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Identification of Tumor Dissemination Facilitating Proteins in Exosomes Associated with Blood Cells of Breast Cancer Patients

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Abstract

Exosomes are important intercellular communication vehicles, secreted into body fluids by multiple cell types, including tumor cells. Exosomes stimulate angiogenesis, tumor cell migration, and invasion, as was proved in cell culture studies. Recently, it was found that some of the exosomes circulating in the blood are associated with the surface of blood cells (exosome-assCS), but their role in the dissemination of the tumor process remains unclear. We performed mass spectrometry analysis of proteomes from isolated plasma exosomes and blood cells associated exosomes of healthy females (HFs) and breast cancer patients (BCPs). Exosomes were separated using ultrafiltration and ultracentrifugation approaches; and their origin was verified using transmission electron microscopy and flow cytometry. Gene Ontology (GO) Functional Enrichment analysis via FunRich software showed that proteins previously detected in the cytoplasm, Oxford comma nucleus are predominant in the composition of plasma exosomes and exosomes-assCS. In breast cancer, a redistribution of the functions of plasma exosomes and blood cell-associated exosomes has been established: the proportion of transport, catalytic, and motor protein increases in plasma exosomes, and, conversely, the proportion of proteins that regulate transcriptional activity decreases in blood cell-associated exosomes. Also, the proportion of proteins involved in signal transduction and cellular communication decreases and the proportion of proteins involved in protein metabolism increases in both exosome fractions in the blood of breast cancer patients. Using the dbDEPC 3.0 database (database of Differently Expressed Proteins in Human Cancer), it was shown that 64% of the proteins of blood cell associated exosomes from BCPs are of tumor origin. Profiling of exosomal blood proteins using QuickGO annotations showed that the proportions of BCPs blood exosomal proteins involved in epithelial-mesenchymal transition (EMT), cell motility, invasion, and immune response are comparable in plasma exosomes and blood cell-associated exosomes. However, the proportion of proteins inhibiting these processes is 1.6–4 times lower in BCPs exosomes than in the blood exosomes of HFs. Thus, conducted proteome analysis of the blood cell associated exosomes in patients with breast cancer highlights the role of these exosomes in the dissemination of the tumor process along with plasma exosomes.

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AKNOWLEDGMENTS

The authors thank the Ministry of Science and Higher Education of the Russian Federation for access to mass spectrometry equipment. The authors thank N.V. Yunusova (Tomsk Research Institute of Oncology, Tomsk) and V.E. Voitsitsky (Novosibirsk Regional Oncological Dispensary, Novosibirsk) for research assistance.

Funding

The study was carried out with the financial support of the Russian Foundation for Basic Research and the Government of the Novosibirsk Region within the framework of the scientific project No. 18-415-540012 r_a.

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Authors and Affiliations

  1. Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    O. S. Tutanov, K. V. Proskura, A. E. Grigor’eva & S. N. Tamkovich

  2. Novosibirsk Regional Oncological Dispensary, 630108, Novosibirsk, Russia

    K. V. Proskura

  3. Institute International Tomografic Center, Russian Academy of Sciences, 630090, Novosibirsk, Russia

    Yu. P. Tsentalovich

  4. Novosibirsk National Research State University, 630090, Novosibirsk, Russia

    Yu. P. Tsentalovich & S. N. Tamkovich

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  1. O. S. Tutanov
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  2. K. V. Proskura
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  3. A. E. Grigor’eva
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Correspondence to S. N. Tamkovich.

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This article adheres to the principles of voluntariness and confidentiality in accordance with the fundamentals of the legislation of the Russian Federation on the protection of public health. The protocol for the study of blood samples was approved by the Ethics Committee of the Institute of Chemical Biology and Fundamental Medicine of the SB of RAS.

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The authors declare that they have no conflict of interests.

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Translated by I. Shipounova

Abbreviations: PBS, 10 mM phoaphate buffered saline, 0.15 М NaCl, рН 7.5; exosome-assCS, blood cell surface-associated exosomes; BC, breat cancer; EMT, epithelial–mesemchymal transition.

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Tutanov, O.S., Proskura, K.V., Grigor’eva, A.E. et al. Identification of Tumor Dissemination Facilitating Proteins in Exosomes Associated with Blood Cells of Breast Cancer Patients. Russ J Bioorg Chem 46, 1018–1033 (2020). https://doi.org/10.1134/S1068162020060357

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