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Bidirectional effect of CD200 on breast cancer development and metastasis, with ultimate outcome determined by tumor aggressiveness and a cancer-induced inflammatory response

Oncogene volume 34, pages 3860–3870 (2015)Cite this article

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Abstract

CD200 acts through its receptor (CD200R) to inhibit excessive inflammation. The role of CD200-CD200R1 interaction in tumor immunity is poorly understood. In this study, we examined the role of CD200-CD200R1 interaction in the progression and metastasis of highly aggressive 4THM murine-breast carcinoma using CD200 transgenic (CD200tg) and CD200R1 knock-out (CD200R1−/−) BALB/c mice. 4THM cells induce extensive visceral metastasis and neutrophil infiltration in affected tissues. CD200 overexpression in the host was associated with decreased primary tumor growth and metastasis, whereas lack of CD200R1 expression by host cells was associated with enhanced visceral metastasis. Absence of CD200R1 expression led to decreased tumor-infiltrating-cytotoxic T cells and increased the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. In contrast, CD200 overexpression led to increased tumor-induced interferon-γ and IL-10 response and decreased TNF-α and IL-6 release. Neutrophil infiltration of tissues was markedly decreased in CD200tg animals and increased in CD200R1−/− mice. These findings are contradictory to what has been reported in the EMT6 mouse breast-cancer model. Other distinguishing features of tumor elicited by EMT6 and 4THM cell injections were also examined. Visceral tissues from mice bearing EMT6 tumors showed a lack of neutrophil infiltration and decreased IL-6 release in CD200R1−/− mice. EMT6 and 4THM cells also differed in vimentin expression and in vitro migration rate, which was markedly lower in EMT6 tumors. These results support the hypothesis that CD200 expression can alter immune responses, and can inhibit metastatic growth of tumor cells that induce systemic and local inflammatory response. Increasing CD200 activity/signaling might be an important therapeutic strategy for treatment of aggressive breast carcinomas.

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Acknowledgements

This work was supported by funds from the TÜBİTAK (the scientific and technological research council of Turkey; project no: 109S449); Akdeniz University Research Units, Antalya, Turkey (project no: 2013.12.0103.001); and the Canadian Cancer Society (grant to RMG). We thank Nilüfer Ekinci for her technical help.

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Authors and Affiliations

  1. Department of Medical Pharmacology, School of Medicine, Akdeniz University, Antalya City, Antalya, Turkey

    N Erin & Ö Duymuş

  2. University Health Network, Toronto General Hospital, Toronto, ON, Canada

    A Podnos, E Cote, I Khatri & R M Gorczynski

  3. Department of Histology and Embryology, School of Medicine, Akdeniz University, Antalya, Turkey

    G Tanriover

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Erin, N., Podnos, A., Tanriover, G. et al. Bidirectional effect of CD200 on breast cancer development and metastasis, with ultimate outcome determined by tumor aggressiveness and a cancer-induced inflammatory response. Oncogene 34, 3860–3870 (2015). https://doi.org/10.1038/onc.2014.317

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