表没食子儿茶素没食子酸酯通过Ang-1与Ang-2比例重调引起NSCLC组织间液压降低、乏氧减轻并促进化疗疗效(英文)

Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2

目的:肿瘤微血管与微环境对非小细胞肺癌(NSCLC)肿瘤组织的增殖、侵袭、转移和进展起到了很重要的作用,同时也可以被多种抗血管生成药物所影响。表没食子儿茶素没食子酸酯(EGCG)是绿茶中提取的天然成分,被证明可以作用于多种血管生成因子,包括血管内皮生长因子(VEGF)、血小板源性生长因子(PDGF)和血管生成素(Angs)。因此我们假设EGCG能够引起NSCLC肿瘤微血管与微环境的改变,并检测了EGCG处理NSCLC移植瘤后微血管密度(MVD)、Ang-1与Ang-2的表达、组织间液压(IFP)、肿瘤乏氧指标以及联合化疗的疗效,以证明我们的假设。方法与结果:EGCG处理人肺腺癌细胞株A549荷瘤裸鼠后引起肿瘤组织中MVD(CD31标记)、Ang-2(量子点免疫双标法)表达量明显下降,Ang-1(量子点免疫双标法)表达量出现下降趋势,无统计学意义;IFP(Wink-in-needle法)、乏氧程度(氧电极检测组织PO2,免疫组化法标记哌莫硝唑)明显下降。为明确以上改变是否可以影响肿瘤对化疗的敏感性,我们将荷瘤裸鼠分别予以EGCG、顺铂及EGCG+顺铂联合处理,观察肿瘤生长速度。结果显示联合治疗组移植瘤生长速度较另两组单药治疗明显较慢(P<0.001)。经过统计学线性回归分析,提示IFP与哌莫硝唑标记量变化呈正相关(R2=0.618,P=0.002),Ang-2表达量与MVD、IFP、哌莫硝唑标记量变化分别呈正相关(R2=0.423,P=0.022,R2=0.663,P=0.01,R2=0.694,P=0.01)。结论:EGCG可以通过调整Ang-1/Ang-2之间的平衡影响NSCLC肿瘤组织的IFP以及氧的运输,并起到化疗增敏剂的效果。研究中观察到的EGCG对肿瘤微血管与微环境的作用,为EGCG作为辅助化疗药物提供了新的应用策略。

AIM： Microvasculature and microenvironment play important roles in proliferation, invasion, metastasis and prognosis in non-small cell lung cancer （NSCLC）, which might be altered by many anti-angiogenic drugs. Epigallocatechin-3-gallate （EGCG）, a natural anti-angiogenesis agent refined from green tea, was defined to have multiple effects on angiogenesis factors, such as endothelial growth factor （VEGF）, platelet-derived growth factor （PDGF） and angiopoietins （ANGs）. Hypothesizing that EGCG might regulate microvasculature and microenvironment in NSCLC, the effects of EGCG on microvessel density （MVD）, expression of Ang-1 and Ang-2, interstitial fluid pressure （IFP）, tumor hypoxia, and chemotherapy sensitivity were examined. METHODS and RESULTS： EGCG treatment of A549 cells in mice bearing xenografts in vivo led to a significant decrease of MVD detected by CD31, and of Ang-2 expression detected by quantum dots double-label immunofluorescence assessment, while Ang-1 decreased with no signifi- cance. Decreased IFP was measured by the Wink-in-needle method, while hypoxia was assessed by polarographic electrode and pi- monidazole （PIMO） immunohistochemistry. Assuming that these changes would increase response to chemotherapy, tumor growth studies were p[erformed in nude mice with xenografts, which were then treated with EGCG and the chemotherapeutic agent cisplatin. EGCG therapy combined with cisplatin led to synergistic inhibition of tumor growth, compared with administration of each treatment separately （P 〈 0.001）. According to linear regression analysis, IFP was positively correlated with PIMO staining （R2 = 0.618, P = 0.002）, Ang-2 was correlated with MVD （R~ = 0.423, P = 0.022）, IFP （Rz = 0.663, P -- 0.01） and PIMO staining （R2 -- 0.694, P = 0.01）. CONCLUSIONS： IFP and delivery of oxygen might be improved by rebalance of Ang-l/Ang-2 under the treatment of EGCG in NSCLC, which also acts as a sensitizer of chemotherapy. These studies established a new mechanism for using EGCG as an adjuvant chemotherapy agent through modifying microvasculature and microenvironment. [