Purpose: The interaction between malignant cells and surrounding healthy tissues is a critical factor in the metastatic progression of breast cancer (BC). Extracellular vesicles, especially exosomes, are known to be involved in inter-cellular communication during cancer progression. In the study presented herein, we aimed to evaluate the role of circulating plasma exosomes in the metastatic dissemination of BC and to investigate the underlying molecular mechanisms of this phenomenon. Methods: Exosomes isolated from plasma of healthy female donors were applied in various concentrations into the medium of MDA-MB-231 and MCF-7 cell lines. Motility and invasive properties of BC cells were examined by random migration and Transwell invasion assays, and the effect of plasma exosomes on the metastatic dissemination of BC cells was demonstrated in an in vivo zebrafish model. To reveal the molecular mechanism of interaction between plasma exosomes and BC cells, a comparison between un-treated and enzymatically modified exosomes was performed, followed by mass spectrometry, gene ontology, and pathway analysis. Results: Plasma exosomes stimulated the adhesive properties, two-dimensional random migration, and transwell invasion of BC cells in vitro as well as their in vivo metastatic dissemination in a dose-dependent manner. This stimulatory effect was mediated by interactions of surface exosome proteins with BC cells and consequent activation of focal adhesion kinase (FAK) signaling in the tumor cells. Conclusions: Plasma exosomes have a potency to stimulate the metastasis-promoting properties of BC cells. This pro-metastatic property of normal plasma exosomes may have impact on the course of the disease and on its prognosis.
Bibliographical noteFunding Information:
Acknowledgements This study was supported by RFBR (grant numbers 15-54-12380 and 18-015-00289), by Russian Science Foundation (grant number 17-14-01416), by the Ministry of Education and Science of the Russian Federation (ID RFMEFI62117 × 0017) (to Anastasia Malek), as well as by the Israel Cancer Association and Estee Lauder Companies (grant number 20180089), by the Israel Cancer Research Foundation (grant number 17-902-AG), and by the Israel Science Foundation (grant number 1462/17) (to Hava Gil-Henn).
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- Breast cancer
- FAK signaling
- Mass spectrometry
- Surface interaction