肝细胞生长因子对人舌鳞癌 Tca8113细胞 VEGF-C 表达的影响及作用机制的初步研究

目的：研究 HGF 对人舌鳞癌 Tca8113细胞中 VEGF-C 表达的影响并探讨其作用机制。方法：体外培养 Tca8113细胞,应用 ELISA 方法测定不同浓度 HGF 作用下以及分别用 LY294002、U0126、SP600125、SB203580信号通路抑制剂阻断PI3K/Akt、P44/P22MAPK、JNK、P38MAPK 信号通路后 VEGF-C 的表达水平。结果：随着培养液中 HGF 浓度的增加,Tca8113细胞中 VEGF-C 的表达水平出现先增高后降低的趋势,当 HGF 浓度为40 ng/ml 时,VEGF-C 表达水平最高。PI3K/Akt 信号通路抑制剂（LY294002）和 P42/44MAPK 信号通路抑制剂（U0126）显著抑制了 HGF 刺激下 Tca8113的 VEGF-C 蛋白的表达（P ＜0．01）;而 JNK 信号通路抑制剂（SP600125）和 P38MAPK 信号通路抑制剂（SB203580）对 HGF 刺激下 Tca8113的 VEGF-C 蛋白的表达影响甚微（P ＞0．05）。结论：在人舌鳞癌 Tca8113细胞中,随着 HGF 浓度的增加,VEGF-C 的表达先增高后降低。PI3K/Akt 和 P44/P22MAPK 信号通路在口腔鳞状细胞癌淋巴转移中可能发挥作用。     

Impact of weight loss on circulating IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C and midkine in gastroesophageal cancer patients

OBJECTIVE: Proinflammatory cytokines are involved in cancer-related weight loss, but the involvement of VEGF-A, VEGF-C, IL-8 and midkine in gastroesophageal cancer patients remains unknown. DESIGN AND METHODS: Serum IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C, and midkine were evaluated in 96 cancer patients and 42 controls using ELISAs and were related to the occurrence of weight loss, patient's age, gender and BMI, cancer TNM status and blood cell counts. RESULTS: All cytokines were elevated in cancer patients with further up-regulation of IL-6, IL-8, midkine and VEGF-A in cachexia. Underweight, midkine and VEGF-A were found independent indicators of weight loss. Primary tumor seems to be a major source of pro-cachectic cytokines, yet neutrophils and platelets also contribute to cytokine elevation. CONCLUSIONS: IL-6 and IL-8, and probably midkine and VEGF-A, appear to participate in the development of cancer-related cachexia in gastroesophageal malignancies, although a detailed mechanism underlying cytokine involvement needs to be elucidated.     

Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats

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Predictive role of the overexpression for CXCR4, C-Met,and VEGF-C among breast cancer patients: A meta-analysis

BackgroundThe overexpression of CXCR4, C-Met and VEGF-C present widely in breast tumors, they may be markers of resistance to treatment. However, the studies are still controversial. Thus, this meta-analysis aims to research the relationship between the overexpression of CXCR4, C-Met, VEGF-C and clinical prognosis among breast cancer patients.MethodsPubMed and EMBASE databases were searched for eligible literature. The outcomes of interest were progression-free survival (PFS), relapse-free survival (RFS) and overall survival (OS). All tests of statistical significance were two sided.ResultsA total of 7830 patients from 28 eligible studies were assessed. The overexpression of the CXCR4 and C-Met both implied significantly worse PFS compared with normal expression [HR = 2.56, 95% CI = 1.34–4.91, P = 0.005; and HR = 1.63 95% CI = 1.20–2.22, P = 0.002]. Meanwhile, if patients had high expression of CXCR4, they would have worse OS [HR = 2.56 95% CI = 1.52–4.31, P = 0.000]. However, the overexpression of C-Met did not relate to OS for breast cancer patients [HR = 1.16, 95% CI = 0.69–1.95, P = 0.570]. Meanwhile, no statistically significant different was observed with respect to PFS and OS between VEGF-C overexpression and normal expression [HR = 0.99, 95% CI = 0.64–1.52, P = 0.968; and HR = 0.76, 95% CI = 0.43–1.33, P = 0.333].ConclusionsOur meta-analysis showed that CXCR4 and C-Met were efficient prognostic factors for breast cancer. Nevertheless, highly expressing VEGF-C was not related to progression-free survival and overall survival. Due to the small samples and insufficient date, further studies should be conducted to clarify the association between the overexpression of CXCR4 or C-Met or VEGF-C and the prognosis about breast cancer patients.     

血管内皮生长因子C及其受体与宫颈癌临床和预后的关系

目的:观察血管内皮生长因子C(VEGF-C)与血管内皮生长因子受体3(VEGFR-3)在宫颈癌组织中的表达并分析其与临床及预后的关系。方法:免疫组织化学SP法检测80例宫颈癌组织中VEGF-C与VEGFR-3的表达,以30例正常宫颈组织为对照组。结果:VEGF-C在癌组织中呈高表达,癌周组织表达相对较低,但两组表达均高于对照组(P<0.05);癌组织中VEGF-C的表达与肿瘤的临床分期相关,淋巴结转移组VEGF-C的阳性表达率为69.6%明显高于无淋巴结转移组的49.1%,差异有统计学意义(P<0.05)。VEGFR-3在癌周组织表达较高,癌组织中表达较低,但都明显高于对照组(P<0.05);淋巴结转移组中的VEGFR-3在癌周组织标记的淋巴管密度为19.67±3.72明显高于无淋巴结转移组10.78±2.65,差异有统计学意义(P<0.05);Ⅰb期组VEGFR-3的表达15.78±5.67明显高于Ⅰa2期9.87±1.95,低于Ⅱa期18.78±4.32,随着宫颈癌临床分期及病理组织学分级的提高,VEGFR-3表达也随之增强,差异有统计学意义(P<0.05)。结论:VEGF-C和VEGFR-3与宫颈癌的发生发展密切相关,癌组织VEGF-C和癌周组织VEGFR-3表达水平的检测可能有利于临床评估宫颈癌的预后。     

Hypoxia-induced factor-1 alpha upregulates vascular endothelial growth factor C to promote lymphangiogenesis and angiogenesis in breast cancer patients

Hypoxia-induced factor-1 alpha （HIF-1α） affects many effector molecules and regulates tumor lymphangio- genesis and angiogenesis during hypoxia. The aim of this study was to investigate the role of HIF-1α in the regu- lation of vascular endothelial growth factor C （VEGF-C） expression and its effect on lymphangiogenesis and an- giogenesis in breast cancer. Lymphatic vessel density （LVD）, microvessel density （MVD） and the expressions of HIF-1α and VEGF-C proteins were evaluated by immunohistochemistry in 75 breast cancer samples. There was a significant correlation between HIF-1α and VEGF-C （P = 0.014, r = 0.273, Spearman＇s coefficient of correlation）. HIF-1α and VEGF-C overexpression was significantly correlated with higher LVD （P = 0.003 and P = 0.017, re- spectively）, regional lymph nodal involvement （P = 0.002 and P = 0.004, respectively） and advanced tumor, node, metastasis （TNM） classification （P = 0.001 and P = 0.01, respectively）. Higher MVD was observed in the group expressing higher levels of HIF-1α and VEGF-C （P = 0.033 and P = 0.037, respectively）. Univariate analysis showed shorter survival time in patients expressing higher levels of HIF-1α and VEGF-C. HIF-1α was also found to be an independent prognostic factor of overall survival in multivariate analysis. The results suggest that HIF-1α may affect VEGF-C expression, thus acting as a crucial regulator of lymphangiogenesis and angiogenesis in breast cancer. This study highlights promising potential of HIF- 1α as a therapeutic target against tumor lymph node me- tastasis.     

VEGF—C及其受体VEGFR-3在骨肉瘤中的表达及临床意义

目的探讨血管内皮细胞生长因子-C（VEGF-C）与血管内皮细胞生长因子受体VEGFR-3（Flt4）,在骨肿瘤．中的表达及临床意义。方法应用免疫组化和原位杂交方法检测105例骨肿瘤组织中的VEGF-C、Fh4的表达,并对其中85例骨肉瘤主要临床资料、病理分级及I临床相关参数进行比较,用X2检验进行统计学处理。结果骨肉瘤中VEGF-C、Flt4的蛋白及mRNA阳性表达率明显高于骨软骨瘤阳性表达率（P〈0．01）。在骨肉瘤临床分期中1Ib期、Ⅲ期明显高于I期、1Ia期（P〈0．01）,并随着病理分级恶性程度增高而显著增加（P〈0.01）。且在软组织浸润和转移组中VEGF-C、Flt4蛋白及mRNA的阳性表达率明显高于非浸润和非转移组（P〈0．01）。结论VEGF-C、Flt4的蛋白及mRNA在骨肉瘤中不同程度异常表达与肿瘤的临床分期、病理分级和浸润、转移呈正相关,提示VEGF—C、F1t4的蛋白及其mRNA高表达尤其在骨肉瘤的浸润转移过程中发挥重要作用。     

胃癌组织survivin的表达及其与bcl-2、VEGF—C的相关性研究

目的研究凋亡抑制蛋白survivin、bcl-2、VEGF—C在胃癌组织中的表达,并探讨三者之间的相关性。方法采用链霉菌抗生物素蛋白-过氧化酶连接（S-P）免疫组化方法,检测survivin、bcl-2、VEGF—C在正常胃黏膜组织及胃癌组织中的表达。结果Survivin蛋白在正常胃黏膜组织中无表达,而在胃癌组织中表达明显（P〈0．01）;Survivin蛋白表达与胃癌组织病理分型、淋巴结转移、TNM分期相关,而与浸润程度不相关;胃癌bcl-2蛋白表达的阳性与阴性中,survivin蛋白表达阳性率分别为79．5％和50．0％,两者差异有统计学意义（P〈0．01）;VEGF-C蛋白表达的阳性和阴性中,survivin蛋白表达阳性率分别为62．5％和28．6％,两者差异有统计学意义（P〈0．05）。结论结论Survivin基因的异常表达而引起的细胞凋亡抑制,在胃癌的发生中起一定作用;Survivin蛋白表达与胃癌组织中bcl-2蛋白及VEGF—C蛋白的异常表达密切相关。     

VEGF-C对宫颈癌细胞增殖和凋亡信号传导通路的影响

目的:研究VEGF-C对体外培养的宫颈癌HeLa细胞增殖和凋亡的影响;研究VEGF-C受体KDR、信号通路PI3K、MAPK在VEGF-C对宫颈癌增殖和凋亡调控中的作用。方法:应用重组人VEGF-C蛋白体外刺激宫颈癌HeLa细胞,MTT法检测细胞增殖,流式细胞仪检测细胞周期和凋亡,Western blot检测增殖与凋亡相关基因Bcl-2、CyclinD1蛋白表达;应用KDR-Ab、信号通路PI3K抑制剂LY294002、信号通路MAPK抑制剂PD98059预处理HeLa细胞,再进行VEGF-C刺激,观察上述指标的变化。结果:重组VEGF-C(50ng/μl)刺激HeLa细胞后增殖指数增加(2.13 vs 1),细胞周期S期比率增多[(64.26±0.20)%vs(30.91±0.09)%,P<0.05],细胞凋亡率降低(3.29±0.35 vs 7.44±0.55,P<0.05);Bcl-2、Cyclin D1表达增加(P<0.05)。KDR-Ab、LY294002预处理后与VEGF-C组相比增殖指数降低,细胞周期S期比率下降,凋亡指数升高,Bcl-2、Cyclin D1表达降低。PD98059预处理后,与VEGF-C组相比增殖指数降低、细胞周期S期比率下降、Bcl-2、Cyclin D1表达降低,但对VEGF-C诱导的凋亡无明显影响。结论:外源性VEGF-C作用于肿瘤细胞自身的KDR受体,激活细胞内信号传导通路MAPK途径和(或)PI3K途径诱导Cyclin D1表达,使肿瘤细胞S期加快,促进细胞周期的进程,进而促进He-La细胞增殖;通过PI3K途径诱导Bcl-2表达,抑制凋亡。