VEGF-C expression correlates with histological differentiation and metastasis in squamous cell carcinoma of the esophagus

Vascular endothelial growth factor C (VEGF-C) is known to act in lymphangiogenesis. Recent reports suggest VEGF-C plays a role in the spread of several cancers to the lymph system. Lymphatic spread is a critical prognostic factor in esophageal cancer, however, the molecular mechanism involved in the spread of cancerous cells remains unclear. In the present study the clinicopathological implication of VEGF-C was analyzed using immunohistochemistry. Seventy-one patients with esophageal squamous cell carcinoma (ESCC) resected in our institute were included in this study. Formalin-fixed paraffin-embedded specimens were stained for VEGF-C and the correlation between the staining, its clinicopathological parameters and its prognostic power were analyzed statistically. Only histological grade (differentiation) was shown to have a statistically significant correlation with VEGF-C expression (p=0.028). Age (p=0.064), lymph node metastasis (pN) (p=0.085) and vascular invasion (p=0.092) tended to correlate with VEGF-C expression although on analysis this correlation was not statistically significant. The results suggested there is no prognostic implication for VEGF-C in ESCC (p=0.80). There is no significant correlation between VEGF-C expression and clinicopathological parameters involved in lymphatic spread. However, VEGF-C expression might play an important role in metastasis of ESCC since histological grade was closely related to lymph node metastasis and distant metastasis.     

HMGB1 在食管鳞癌中的表达及其意义*

目的:初步探讨食管鳞癌中高迁移率蛋白B1（HMGB 1）的表达及其与淋巴结转移和患者预后的关系。方法:收集72例有完整临床及随访资料的胸段食管鳞癌石蜡标本,采用免疫组织化学染色和统计学的方法,观察HMGB 1 和VEGF-C、VEGF-D 、LYVE-1 在食管鳞癌组织中的表达,并分析HMGB 1 与VEGF-C、VEGF-D 、微淋巴管密度（MLD）、淋巴结转移及各种临床病理参数和患者预后之间的关系。结果:HMGB 1 在食管鳞癌组织中呈高表达,阳性率达69.44% ,而在正常组织中很少表达,并且有淋巴结转移的表达率为81.82% ,无淋巴结转移的表达率为58.97% ,有显著性差异（P<0.05）。 另外,HMGB 1 的表达与食管鳞癌的分期、VEGF-C、VEGF-D 的表达、MLD及患者的预后密切相关（P<0.05或P<0.01）;同时,VEGF-C、VEGF-D 的表达也与食管鳞癌的淋巴结转移、MLD密切相关（P<0.05或P<0.01）。 结论:在食管鳞癌中,HMGB 1 的大量表达可能是通过调控VEGF-C、VEGF-D 的表达来促进新生淋巴管生成,从而促进其淋巴结转移并影响患者的预后。因此,HMGB 1 有可能作为反映食管癌预后的重要生物学指标及抗食管癌淋巴管生成的重要靶点。      

Relationship between Lymphatic Vessel Density and Lymph Node Metastasis of Invasive Micropapillary Carcinoma of the Breast

OBJECTIVE To investigate the relationship between lymphatic vessel density and lymph node metastasis of invasive micropapillary carcinoma (IMPC) of the breast. METHODS The immunohistochemical study for vascular endothelial growth factor-c (VEGF-C), VEGF Receptor-3 (VEGFR-3) and lymphatic vessel density of 51 cases of IMPC were performed, and lymph node metastases were examined by microscopic analysis of these cases. RESULTS In IMPC, VEGF-C was expressed in the cytoplasm and/or on the membrane of the tumor cells, and the expression of VEGF-C showed a positive correlation with lymph node metastasis (P<0.01). Lymphatic vessel density was determined by the number of micro-lymphatic vessels with VEGFR-3 positive staining. Lymphatic vessel density was positively correlated with VEGF-C expression (P<0.01) and lymph node metastasis (P<0.01). The percentage of IMPC in the tumor was not associated with the incidence of lymph node metastasis. The metastatic foci in lymph nodes were either pure or predominant micropapillary carcinoma. CONCLUSION The results suggested that VEGF-C overexpression stimulated tumor lymphangiogenesis, and the increased lymphatic vessel density may be the key factor that influenced lymph node metastasis of IMPC.     

VEGF-C在胃癌中的表达与微血管密度和淋巴结转移的关系及临床意义

目的 探讨VEGF-C在胃癌中的表达与微血管密度和淋巴结转移及胃癌发生发展及预后的关系.方法 纳入行胃癌手术切除患者的病例样本共计96例,对这96例胃癌样本采用qPCR检测血管内皮生长因子-C(VEGF-C)的相对表达量及检测微血管密度(MVD)参数,并与淋巴结转移等预后情况进行相关性分析.结果 VEGF-C相对表达量与患者的一般资料如年龄、性别、以及肿瘤的特征如大小、发病的部位、侵袭深度,肿瘤的分期及分化程度、是否远处转移等并不存在相关性(P>0.05).而淋巴受累方面,淋巴受累组的VEGF-C相对表达量明显上调(P<0.05),而无淋巴受累组的相对表达量与正常组相比差异无统计学意义(P>0.05),VEGF-C相对表达量明显上调与淋巴结受累转移的风险有关.VEGF-C表达水平与MVD差异表达具有相关性.结论 VEGF-C相对表达量水平与胃癌的淋巴结转移及预后有一定的相关性,但还需进一步系统研究.     

The Expression of High Mobility Group Box 1 is Associated with Lymph Node Metastasis and Poor Prognosis in Esophageal Squamous Cell Carcinoma

The objective is to explore the expression of high mobility group box 1 (HMGB1) in esophageal squamous cell carcinoma (ESCC) and its relationship with lymph node metastasis and the prognosis of patients as well as possible mechanism. The expression of HMGB1, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) in ESCC tissues, which were obtained from 72 patients who underwent radical esophagectomy, was detected through immunohistochemistry, firstly. The correlations between HMGB1 and VEGF-C, and micro-lymphatic vessel density (MLD), and lymph node metastasis, and the prognosis of patients, were analyzed by statistic analysis. The plasmid of small interference RNA (siRNA) targeting HMGB1, giving siHMGB1, was transfected into exponentially growing KYSE150 human esophageal squamous cancer cells and the expression of HMGB1 mRNA and protein was observed by Real-time PCR and Western Blot and the expression of VEGF-C was examined by ELISA. HMGB1 expressed highly in the nuclei and cytoplasm of carcinoma cells as well as the extracellular space in ESCC and was associated with lymph node metastasis, MLD, the expression of VEGF-C, TNM stage and the prognosis of patients (P?相似文献   

乳腺癌淋巴管生成与淋巴结转移、血管内皮生长因子-C表达的关系

目的 探讨乳腺癌中淋巴管生成的分布特点及与血管内皮生长因子-C(VEGF-C)的表达,淋巴结转移和预后的关系.方法 应用免疫组化方法检测70例乳腺癌组织VEGF-C蛋白的表达,并用淋巴管内皮细胞特异性抗体D2-40标记淋巴管,计数肿瘤淋巴管密度(LVD),结合临床病理特征和随访资料进行分析.结果 VEGF-C蛋白的高表达与淋巴结转移(P=0.010)、淋巴管浸润(P=0.031)呈正相关,与肿瘤组织学分级 (P＜0.001) 呈负相关.乳腺癌LVD与淋巴结转移(P＜0.001)、淋巴管浸润(LVI)(P=0.001)、VEGF-C表达(P=0.012)呈正相关,与无病生存率(P=0.011)及总生存率(P=0.001)呈显著负相关.多因素分析显示LVD是影响无病生存率(P=0.015)和总生存率(P=0.002)的独立因子.结论 乳腺癌组织中新生淋巴管主要分布于肿瘤间质,LVD与VEGF-C表达和癌细胞转移相关,乳腺癌微淋巴管密度测定对评估其淋巴结转移和预后判断可能具有意义.     

原发鼻咽癌及颈部淋巴结转移灶中VEGF-C和E-cadherin的表达

目的 探讨血管内皮生长因子C（vascular endothelial growth factor C,VEGF-C）和E-cadherin在鼻咽癌组织及其淋巴结转移灶中的表达及意义.方法 采用免疫组化SP法检测45例鼻咽癌组织及28例相应淋巴结转移灶中VEGF-C和E-cadherin的表达.结果 VEGF-C和E-cadherin在45例鼻咽癌组织中阳性率分别为40.00%和55.56%,在28例淋巴结转移灶中阳性率分别为78.57%和25.00%,两者在鼻咽癌组织和鼻咽癌淋巴结转移组织中阳性率比较均有显著性差异（P＜0.05）;淋巴结转移的鼻咽癌组织中VEGF-C阳性率明显高于无淋巴结转移组;淋巴结转移的鼻咽癌组织中E-cadherin阳性率明显低于无淋巴结转移组织.结论 VEGF-C高表达或E-cadherin低表达可能与鼻咽癌淋巴结转移密切相关.     

Induction of lymphangiogenesis through vascular endothelial growth factor-C/vascular endothelial growth factor receptor 3 axis and its correlation with lymph node metastasis in nasopharyngeal carcinoma

The contribution of the lymphatic system to tumor metastasis is being increasingly appreciated through studies of human cancers. As the biological behavior of nasopharyngeal carcinoma (NPC) depends on its nodal status, patients with advanced nodal status show a higher tendency toward a poor outcome. Here, we examined the role of lymphangiogenesis on lymphatic spread of NPC. We also evaluated the involvement of vascular endothelial growth factor (VEGF)-C/VEGF receptor 3 (VEGFR3) signaling pathway on lymphangiogenesis in NPC. Furthermore, we tested whether Epstein-Barr virus (EBV)-latent membrane protein (LMP) 1 induces VEGF-C. Forty-one patients with NPC were evaluated for expressions of VEGF-C and its receptor, VEGFR3, and LMP1 proteins and lymphatic vessel counts (LVC) highlighted by anti-podoplanin employing immunohistochemistry. The VEGF-C induction by LMP1 was then tested with Western blotting and enzyme-linked immunosorbent assay in vitro. The LVC and VEGF-C expression were significantly higher in cases with advanced regional lymph node metastasis (N2,3) than those with no or limited lymph node involvement (N0,1) (p=0.0380 and p=0.0109, respectively). In VEGF-C/VEGFR3-positive cases, the LVC were significantly increased compared with VEGF-C/VEGFR3-negative cases (p=0.0007). However, LMP1 expression did not show significant associations with LVC and VEGF-C-expression scores (p=0.1210 and p=0.1324, respectively). Induction of VEGF-C protein by LMP1 was not detected in vitro. These results suggest the involvement of the VEGF-C/VEGFR3 axis in the induction of lymphangiogenesis which results in lymphatic spread of NPC. However, EBV-LMP1 was not associated with the mechanism.     

VEGF-C and VEGF-D Expression and its Correlation with Lymph Node Metastasis in Esophageal Squamous Cell Cancer Tissue

Background: To explore vascular endothelial growth factor C (VEGF-C) and VEGF-D expression andits correlation with lymph node metastasis in esophageal squamous cell cancer (ESCC) tissue. Materials andMethods: Immunohistochemical methods were applied to detect the levels of VEGF-C and VEGF-D expressionin 64 surgicall removal ESCC tissues, tissues adjacent to cancer and normal tissues, and the relationship betweenVEGF-C and VEGF-D expression and lymph node metastasis was analyzed. Results: Both VEGF-C and VEGF-Dwere expressed by varying degrees in esophageal cancer tissue, the tissue adjacent to cancer and normal tissue,and the positive expression rate went down successively. The positive expression rates of VEGF-C (59.4%) andVEGF-D (43.8%) in esophageal cancer tissue were significantly higher than in the tissue adjacent to cancer(34.4%, 15.6%) and normal tissue (20.3%, 12.5%), respectively, in which significant differences were manifested(p<0.01). Positive expression rates of VEGF-C and VEGF-D in esophageal cancers with lymph node metastasiswere markedly higher than without such metastasis (p<0.01), while those in the tissue with TNM staging I~IIwere markedly lower than that with TNM staging III~IV (p<0.01). Conclusions: Both VEGF-C and VEGF-Dare highly expressed in ESCC tissue, which may be related to the lymph node metastasis of cancer cells. Hence,VEGF-C and VEGF-D can be clinically considered as important reference indexes of lymph node metastasis inesophageal cancer.     

血管内皮生长因子-C mRNA的表达与食管鳞癌临床病理特征的关系

目的 探讨血管内皮生长因子-C(VEGF-C)mRNA的表达与食管鳞癌临床病理特征的关系.方法 采用实时荧光定量逆转录多聚酶链反应(QRT-PCR)法,测定59例食管癌和正常黏膜中VEGF-C mRNA的表达.结果 食管癌组织中VEGF-C mRNA表达显著高于正常黏膜(6.30和2.81,P=0.02),淋巴结转移者的VEGF-C mRNA表达显著高于无转移者(10.11和4.15,P=0.04),转移淋巴结≥4枚患者的VEGF-C mRNA表达显著高于<4枚的患者(62.19和6.30,P=0.01),转移淋巴结组≥3组患者的VEGF-C mRNA表达显著高于<3组的患者(18.98和4.92,P=0.04),Ⅱb+Ⅲ+Ⅳ期患者的VEGF-C mRNA表达显著高于Ⅰ+Ⅱa期患者(9.99和3.80,P=0.03),颈淋巴结转移与区域淋巴结转移患者的VEGF-C mRNA表达无统计学意义.Logistic多元回归分析显示,VEGF-C mRNA高表达是食管癌淋巴结转移的独立危险因素(P=0.01).单因素和多因素分析均显示,EGFR-C mRNA表达与食管鳞癌患者的预后无关,而淋巴结转移组数是食管癌预后的独立危险因素(P<0.01).结论 VEGF-C mRNA的表达与食管鳞癌淋巴结转移密切相关,在食管鳞癌的淋巴结转移中起着非常重要的作用.     

VEGF-C在食管鳞癌和神经胶质瘤中的表达及其意义

背景和目的：近几年研究发现,某些恶性肿瘤能表达血管内皮生长因子C(vascular endothelial growth factor—C,VEGF-C),VEGF—C是迄今发现的惟一特异性促淋巴管生长因子。目前恶性肿瘤组织中VEGF—C的表达与肿瘤淋巴转移的关系方面的研究资料尚少。本研究拟通过检测、比较VEGF-C在两种不同转移特性的恶性肿瘤即人食管鳞癌和神经胶质瘤组织中的表达,分析恶性肿瘤组织中VEGFP—C的表达与肿瘤淋巴转移的关系。方法：采用免疫组化法检测VEGF-C在72例食管鳞癌(其中淋巴结转移29例,无淋巴结转移43例)和23例神经胶质瘤组织(病理学诊断为星形细胞瘤,I～Ⅳ级)中的表达,并对VEGF-C的表达与临床病理因素之间的关系作进一步的分析研究。结果：神经胶质瘤组织中未见VEGF—C抗原表达;食管鳞癌组织VEGF-C阳性表达率为38．88％(28／72),其中VEGF-C阳性表达率在有淋巴结转移组为62．07％(18／29),在无淋巴结转移组为23．26％(10／43),在浸润深度T2、T3期为58．82％(20／34),在T1期为21．05％(8／38),结论：VEGF-C阳性表达与食管鳞癌的淋巴结转移、浸润深度有关。VEGF—C是促进食管鳞癌经淋巴转移的重要因素。     

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.     

Endostatin? VEGF-C和VEGFR-3在非小细胞肺癌及其淋巴结组织中的表达与意义

探讨内皮抑素（endostatin）、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）在癌组织及其淋巴结组织中的表达与非小细胞肺癌（NSCLC）生物学行为之间的关系,了解endostatin、VEGF-C和VEGFR-3三者之间的内在联系。方法:使用免疫组化链霉菌抗生物素蛋白-过氧化物酶（SP）连接法对98例肺癌根治手术后癌组织和淋巴结组织标本的endostatin、VEGF-C和VEGFR-3的表达情况进行研究。结果:endostatin、VEGF-C、VEGFR-3在癌组织中的阳性表达率分别为30.6%、79.6%、61.2%。其中endostatin的表达与VEGF-C的表达呈正相关（P=0.025）,VEGF-C的表达与VEGFR-3的表达呈正相关（P=0.007）。不同N分期及不同淋巴结转移枚数分组的患者,其endostatin和VEGF-C的阳性表达率均有显著性差异（P<0.05）,且两者之间的变化呈相反趋势。VEGFR-3的表达与分化程度相关（P=0.013）。VEGF-C的表达情况与脉管癌栓相关（P=0.050）。在转移性淋巴结中,VEGF-C和VEGFR-3的阳性表达率均达88.0%,未转移淋巴结中,两者的阳性表达率分别为32.7%和57.1%,差异有统计学意义（P<0.001）。转移性淋巴结中微淋巴管密度（MLVD）明显高于非转移淋巴结（P<0.001）。结论:endostatin和VEGF-C的表达与肺癌淋巴结转移密切相关,endostatin可能通过下调VEGF-C的表达来抑制淋巴结转移,VEGF-C/VEGFR-3通路通过促进微淋巴管的增生直接参与淋巴结转移,对寻找治疗肺癌的新途径有重要意义。      

食管鳞癌组织MTA2表达与淋巴结转移相关性的探讨

目的:探讨食管鳞状细胞癌(ESCC)组织中转移相关基因2(MTA2)的表达与淋巴结转移的关系及其临床意义.方法:免疫组织化学(SP)方法及流式细胞技术检测102例ESCC标本反12例癌旁正常黏膜组织中MTA2蛋白的表达,统计分析其表达与ESCC淋巴结转移的关系.结果:MTA2在癌旁正常食管黏膜组织中无表达,在部分ESCC组织中呈阳性表达,阳性率为68.6％(70/102),其中强阳性28例;ESCC组织中淋巴结转移组与未转移组MTA2蛋白表达的强阳性率分别为68.2％(15/22)、27.1％(13/48),差异有统计学意义,P=0.003; MTA2的阳性表达与ESCC的淋巴结转移数目及淋巴结转移率均呈正相关,P值分别为0.006、0.001;流式细胞技术结果显示,淋巴结转移组与非转移组MTA2蛋白相对含量分别为252.11±30.22、161.42±22.89,差异有统计学意义,t=15.11,P=0.000.结论:MTA2蛋白的阳性表达与SCC的淋巴结转移密切相关,MTA2可能是ESCC一种新的标志及治疗靶点.     

VEGF-C及癌周淋巴管密度与头颈鳞癌颈部淋巴结转移的关系

目的探讨血管内皮细胞生长因子-C（VEGF-C）表达及癌周淋巴管密度（P-LVD）与头颈鳞癌（HNSCC）颈部淋巴结转移的关系。方法采用免疫组化法,检测104例HNSCC组织中VEGF-C及癌周LYVE-1的表达,幷计算P-LVD,分析P-LVD及VEGF-C表达与其临床病理因素的关系。结果 104例HNSCC组织中,VEGF-C阳性表达率显著高于正常头颈部黏膜组织（74.04%vs 0,P〈0.05）。淋巴结转移组VEGF-C阳性表达率高于无淋巴结转移组（P〈0.05）。对LYVE-1标记的淋巴管密度（LVD）分析显示,癌周组织P-LVD高于癌内及正常组织（P〈0.05）,而VEGF-C阳性表达者及颈部淋巴结转移者P-LVD分别显著高于VEGF-C阴性表达者和无颈部淋巴结转移者（P〈0.05）。结论 HNSCC中VEGF-C表达及P-LVD与肿瘤淋巴结转移密切相关,对判断肿瘤侵袭、转移具有一定参考价值。     

VEGF-C及其受体Flt-4在乳腺癌细胞增殖及转移中的作用

背景与目的:血管内皮细胞生长因子-C(vascularendothelialgrowthfactor-C,VEGF-C)是VEGF家族成员之一,是惟一可与淋巴管内皮细胞表面受体VEGFR-3(即fms-liketyrosinekinase-4,Flt-4)结合并调节淋巴管生理功能的因子。目前发现VEGF-C/Flt-4系统在多种肿瘤的转移中起调控作用,但对该系统在乳腺癌方面的研究国内外报道很少。本实验旨在探讨VEGF-C/Flt-4在乳腺癌增殖及转移中的作用和意义。方法:采用免疫组织化学方法对101例乳腺癌组织切片染色,观察乳腺癌组织中VEGF-C、Flt-4、增殖细胞核抗原(proliferatingcellnuclearantigen,PCNA)的表达情况。结果:101例乳腺癌组织中,VEGF-C阳性率为93.1%(94/101),Flt-4阳性率为86.1%(87/101),且Flt-4阳性指数随VEGF-C表达的增强而增加(r=0.816,P<0.001);PCNA的阳性率为88.8%(89/101),且随着VEGF-C表达强度增强,肿瘤细胞增殖活性也随之增强(r=0.673,P<0.001)。VEGF-C阳性指数在转移组(61.89±17.79)明显高于未转移组(44.28±17.87)(P<0.05)。随着癌细胞VEGF-C表达强度增强,Flt-4阳性脉管数也随之增加,各组间均有显著性差异(P<0.001)。乳腺癌中Flt-4阳性脉管数在淋巴结转移组(15.55±3.63)明显高于未转移组(10.71±2.90)(P<0.05)。结论:VEGF-C及其受体Flt-4在人乳腺癌细     

宫颈癌中iNOS的表达与肿瘤新生淋巴管及VEGF-C的关系

目的:探测人宫颈癌中的诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)、血管内皮生长因子-C(vascular endothelial growth factor,VEGF-C)的表达与D2-40标记的淋巴管密度的关系.方法:采用免疫组化SP法检测宫颈鳞状细胞癌中iNOS、VEGF-C的表达情况,并用D2-40进行癌组织淋巴管染色,测定其淋巴管密度(lymphatic vessel density,LVD),另取正常宫颈组织10例作对照,观察上述因子在宫颈癌及正常宫颈中的表达及其与肿瘤病理参数之间的相关性.结果:与正常宫颈组织相比,宫颈癌组织中具有更高的iNOS、VEGF-C的表达率及淋巴管密度(t=2.39、3.08,P=0.021、0.003).与无淋巴结转移组相比,淋巴结转移组具有更高的iNOS、VEGF-C阳性表达率(P =0.044、0.035)及淋巴管密度(t=3.79,P＜0.001);iNOS、VEGF-C阳性共表达与肿瘤淋巴结转移之间存在正相关(P=0.046),宫颈癌组织中iNOS、VEGF-C的表达具有相关性(P＜0.001).结论:iNOS、VEGF-C在宫颈癌组织中呈过表达,其与宫颈癌的淋巴转移关系密切;iNOS可能通过催化产生NO上调VEGF-C的表达,诱导肿瘤淋巴管生成,导致宫颈癌的淋巴道转移.iNOS、VEGF-C均参与宫颈的发展、浸润和转移,可作为评估宫颈癌的生物学行为和判断预后的指标.针对iNOS、VEGF-C的靶向治疗可成为宫颈癌治疗的新靶点.