Exosomes from Macrophages Exposed to Apoptotic Breast Cancer Cells Promote Breast Cancer Proliferation and Metastasis

Xiuyan Yu¹, Qun Zhang¹, Xuehui Zhang¹, Qing Han¹, Hui Li¹, Yiqing Mao¹, Xi Wang¹, Hongyan Guo^2,✉, David M. Irwin^3,✉, Gang Niu^4,✉, Huanran Tan^1,✉

1. Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China
2. Department of Gynaecology and Obstetrics, Peking University Third Hospital, Beijing 100191, China
3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada
4. Beijing N&N Genetech Company, Beijing 100082, China

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Citation:
Yu X, Zhang Q, Zhang X, Han Q, Li H, Mao Y, Wang X, Guo H, Irwin DM, Niu G, Tan H. Exosomes from Macrophages Exposed to Apoptotic Breast Cancer Cells Promote Breast Cancer Proliferation and Metastasis. J Cancer 2019; 10(13):2892-2906. doi:10.7150/jca.31241. Available from http://www.jcancer.org/v10p2892.htm

Abstract

Exosomes have recently become the subject of increasing research interest. Interactions between tumor and host cells via exosomes play crucial roles in the initiation, progression and invasiveness of breast cancer. In our study, we used exosomes isolated from a co-culture model of THP-1-derived macrophages exposed to apoptotic MCF-7 or MDA-MB-231 breast cancer cell line cells to investigate their effects on naïve MCF-7 or MDA-MB-231 cells in vitro and in vivo. This post-chemotherapy tumor microenvironment model allowed us to explore possible mechanisms that explain increased proliferation and metastasis of breast cancer seen in some patients. Our results suggest that while exosomes derived from macrophages normally inhibit proliferation and metastasis of MCF-7 or MDA-MB-231 cells, exposure of macrophages to breast cancer cells that have experienced chemotherapy are modified them to promote these processes. Exosomes from macrophages exposed to apoptotic cancer cells have increased amounts of IL-6 that increases the phosphorylation of STAT3, which likely explains the increased transcription of STAT3 target genes such as CyclinD1, MMP2 and MMP9. These observations suggest that the inhibition of exosome secretion and STAT3 signaling pathway activation might suppress the growth and metastasis of malignant tumors, and provide new targets for therapeutic treatment of malignant tumors after chemotherapy.

Keywords: exosome, apoptosis, metastasis, STAT3, breast cancer