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

ABSTRACT: 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.

SUBMITTER: Gu P

PROVIDER: S-EPMC8264457 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tumor exosomes educate selected host tissues toward a prometastatic phenotype. We demonstrated this for exosomes of the metastatic rat adenocarcinoma BSp73ASML (ASML), which modulate draining lymph nodes and lung tissue to support settlement of poorly metastatic BSp73ASML-CD44v4-v7 knockdown (ASML-CD44v(kd)) cells. Now, we profiled mRNA and microRNA (miRNA) of ASML(wt) and ASML-CD44v(kd) exosomes to define the pathway(s), whereby exosomes prepare the premetastatic niche. ASML exosomes, recovered in draining lymph nodes after subcutaneous injection, preferentially are taken up by lymph node stroma cells (LnStr) and lung fibroblasts (LuFb) that were chosen as exosome targets. ASML(wt) and ASML-CD44v(kd) exosomes contain a restricted mRNA and miRNA repertoire that differs significantly between the two lines and exosomes thereof due to CD44v6 influencing gene and miRNA transcription/posttranscriptional regulation. Exosomal mRNA and miRNA are recovered in target cells, where transferred miRNA significantly affected mRNA translation. Besides others, this was exemplified for abundant ASML(wt)-exosomal miR-494 and miR-542-3p, which target cadherin-17 (cdh17). Concomitantly, matrix metalloproteinase transcription, accompanying cdh17 down-regulation, was upregulated in LnStr transfected with miR-494 or miR-542-3p or co-cultured with tumor exosomes. Thus, tumor exosomes target non-transformed cells in premetastatic organs and modulate premetastatic organ cells predominantly through transferred miRNA, where miRNA from a metastasizing tumor prepares premetastatic organ stroma cells for tumor cell hosting. Fitting the demands of metastasizing tumor cells, transferred exosomal miRNA mostly affected proteases, adhesion molecules, chemokine ligands, cell cycle- and angiogenesis-promoting genes, and genes engaged in oxidative stress response. The demonstration of function-competent exosomal miRNA in host target cells encourages exploiting exosomes as a therapeutic gene delivery system.

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

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