Abstract LB-495: Myeloid-derived suppressor cells promote cancer-associated fibroblast migration and carcinoma cell invasion

Abstract

Abstract Metastasis the most devastating part of cancer, yet we know very little about the earliest steps of metastasis. Myeloid-Derived Suppressor Cells (MDSC) are CD11b+, Gr-1+ bone marrow-derived cells that have been shown to promote tumor development by suppressing T cells. In addition to immune suppression, MDSC can promote metastasis. MDSC localize to the invasive edges of primary tumors and promote breast cancer lung metastasis. Localized invasion of cancer cells is the earliest step of metastasis and fibroblasts are required for breast cancer cell invasion. Fibroblasts remodel the ECM and leave tracks for collective migration of carcinoma cells. These studies seek to identify the mechanism of MDSC promotion of metastasis by determining if MDSC can stimulate fibroblast migration and lead localized carcinoma invasion. Freshly isolated MDSC from a mammary tumor-bearing mouse increase fibroblast migration. TGFβRII-/- fibroblasts demonstrate a further increase in migration in response to MDSC, suggesting that TGFβ signaling is not required for MDSC promotion of fibroblast migration. MDSC secretions act directly on fibroblasts since conditioned medium from MDSC increases fibroblast migration to the same extent as live MDSC. Antibody array analysis identified several MDSC secreted proteins, including CXCL11, CXCL15, FGF2, IGF-I, IL-4 and Shh. MDSC increase carcinoma cell invasion through Matrigel, but only when fibroblasts are present. MDSC treatment of fibroblasts stimulates Akt and ERK1/2 phosphorylation and loss of secreted proteins, including SDF-1, TIMP-1, TNFα and VEGF. Analysis of subsets of MDSC identified that monocytic MDSC (CD11b+, Ly6Chi, Ly6G-) increase fibroblast migration more than other myeloid cell populations. Tumor-derived MDSC promote fibroblast migration more that splenic MDSC. These studies show that MDSC can lead fibroblasts to stimulate carcinoma invasion and suggest that perivascular MDSC may be the earliest stimulus for localized invasion during metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-495. doi:1538-7445.AM2012-LB-495