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A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model

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dc.contributor.authorOh, Keunhee-
dc.contributor.authorLee, Ok-Young-
dc.contributor.authorShon, Suh Youn-
dc.contributor.authorNam, Onyou-
dc.contributor.authorRyu, Po Mee-
dc.contributor.authorSeo, Myung Won-
dc.contributor.authorLee, Dong-Sup-
dc.date.accessioned2017-02-03T01:51:01Z-
dc.date.available2017-02-03T01:51:01Z-
dc.date.issued2013-09-10-
dc.identifier.citationBreast Cancer Research, 15(5):R79ko_KR
dc.identifier.urihttps://hdl.handle.net/10371/100401-
dc.descriptionThis is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
ko_KR
dc.description.abstractAbstract

Introduction
Tumor cell interactions with the microenvironment, especially those of bone-marrow-derived myeloid cells, are important in various aspects of tumor metastasis. Myeloid-derived suppressor cells (MDSCs) have been suggested to constitute tumor-favoring microenvironments. In this study, we elucidated a novel mechanism by which the MDSCs can mediate spontaneous distant metastasis of breast cancer cells.


Methods
Murine breast cancer cells, 4T1 and EMT6, were orthotopically grafted into the mammary fat pads of syngeneic BALB/c mice. CD11b+Gr-1+ MDSCs in the spleen, liver, lung and primary tumor mass were analyzed. To evaluate the role of MDSCs in the distant metastasis, MDSCs were depleted or reconstituted in tumor-bearing mice. To evaluate whether MDSCs in the metastasizing tumor microenvironment affect breast cancer cell behavior, MDSCs and cancer cells were co-cultivated. To investigate the role of MDSCs in in vivo metastasis, we blocked the interactions between MDSCs and cancer cells.


Results
Using a murine breast cancer cell model, we showed that murine breast cancer cells with high IL-6 expression recruited more MDSCs and that the metastasizing capacity of cancer cells paralleled MDSC recruitment in tumor-bearing mice. Metastasizing, but not non-metastasizing, tumor-derived factors induced MDSCs to increase IL-6 production and full activation of recruited MDSCs occurred in the primary tumor site and metastatic organ in the vicinity of metastasizing cancer cells, but not in lymphoid organs. In addition, tumor-expanded MDSCs expressed Adam-family proteases, which facilitated shedding of IL-6 receptor, thereby contributing to breast cancer cell invasiveness and distant metastasis through IL-6 trans-signaling. The critical role of IL-6 trans-signaling was confirmed in both the afferent and efferent pathways of metastasis.


Conclusion
In this study, we showed that metastasizing cancer cells induced higher MDSCs infiltration and prompted them to secret exaggerated IL-6 as well as soluble IL-6Rα, which, in turn, triggered a persistent increase of pSTAT3 in tumor cells. This potential tumor-MDSC axis involving IL-6 trans-signaling directly affected breast cancer cell aggressiveness, leading to spontaneous metastasis.
ko_KR
dc.language.isoenko_KR
dc.publisherBioMed Centralko_KR
dc.subjectMyeloid-derived suppressor cell (MDSC)ko_KR
dc.subjectBreast cancer cellko_KR
dc.subjectMetastasisko_KR
dc.subjectIL-6 trans-signalingko_KR
dc.titleA mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine modelko_KR
dc.typeArticleko_KR
dc.contributor.AlternativeAuthor오근희-
dc.contributor.AlternativeAuthor이옥영-
dc.contributor.AlternativeAuthor손서윤-
dc.contributor.AlternativeAuthor남온유-
dc.contributor.AlternativeAuthor류포미-
dc.contributor.AlternativeAuthor서명원-
dc.contributor.AlternativeAuthor이동섭-
dc.identifier.doi10.1186/bcr3473-
dc.language.rfc3066en-
dc.rights.holderOh et al.; licensee BioMed Central Ltd.-
dc.date.updated2017-01-22T03:06:37Z-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
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