Abstract
IntroductionTumor 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.MethodsMurine 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.ResultsUsing 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.ConclusionIn 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.
Highlights
Tumor cell interactions with the microenvironment, especially those of bone-marrow-derived myeloid cells, are important in various aspects of tumor metastasis
To elucidate the relationship between Myeloid-derived suppressor cell (MDSC) recruitment and distant metastasis of cancer cells, we created a murine breast cancer model using 4T1 and EMT6 breast cancer cells, which exhibit differential IL-6 expression [see Additional file 1, Figure S1]. 4T1 and EMT6 cells were orthotopically grafted into the mammary fat pads of syngeneic BALB/c mice
Our findings reveal that breast cancer cells and MDSCs form a synergistic mutual feedback loop and that thuspotentiated MDSCs directly affect breast cancer cell aggressiveness, leading to spontaneous metastasis
Summary
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. We elucidated a novel mechanism by which the MDSCs can mediate spontaneous distant metastasis of breast cancer cells. Metastasis of breast cancer remains a largely incurable disease and is the major cause of mortality among breast cancer patients [3]. Cancer metastasis is a complex process comprising dissociation of cancer cells from the bulk tumor, invasion of the neighboring tissue, intravasation, transport through the vascular system, extravasation, engraftment of disseminated cells and, outgrowth of micrometastases [4]. IL-6 is known to be an important mediator of the expansion and recruitment of myeloid-derived suppressor cells (MDSCs) [7,8]
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