Metformin inhibits esophageal squamous cell carcinoma-induced angiogenesis by suppressing JAK/STAT3 signaling pathway.
Metformin inhibits esophageal squamous cell carcinoma-induced angiogenesis by suppressing JAK/STAT3 signaling pathway.
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二甲双胍通过抑制JAK/STAT3信号通路抑制食管鳞癌诱导的血管生成
DOI：
10.18632/oncotarget.20341
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发表时间：
2017-09-26
期刊：
影响因子：
--
通讯作者：
Dong Z
中科院分区：
文献类型：
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作者：
Yang Y;Jin G;Liu H;Liu K;Zhao J;Chen X;Wang D;Bai R;Li X;Jang Y;Lu J;Xing Y;Dong Z
虽然已经知道肿瘤微环境影响血管生成，但确切的机制仍不清楚。本研究采用肿瘤条件培养液（TCM）模拟人食管鳞状细胞癌（ESCC）微环境，探讨TCM对正常内皮细胞（NECs）的影响。我们发现，中药诱导的NECs表现出增强的血管生成特性，如迁移，侵袭和管形成。此外，中药诱导的NECs表达肿瘤内皮细胞（TECs）标志物，提示中药可能通过促使NECs向TECs转化而促进肿瘤血管生成。基因表达谱芯片分析结果表明，中药诱导NECs基因组发生显著变化，并改变了多个调控网络，尤其是c-MYC和JAK/STAT 3信号通路。更重要的是，我们研究了二甲双胍的抗血管生成作用，发现二甲双胍通过抑制JAK/STAT 3/c-MYC信号通路消除了ESCC微环境诱导的NECs向TECs的转变。此外，我们首次通过人ESCC患者来源的异种移植（PDX）小鼠模型验证了二甲双胍的体内抗血管生成活性。综上所述，我们的研究为二甲双胍的抗血管生成作用提供了一种新的机制，并为通过阻断NECs向TECs的转变来开发新的抗血管生成药物奠定了实验基础，这可能为癌症的靶向治疗开辟新的途径。
Although it has been known that the tumor microenvironment affects angiogenesis, the precise mechanism remains unclear. In this study, we simulated the microenvironment of human esophageal squamous cell carcinoma (ESCC) by tumor conditioned medium (TCM) to assess the influence on normal endothelial cells (NECs). We found that the TCM-induced NECs showed enhanced angiogenic properties, such as migration, invasion and tube formation. Moreover, the TCM-induced NECs expressed tumor endothelial cells (TECs) markers at higher levels, which indicated that TCM probably promoted tumor angiogenesis by coercing NECs to change toward TECs. The microarray gene expression analysis indicated that TCM induced great changes in the genome of NECs and altered many regulatory networks, especially c-MYC and JAK/STAT3 signaling pathway. More importantly, we investigated the anti-angiogenic effect of metformin, and found that metformin abrogated the ESCC microenvironment-induced transition of NECs toward TECs by inhibiting JAK/STAT3/c-MYC signaling pathway. Furthermore, we verified the anti-angiogenic activity of metformin in vivo by a human ESCC patient-derived xenograft (PDX) mouse model for the first time. Taken together, our research provides a novel mechanism for the anti-angiogenic effect of metformin, and sets an experimental basis for the development of new anti-angiogenic drugs by blocking the transition of NECs toward TECs, which possibly open new avenues for targeted treatment of cancer.