Breast Tumor-Derived Exosomal MicroRNA-200b-3p Promotes Specific Organ Metastasis Through Regulating CCL2 Expression in Lung Epithelial Cells

Pengfei Gu, Mayu Sun, Lei Li, Yang Yang, Zheshun Jiang, Yang Ge, Wenbo Wang, Wei Mu, Hui Wang

Malignant metastasis is the most important cause of death in breast cancer (BC) patients, while the lung is a major inflammation and metastatic target organ. Exosomes are nano-sized vesicles that could be uptaken by resident cells to generate the pre-metastatic niche before tumor cells preferentially motility. In the present study, we demonstrated that high expression of C-C motif chemokine ligand 2 (CCL2) in lung could recruit the myeloid-derived suppressor cells (MDSCs) and contribute to the establishment of microenvironment. CCL2 provided recruitment of immune cells under carcinomas conditions and inflammatory responses. We also developed the novel mice model for specific over-expressing CCL2 in the lung, and verified that the BC organotropic metastasis was not because of the enhanced tumor cell proliferation, but the regulatory expression of CCL2 in the target organ. To better explore the crosstalk of exosomal molecules and CCL2 in host tissue, we constructed the "education" lung by exosomes intravenous injection and determined the prominent exosome-uptake by alveolar epithelial type II cells in vivo. Furthermore, we identified the exosomal microRNA-200b-3p could bind to PTEN, which may involved in the regulation of AKT/NF-κB/CCL2 cascades. Therefore, our study suggest that CCL2 expression in the lung was regulated by BC-derived exosomal microRNA, which primed the pre-metastastatic niche and may be a prognostic marker for the development of BC lung metastasis.