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

Abstract

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. I evaluated whether MDSCs potentiated by cancer cells directly increased breast cancer aggressiveness, leading to spontaneous distant metastasis of cancer cells.Usingamurine breast cancer cell model, I 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. Collectively, my findings reveal that breast cancer cells and MDSCs form a synergistic mutual feedback loop and that thus-potentiated MDSCs directly affect breast cancer cell aggressiveness, leading to spontaneous metastasis.