Abstract
Metastasis is the most devastating aspect of cancer, however we know very little about the mechanisms of local invasion, the earliest step of metastasis. During tumor growth CD11b+ Gr1+ cells, known also as MDSCs, have been shown to promote tumor progression by a wide spectrum of effects that suppress the anti-tumor immune response. In addition to immunosuppression, CD11b+ Gr1+ cells promote metastasis by mechanisms that are currently unknown. CD11b+ Gr1+ cells localize near fibroblasts, which remodel the ECM and leave tracks for collective cell migration of carcinoma cells. In this study we discovered that CD11b+ Gr1+ cells promote invasion of mammary carcinoma cells by increasing fibroblast migration. This effect was directed by secreted factors derived from CD11b+ Gr1+ cells. We have identified several CD11b+ Gr1+ cell secreted proteins that activate fibroblast migration, including CXCL11, CXCL15, FGF2, IGF-I, IL1Ra, Resistin, and Shh. The combination of CXCL11 and FGF2 had the strongest effect on fibroblast migration that is associated with Akt1 and ERK1/2 phosphorylation. Analysis of subsets of CD11b+ Gr1+ cells identified that CD11b+ Ly6Chigh Ly6Glow cells increase fibroblast migration more than other myeloid cell populations. Additionally, tumor-derived CD11b+ Gr1+ cells promote fibroblast migration more than splenic CD11b+ Gr1+ cells of tumor-bearing mice. While TGFβ signaling in fibroblasts does not regulate their migration toward CD11b+ Gr1+ cells, however deletion of TGFβ receptor II on CD11b+ Gr1+ cells downregulates CXCL11, Shh, IGF1 and FGF2 resulting in reduced fibroblast migration. These studies show that TGFβ signaling in CD11b+ Gr1+ cells promotes fibroblast directed carcinoma invasion and suggests that perivascular CD11b+ Ly6Chigh Ly6Glow cells may be the stimulus for localized invasion leading to metastasis.