Metformin inhibits esophageal squamous cell carcinoma-induced angiogenesis by suppressing JAK/STAT3 signaling pathway

// Yi Yang 1, 2, 3 , Guoguo Jin 1, 2 , Hangfan Liu 1, 2 , Kangdong Liu 1, 2 , Jimin Zhao 1, 2 , Xinhuan Chen 1, 2 , Dongyu Wang 1, 2 , Ruihua Bai 4 , Xiang Li 1, 2 , Yanan Jang 1, 2 , Jing Lu 1, 2 , Ying Xing 1, 3 and Ziming Dong 1, 2 1 Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China 2 Collaborative Innovation Center of Henan Province for Cancer Chemoprevention, Zhengzhou, Henan 450001, P.R. China 3 Department of Physiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China 4 Department of Pathology, Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan 450008, P.R. China Correspondence to: Jing Lu, email: lujing@zzu.edu.cn Ying Xing, email: xingy@zzu.edu.cn Ziming Dong, email: dongzm@zzu.edu.cn Keywords: metformin, angiogenesis, ESCC, microenvironment, TECs Received: January 23, 2017 Accepted: July 18, 2017 Published: August 18, 2017 ABSTRACT 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.