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


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.

SUBMITTER: Yang Y 

PROVIDER: S-EPMC5650371 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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

Yang Yi Y   Jin Guoguo G   Liu Hangfan H   Liu Kangdong K   Zhao Jimin J   Chen Xinhuan X   Wang Dongyu D   Bai Ruihua R   Li Xiang X   Jang Yanan Y   Lu Jing J   Xing Ying Y   Dong Ziming Z  

Oncotarget 20170818 43


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  ...[more]

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