Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, China.
Chin J Nat Med. 2013 May;11(3):245-53. doi: 10.1016/S1875-5364(13)60023-0.
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.
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 significance. Decreased IFP was measured by the Wink-in-needle method, while hypoxia was assessed by polarographic electrode and pimonidazole (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 (R(2) = 0.618, P = 0.002), Ang-2 was correlated with MVD (R(2) = 0.423, P = 0.022), IFP (R(2) = 0.663, P = 0.01) and PIMO staining (R(2) = 0.694, P = 0.01).
IFP and delivery of oxygen might be improved by rebalance of Ang-1/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.
微血管和微环境在非小细胞肺癌（NSCLC）的增殖、侵袭、转移和预后中起着重要作用，这可能会被许多抗血管生成药物改变。表没食子儿茶素没食子酸酯（EGCG）是从绿茶中提炼的一种天然抗血管生成剂，被证明对血管生成因子有多种作用，如内皮生长因子（VEGF）、血小板衍生生长因子（PDGF）和血管生成素（ANGs）。假设 EGCG 可能调节 NSCLC 中的微血管和微环境，研究了 EGCG 对微血管密度（MVD）、Ang-1 和 Ang-2 表达、间质液压力（IFP）、肿瘤缺氧和化疗敏感性的影响。
EGCG 处理体内异种移植荷瘤小鼠的 A549 细胞，导致 CD31 检测的 MVD 和量子点双标记免疫荧光评估的 Ang-2 表达显著下降，而 Ang-1 则无明显下降。通过针内测压法测量降低的 IFP，通过极谱电极和吡莫硝唑（PIMO）免疫组织化学评估缺氧。假设这些变化会增加对化疗的反应，在裸鼠异种移植瘤中进行了肿瘤生长研究，然后用 EGCG 和化疗药物顺铂进行治疗。与单独使用每种药物相比，EGCG 治疗联合顺铂治疗导致肿瘤生长协同抑制（P < 0.001）。根据线性回归分析，IFP 与 PIMO 染色呈正相关（R(2) = 0.618，P = 0.002），Ang-2 与 MVD 相关（R(2) = 0.423，P = 0.022），IFP（R(2) = 0.663，P = 0.01）和 PIMO 染色（R(2) = 0.694，P = 0.01）。
在 EGCG 治疗 NSCLC 中，Ang-1/Ang-2 的再平衡可能会改善 IFP 和氧的输送，同时也作为化疗的增敏剂。这些研究通过改变微血管和微环境，为将 EGCG 作为辅助化疗药物提供了一个新的机制。
