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Serum-derived exosomes from mice with highly metastatic breast cancer transfer increased metastatic capacity to a poorly metastatic tumor.

Authors
  • Gorczynski, Reginald M1, 2
  • Erin, Nuray3
  • Zhu, Fang1
  • 1 Toronto General Hospital, University Health Network, Toronto, Ontario, Canada. , (Canada)
  • 2 Faculty of Medicine, Department of Immunology, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. , (Canada)
  • 3 Department of Medical Pharmacology, School of Medicine, Akdeniz University, Antalya, Turkey. , (Turkey)
Type
Published Article
Journal
Cancer Medicine
Publisher
Wiley
Publication Date
Feb 01, 2016
Volume
5
Issue
2
Pages
325–336
Identifiers
DOI: 10.1002/cam4.575
PMID: 26725371
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Altered interaction between CD200 and CD200R represents an example of "checkpoint blockade" disrupting an effective, tumor-directed, host response in murine breast cancer cells. In CD200R1KO mice, long-term cure of EMT6 breast cancer, including metastatic spread to lung and liver, was achieved in BALB/c mice. The reverse was observed with 4THM tumors, an aggressive, inflammatory breast cancer, with increased tumor metastasis in CD200R1KO. We explored possible explanations for this difference. We measured the frequency of circulating tumor cells (CTCs) in peripheral blood of tumor bearers, as well as lung/liver and draining lymph nodes. In some cases mice received infusions of exosomes from nontumor controls, or tumor bearers, with/without additional infusions of anticytokine antibodies. The measured frequency of circulating tumor cells (CTCs) in peripheral blood was equivalent in the two models in WT and CD200R1KO mice. Increased metastasis in EMT6 tumor bearers was seen in vivo following adoptive transfer of serum, or serum-derived exosomes, from 4THM tumor bearers, an effect which was attenuated by anti-IL-6, and anti-IL-17, but not anti-TNFα, antibody. Anti-IL-6 also attenuated enhanced migration of EMT6 cells in vitro induced by 4THM serum or exosomes, or recombinant IL-6. Exosome cytokine proteomic profiles responses in 4THM and EMT6 tumor-bearing mice were regulated by CD200:CD200R interactions, with attenuation of both IL-6 and IL-17 in 4THM CD200(tg) mice, and enhanced levels in 4THM CD200R1KO mice. We suggest these cytokines act on the microenvironment at sites within the host, and/or directly on tumor cells themselves, to increase metastatic potential. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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