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Molecular Cancer Research
Molecular Cancer Research
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Signal Transduction

Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells

Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Aska Toda, Erika Nakatsuka, Kae Hashimoto, Seiji Mabuchi, Ken-ichirou Morishige, Hirohisa Kurachi, Ernst Lengyel and Tadashi Kimura
Koji Nakamura
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Kenjiro Sawada
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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  • For correspondence: daasawada@gyne.med.osaka-u.ac.jp
Yasuto Kinose
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Akihiko Yoshimura
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Aska Toda
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Erika Nakatsuka
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Kae Hashimoto
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Seiji Mabuchi
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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Ken-ichirou Morishige
2Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Gifu, Japan.
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Hirohisa Kurachi
3Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
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Ernst Lengyel
4Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, Illinois.
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Tadashi Kimura
1Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
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DOI: 10.1158/1541-7786.MCR-16-0191 Published January 2017
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Abstract

Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMC) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell–cell communications is exosomes, 30–100 nm membrane vesicles of endocytic origin, through the cell–cell transfer of proteins, mRNAs, or microRNAs. Therefore, the goal was to mechanistically characterize how EOC-derived exosomes modulate metastasis. Exosomes from ovarian cancer cells were fluorescently labeled and cocultured with HPMCs which internalized the exosomes. Upon exosome uptake, HPMCs underwent a change in cellular morphology to a mesenchymal, spindle phenotype. CD44, a cell surface glycoprotein, was found to be enriched in the cancer cell–derived exosomes, transferred, and internalized to HPMCs, leading to high levels of CD44 in HPMCs. This increased CD44 expression in HPMCs promoted cancer invasion by inducing the HPMCs to secrete MMP9 and by cleaning the mesothelial barrier for improved cancer cell invasion. When CD44 expression was knocked down in cancer cells, exosomes had fewer effects on HPMCs. The inhibition of exosome release from cancer cells blocked CD44 internalization in HPMCs and suppressed ovarian cancer invasion. In ovarian cancer omental metastasis, positive CD44 expression was observed in those mesothelial cells that directly interacted with cancer cells, whereas CD44 expression was negative in the mesothelial cells remote from the invading edge. This study indicates that ovarian cancer–derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion.

Implications: Mechanistic insight from the current study suggests that therapeutic targeting of exosomes may be beneficial in treating ovarian cancer. Mol Cancer Res; 15(1); 78–92. ©2016 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • E. Lengyel and T. Kimura shared senior authorship.

  • Received June 2, 2016.
  • Revision received September 18, 2016.
  • Accepted September 24, 2016.
  • ©2016 American Association for Cancer Research.
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Molecular Cancer Research: 15 (1)
January 2017
Volume 15, Issue 1
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Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells
Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Aska Toda, Erika Nakatsuka, Kae Hashimoto, Seiji Mabuchi, Ken-ichirou Morishige, Hirohisa Kurachi, Ernst Lengyel and Tadashi Kimura
Mol Cancer Res January 1 2017 (15) (1) 78-92; DOI: 10.1158/1541-7786.MCR-16-0191

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Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells
Koji Nakamura, Kenjiro Sawada, Yasuto Kinose, Akihiko Yoshimura, Aska Toda, Erika Nakatsuka, Kae Hashimoto, Seiji Mabuchi, Ken-ichirou Morishige, Hirohisa Kurachi, Ernst Lengyel and Tadashi Kimura
Mol Cancer Res January 1 2017 (15) (1) 78-92; DOI: 10.1158/1541-7786.MCR-16-0191
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Molecular Cancer Research
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