Journal
PLOS ONE
Volume 10, Issue 1, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0117908
Keywords
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Categories
Funding
- Vanderbilt-Ingram Cancer Center [P30 CA068485]
- T.J. Martell Foundation/Frances Preston Williams Laboratory
- Department of Defense Breast Cancer Research Program [W81XWH-09-4-0468, W81XWH-09-1-0421]
- National Institutes of Health [CA085492, CA102162]
- Robert J. and Helen C. Kleberg Foundation
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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(+)Ly6C(high)Ly6G(low) 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 TGF beta signaling in fibroblasts does not regulate their migration toward CD11b(+)Gr1(+) cells, however deletion of TGF beta receptor II on CD11b(+)Gr1(+) cells downregulates CXCL11, Shh, IGF1 and FGF2 resulting in reduced fibroblast migration. These studies show that TGF beta signaling in CD11b(+)Gr1(+) cells promotes fibroblast directed carcinoma invasion and suggests that perivascular CD11b(+)Ly6C(high)Ly6G(low) cells may be the stimulus for localized invasion leading to metastasis.
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