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BMC Cancer. 2018 May 2;18(1):504. doi: 10.1186/s12885-018-4418-2.

Cancer-derived exosomes from HER2-positive cancer cells carry trastuzumab-emtansine into cancer cells leading to growth inhibition and caspase activation.

Author information

1
Laboratory of Molecular Oncology, University of Helsinki, Biomedicum Helsinki, Haartmaninkatu 8, FIN-00290, Helsinki, Finland. barok.mark@gmail.com.
2
Institute for Molecular Medicine FIMM and EV Core, University of Helsinki, Helsinki, Finland.
3
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
4
MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine, University of Debrecen, Debrecen, 4032, Hungary.
5
Laboratory of Cancer Biology, Medical Faculty, University of Tampere, Biokatu 6, 33014, Tampere, Finland.
6
Department of Oncology, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 4, FIN-00029, Helsinki, Finland.

Abstract

BACKGROUND:

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome-bound T-DM1 may contribute to the activity of T-DM1.

METHODS:

Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Western blotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated with confocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBlue cell proliferation assay and the Caspase-Glo 3/7 caspase activation assay.

RESULTS:

T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived from HER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containg exosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibition and activation of caspases 3 and/or 7.

CONCLUSION:

T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried to other cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanism of action for T-DM1, mediated by exosomes derived from HER2-positive cancer.

KEYWORDS:

Breast cancer; Exosome; HER2; T-DM1; Trastuzumab-emtansine

PMID:
29720111
PMCID:
PMC5930687
DOI:
10.1186/s12885-018-4418-2
[Indexed for MEDLINE]
Free PMC Article

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