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Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling

  • Preclinical study
  • Published:
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Abstract

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.

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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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Authors and Affiliations

  1. N.N. Petrov National Medical Research Center of Oncology, Leningradskaya 68, St.-Petersburg, Russia, 197758

    Tatiana Shtam, Roman Samsonov, Igor Mizgirev & Anastasia Malek

  2. Oncosystem Ltd., Lugovaya 4, Skolkovo Innovation Center, Moscow, Russia, 143026

    Tatiana Shtam, Roman Samsonov & Anastasia Malek

  3. Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Center “Kurchatov Institute”, Orlova roscha 1, Gatchina, Russia, 188300

    Tatiana Shtam, Stanislav Naryzhny & Yana Zabrodskaya

  4. Orekhovich Institute of Biomedical Chemistry of Russian Academy of Medical Sciences, Pogodinskaya 10, Moscow, Russia, 119121

    Stanislav Naryzhny, Artur Kopylov & Elena Petrenko

  5. The Azrieli Faculty of Medicine, Bar-Ilan University, Henrietta Szold 8, 1311502, Safed, Israel

    David Karasik & Hava Gil-Henn

  6. Smorodintsev Research Institute of Influenza, Ministry of Healthcare of the Russian Federation, prof. Popov str. 15/17, St.-Petersburg, Russia, 197376

    Yana Zabrodskaya

  7. National Research Center “Kurchatov Institute”, Akademika Kurchatova pl., 1, Moscow, Russia, 123182

    Roman Kamyshinsky

  8. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia

    Daniil Nikitin & Anton Buzdin

  9. Omics Way Corp., Walnut, CA, USA

    Daniil Nikitin, Maxim Sorokin & Anton Buzdin

  10. I.M. Sechenov First Moscow State Medical University (Sechenov University), 8-2 Trubetskaya st., Moscow, Russia, 119991

    Maxim Sorokin & Anton Buzdin

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  1. Tatiana Shtam
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Correspondence to Hava Gil-Henn or Anastasia Malek.

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The design of study has been approved by Ethical Committee of N.N. Petrov National Medical Research Center of Oncology. All procedures were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration. All applicable international, national, and institutional guidelines for the care and use of animals were followed.

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Shtam, T., Naryzhny, S., Samsonov, R. et al. Plasma exosomes stimulate breast cancer metastasis through surface interactions and activation of FAK signaling. Breast Cancer Res Treat 174, 129–141 (2019). https://doi.org/10.1007/s10549-018-5043-0

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