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

Breast Cancer Research

Dong-Sup Lee³  Myung Won Seo³  Po Mee Ryu¹  Onyou Nam²  Suh Youn Shon¹  Ok-Young Lee²  Keunhee Oh³ 

[1] Laboratory of Immunology and Cancer Biology, Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul 110-799, Republic of Korea;Interdisciplinary Program of Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul 110-799, Republic of Korea;Transplantation Research Institute, Seoul National University College of Medicine, 103 Daehak-ro Jongno-gu, Seoul 110-799, Republic of Korea

关键词: IL-6 trans-signaling;    Metastasis;    Breast cancer cell;    Myeloid-derived suppressor cell (MDSC);   

Others  :  793569
DOI  :  10.1186/bcr3473

 received in 2012-10-21, accepted in 2013-09-10,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Oh et al.; licensee BioMed Central Ltd.

【 图 表 】

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