiogenesis were investigated by means of immunohistochemical technique. The expression of bFGF and FGFR-1 was detected by antibody of bFGF or FGFR-1.The tumors‘ angiogenesis was evaluated by microvascular density (MVD) and, which was observed by use of CD34-antibody immunohistochemically. The results showed that there were varied degrees of the expression of bFGF and FGFR-1 proteins in meningiomas. The expression was correlated with the tumors‘ histological characters and angiogenesis. It was concluded that bFGF and FGFR-1 might play important roles in meningiomas‘ angiogenesis and proliferation. The expression positive rate of bFGF and FGFR-1 may provide an indication of evaluating the histological and malignant degree of the tumor.     

Expression of nerve growth factor and hypoxia inducible factor-1α and its correlation with angiogenesis in non-small cell lung cancer

Summary： In order to investigate the expression of nerve growth factor （NGF） and hypoxia inducible factor-1α （HIF-1α） and its correlation with angiogenesis in non-small cell lung cancer （NSCLC）, paraffin-embedded tissue blocks from 20 patients with NSCLC were examined. Twenty corresponding para-cancerous lung tissue specimens were obtained to serve as a control. The expression of NGF, HIF-1α, and vascular endothelial growth factor （VEGF） in the NSCLC tissues was detected by using immunohistochemistry. The microvascular density （MVD） was determined by CD31 staining. The resuits showed that the expression levels ofNGF, HIF-1α and VEGF in the NSCLC tissues were remarkably higher than those in the para-cancerous lung tissues （P〈0.05）. There was significant difference in the MVD between the NSCLC tissues （9.19±1.43） and para-cancerous lung tissues （2.23±1.19） （P〈0.05）. There were positive correlations between NGF and VEGF, between HIF-1α and VEGF, and between NGF and HIF-1α in NSCLC tissues, with the spearman correlation coefficient being 0.588, 0.519 and 0.588, respectively. In NSCLC tissues, the MVD had a positive correlation with the three factors （P〈0.05）. Theses results suggest that NGF and HIF-1α are synergically involved in the angiogenesis of NSCLC.     

血管内皮生长因子在食管癌中的表达及其意义

目的探讨血管内皮生长因子(VEGF)在食管癌中的表达规律及其在血管生成和肿瘤侵润转移中.的作用机制.方法应用原位杂交和免疫组织化学方法,检测58例食管癌组织中VECF的mRNA和蛋白的表达,并用CD34标记癌组织血管内皮细胞,计数肿瘤内微血管密度(HVD).结果食管癌细胞高表达VBG-FmRNA和蛋白,阳性率分别为62.1%(36/58),60.3%(35/58),VECF的表达与食管癌的浸润深度、淋巴结转移及THH分期密切相关,而与分化程度和组织分型无关;VECF阳性表达组的微血管密度明显高于低表达组(P＜0.01).结论VEGF可促进食管癌血管形成,同时也促进肿瘤的浸润和转移,可作为反映食管癌进展的生物学指标.     

血管内皮生长因子在原发性食管鳞状细胞癌中的表达及意义

目的：探讨原发性食管鳞状细胞癌中血管内皮生长因子（VEGF）的表达情况及其与肿瘤血管生成和预后的关系。方法：采用免疫组织化学染色方法,分别以抗VEGF多克隆抗体的抗F－VIII单克隆抗体检测82例手术切除标本中VEGF的表达水平和肿瘤微血管密度（MVD）值,分析二者之间及与患者预后的相关性。结果：全组病例中,肿瘤细胞VEGF阳性率为63．4％（52／82）VEGF阴性和VEGF阳性的3年和5年生存率分别为53．4％和46．6％;19．2％和11．5％。MVD中位值为37个/mm^2(9-150个／mm^2)。VEGF的表达水平与MVD值密切相关（P＝0．001）。MVD与患者的预后显著相关（P＝0．017）。随着VEGF表达水平增高,患者预后明显恶化（P＝0．000）。结论：VEGF在食管鳞状细胞癌的肿瘤血管生成过程中发挥重要的调控作用。多因素预后分析表明VEGF的表达可作为食管鳞状细胞癌患者独立的预后判断指标。     

环氧合酶-2、血管内皮生长因子和微血管密度与食管鳞癌病理特征的关系

目的：研究食管鳞癌中环氧合酶—2(COX—2)、血管内皮生长因子(VEGF)的表达和微血管密度(MVD)与肿瘤病理特征之间的关系。方法：应用免疫组化的方法检测62例食管鳞癌组织、42例正常食管上皮中的COX—2、VEGF、CD31的表达，以CD31作为MVD指标．分析它们的表达与肿瘤病理特征之间的关系以及它们三者之间的相互关系。结果：食管鳞癌中COX—2和VEGF的表达较正常食管上皮明显增加；COX—2、VEGF的表达与MVD值正相关；三者水平与肿瘤TNM分期、浸润深度、淋巴结转移正相关。结论：COX—2、VEGF在食管鳞癌组织中高表达，与血管生成关系密切，可能参与了肿瘤生长、浸润和转移，可作为判断食管鳞癌生物学行为的重要指标。     

血管内皮生长因子受体3在上皮性卵巢癌组织的表达及意义

目的探讨血管内皮生长因子受体3(VEGFR-3)在上皮性卵巢癌组织的表达及与血管内皮生长因子C、D(VEGF-C、VEGF-D)表达、癌周淋巴管生成和淋巴转移的关系.方法采用免疫组化方法,检测VEGFR-3、VEGF-C及VEGF-D在上皮性卵巢癌组织的表达,进行淋巴管密度计数、微血管密度(MVD)计数,并结合临床病理资料进行分析.结果VEGFR-3在癌细胞及癌周脉管内皮细胞表达,表达水平与VEGF-C、VEGF-D表达及淋巴转移显著正相关.淋巴管密度与淋巴转移、临床分期、VEGF-C表达、VEGF-D表达显著正相关,MVD与远处转移、临床分期显著正相关.结论VEGF-C、VEGF-D在上皮性卵巢癌组织的表达上调刺激VEGFR-3表达并与之结合,诱导癌周淋巴管生成,促进肿瘤的淋巴转移.     

血管内皮生长因子及其受体Flt-1在乳腺癌中的表达及意义

目的　试图揭示血管内皮生长因子 (VEGF)及其受体 (Flt 1)在乳腺癌组织中的表达规律 ,探讨其与血管生成和肿瘤浸润、转移等生物学行为的关系。方法　应用原位杂交和免疫组织化学技术 ,检测 4 8例乳腺癌组织中VEGF和Flt 1的mRNA和蛋白表达特性。结果　乳腺癌细胞高表达VEGFmRNA和蛋白 ,阳性率分别为 75 %、70 8% ,而血管内皮细胞几乎不表达 ;血管内皮细胞主要表达受体Flt 1mRNA和蛋白 ,阳性血管数分别为 2 6个 / 0 72mm2 ± 12个 / 0 72mm2 、2 4个 / 0 72mm2 ± 12个 / 0 72mm2 ,而少数癌细胞有少量表达 ;VEGF和Flt 1高表达组血管密度明显高于低表达组 ;VEGF和Flt 1表达与组织学分级和淋巴结转移密切相关。结论　VEGF以旁分泌途径促进乳腺癌血管形成 ,并参与肿瘤浸润和淋巴道转移过程 ,检测VEGF和Flt 1表达可做为判定乳腺癌血管生成、恶性度以及浸润转移等生物学行为的可靠指标。     

微血管密度和血管套及血管内皮生长因子在子宫颈癌中的表达

目的 :研究微血管密度 (MVD)、血管套 (VC)和血管内皮生长因子 (VEGF)在子宫颈癌组织中的表达与子宫颈癌的生长、浸润及转移的关系。方法 :采用免疫组织化学方法 (SP)检测 5 7例子宫颈癌 (鳞癌 30例、腺癌 2 0例、腺鳞癌 7例 ) ,2 9例宫颈上皮内肿瘤 (CIN)和 16例正常子宫颈组织中 VEGF蛋白的表达 ,以 CD34抗原作为血管内皮细胞标记 ,测定其微血管密度及癌巢与基质间的血管套。结果 :随着宫颈病变的进展 ,MVD逐渐增高 ,VC表现明显 ,VEGF的阳性表达率渐增高。MVD在以上 5组间差异有显著性 (P<0 .0 1)。正常组 VC与各组癌之间差异有显著性 (P<0 .0 1)。 VEGF在正常宫颈组织、CIN、子宫颈鳞癌、腺癌、腺鳞癌细胞浆中的阳性表达率分别为 :18.8% (3/ 16)、82 .8% (2 4 / 2 9)、93.3% (2 8/ 30 )、10 0 % (2 0 / 2 0 )、7/ 7(10 0 % ) ,差异有显著性 (P<0 .0 1)。 MVD与VEGF的表达呈正相关 (rs=0 .335 ,P<0 .0 1) ,VEGF的不同表达强度与 MVD的表达量间差异均有显著性 (P<0 .0 1)。子宫颈癌淋巴转移者 MVD的表达量较阴性者高 (P<0 .0 5 )。结论 :VEGF在子宫颈癌的发生发展中有促进血管形成作用 ,MVD与子宫颈癌的恶性程度密切相关。     

食管鳞癌中细胞凋亡、MVD及PCNA、VEGF表达的临床意义

目的研究食管鳞癌中细胞凋亡、PCNA、VEGF、MVD与传统组织病理学因素对食管鳞癌预后的影响.方法该研究采用原位DNA末端标记(TUNEL法)、免疫组化(S-P法)及组织病理学等方法研究食管鳞癌组织中凋亡、PCNA、CD34、VEGF的表达,计算出凋亡指数(AI)、增殖指数(PI)及微血管密度(MVD),并测出VEGF的平均吸光度.结果AI、PI、VEGF、MVD与肿瘤的分化程度、TNM分期有密切关系.低分化程度组和高TNM分期组PI、MVD值、VEGF吸光度明显高于高分化程度组及低TNM分期组(P＜0.01),而其AI值明显低于高分化程度组及低TNM分期组(P＜0.01).浸润深度超过肌层组及有淋巴结转移组VEGF、MVD明显高于浸润深度未超过肌层及无淋巴结转移组(P＜0.01),而AI与浸润深度无关(P＞0.05),PI与淋巴结转移无关(P＞0.05).单因素分析结果显示患者生存率降低与AI、PI、MVD、VEGF、TNM分期、淋巴结转移、分化程度和浸润深度有关.结论细胞凋亡、细胞增殖和血管形成参与了食管鳞癌的形成,并对其生长起促进作用.VEGF与食管鳞癌的血管形成有密切关系,VEGF和MVD表达增高有助于食管鳞癌的浸润转移;患者生存率降低与AI、PI、MVD、VEGF、TNM分期、淋巴结转移、分化程度和浸润深度有关.     

血管内皮生长因子及微血管密度在肝癌中的表达与临床病理意义

为研究血管内皮生长因子 (VEGF)和微血管密度 (MVD)的表达在原发性肝癌中的临床病理意义 ,选择 80例原发性肝癌手术标本 ,采用免疫组织化学染色方法检测VEGF及Ⅷ因子的表达。结果显示 :VEGF在原发性肝癌中的阳性表达率为 62 .5 % ;原发性肝癌中MVD为 3 1.76± 13 .5 6,其中VEGF表达阳性者MVD为 45 .3 8± 14 .85 ,VEGF表达阴性者MVD为 18.87± 8.67.,二者差异有高度显著性 (P <0 .0 1)。VEGF的表达与肿瘤的大小和有无门脉癌栓明显相关 (P<0 .0 1) ,而与肿瘤有无包膜、分化程度、AFP水平、HBsAg阳性无关 (P >0 .0 5 )。提示VEGF能促进肿瘤中微血管的形成 ,与原发性肝癌的生长、浸润和转移有关。     

VEGF和MVD在大肠癌组织中的表达及其临床意义

目的探讨血管内皮生长因子(VEGF)和微血管密度与大肠癌发展的关系。方法采用免疫组化方法对65例大肠癌、65例癌旁组织及16例正常大肠黏膜组织进行VEGF表达及微血管密度(MVD)测定。结果大肠癌组织中VEGF的表达阳性率明显高于癌旁组织及正常组织(P<0.05),与组织学分级无关(P>0.05)。VEGF阳性者MVD值显著高于VEGF阴性者(P<0.05);大肠癌组织中VEGF的表达水平与MVD呈显著性正相关(rs=0.410,P=0.001)。VEGF表达和MVD与大肠癌浸润深度、TNM分期、血行转移密切相关(P<0.05)。VEGF表达阳性或高MVD的大肠癌患者预后差(P<0.05)。结论VEGF表达与大肠癌血管生成密切相关,VEGF和MVD可作为大肠癌预后检测的指标。