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STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression

Abstract

Metastasis is a life-threatening feature of cancer and is primarily responsible for cancer patient mortality. Cross talk between tumor cells and endothelium is important for tumor progression and metastasis. However, very little is known about the mechanisms by which endothelial cells (ECs) that are close to tumor cells, respond to the tumor cells during tumor progression and metastasis. In this study, we exploited the use of EC-specific signal transducer activator of transcription 3 (STAT3) knockout mice to investigate the role of STAT3 in ECs in tumor progression and metastasis. We found that the loss of STAT3 in ECs did not affect primary Lewis lung carcinoma (LLC) tumor growth, but it reduced in vivo LLC metastasis in experimental and spontaneous metastasis models. Mechanistically, STAT3 activation upregulated cell adhesion molecule expression, including E-selectin and P-selectin, in murine endothelial MS-1 cells treated with tumor cell-conditioned media in vitro and in pre-metastatic lungs of tumor-bearing mice in vivo. We also found that both E-selectin and P-selectin were, at least in part, responsible for STAT3-induced adhesion and invasion of LLC cells through an EC monolayer. However, tumor cell-conditioned media from B16F10 melanoma cells did not activate STAT3 in MS-1 cells. As a result, EC STAT3 knockout did not affect B16F10 melanoma cell metastasis. In addition, various human cancer cells activated STAT3 in human ECs (HUVECs), resulting in increased cell adhesion molecule expression. Collectively, our findings demonstrate that STAT3 activation in ECs promotes tumor metastasis through the induction of cell adhesion molecules, demonstrating a role for ECs in response to tumor cells during tumor metastasis.

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Acknowledgements

We acknowledge Daeho So for technical support of EV isolation and depletion, and Dr Jong-Wan Park for helpful suggestions during the course of this work. This work is supported by the National Research Foundation of Korea grant funded by the Korea government (2014R1A2A1A11050981 and 2012R1A5A2A44671346 to CHC).

Author contributions

Conception and design: KJK, SKY, CHC. Acquisition of data: KJK SHK, JHY, HSJ, HRK. Analysis and interpretation of data: HRK, SKY, CHC. Writing, review and/or revision of the manuscript: EHL, CHC. Study supervision: SKY, CHC.

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Correspondence to S-K Ye or C-H Cho.

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Kim, KJ., Kwon, SH., Yun, JH. et al. STAT3 activation in endothelial cells is important for tumor metastasis via increased cell adhesion molecule expression. Oncogene 36, 5445–5459 (2017). https://doi.org/10.1038/onc.2017.148

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