Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong.
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong; Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong.
Cancer Lett. 2018 Jan 1;412:10-20. doi: 10.1016/j.canlet.2017.09.054. Epub 2017 Oct 9.
Anti-angiogenesis effect of a prodrug of green tea polyphenol (-)-epigallocatechin-3-gallate (Pro-EGCG) in malignant tumors is not well studied. Here, we investigated how the treatment with Pro-EGCG inhibited tumor angiogenesis in endometrial cancer. Tumor xenografts of human endometrial cancer were established and subjected to microarray analysis after Pro-EGCG treatment. First, we showed Pro-EGCG inhibited tumor angiogenesis in xenograft models through down-regulation of vascular endothelial growth factor A (VEGFA) and hypoxia inducible factor 1 alpha (HIF1α) in tumor cells and chemokine (C-X-C motif) ligand 12 (CXCL12) in host stroma by immunohistochemical staining. Next, we investigated how HIF1α/VEGFA was down-regulated and how the reduction of CXCL12 inhibited tumor angiogenesis. We found that VEGFA secretion from endometrial cancer cells was decreased by Pro-EGCG treatment through inhibiting PI3K/AKT/mTOR/HIF1α pathway. Furthermore, the down-regulation of CXCL12 in stromal cells by Pro-EGCG treatment restricted migration and differentiation of macrophages thereby inhibited infiltration of VEGFA-expressing tumor-associated macrophages (TAMs). Taken together, we demonstrated that treatment with Pro-EGCG not only decreases cancer cell-secreted VEGFA but also inhibits TAM-secreted VEGFA in endometrial cancer. These findings demonstrate that Pro-EGCG is a novel angiogenesis inhibitor for endometrial cancer.
绿茶多酚（-）-表没食子儿茶素-3-没食子酸酯（Pro-EGCG）前药对恶性肿瘤的抗血管生成作用尚未得到充分研究。在这里，我们研究了 Pro-EGCG 如何抑制子宫内膜癌中的肿瘤血管生成。在 Pro-EGCG 处理后，建立了人子宫内膜癌的肿瘤异种移植物，并进行了微阵列分析。首先，我们通过免疫组织化学染色显示，Pro-EGCG 通过下调肿瘤细胞中的血管内皮生长因子 A（VEGFA）和缺氧诱导因子 1α（HIF1α）以及宿主基质中的趋化因子（C-X-C 基序）配体 12（CXCL12），抑制了异种移植模型中的肿瘤血管生成。接下来，我们研究了 HIF1α/VEGFA 如何下调以及 CXCL12 的减少如何抑制肿瘤血管生成。我们发现，Pro-EGCG 通过抑制 PI3K/AKT/mTOR/HIF1α 通路，降低子宫内膜癌细胞中 VEGFA 的分泌。此外，Pro-EGCG 处理下调基质细胞中的 CXCL12 会限制巨噬细胞的迁移和分化，从而抑制表达 VEGFA 的肿瘤相关巨噬细胞（TAMs）的浸润。总之，我们证明 Pro-EGCG 治疗不仅降低了癌细胞分泌的 VEGFA，还抑制了子宫内膜癌中 TAM 分泌的 VEGFA。这些发现表明 Pro-EGCG 是一种新型的子宫内膜癌血管生成抑制剂。
