Microsomal prostaglandin E synthase-1 promotes lung metastasis via SDF-1/CXCR4-mediated recruitment of CD11b⁺Gr1⁺MDSCs from bone marrow.

BACKGROUND:Accumulation of myeloid-derived suppressor cells (MDSCs) to tumors is related to cancer prognosis. We investigated the contribution of host stromal microsomal prostaglandin E synthase-1 (mPGES-1) to the accumulation of MDSCs in metastasized lungs of prostate cancer in mice. MATERIAL AND METHODS:Eight-week-old male C57Bl/6 wild type (WT) mice and mPGES-1 knock out mice (mPGES-1KO) were injected with RM9 murine prostate cancer cell line (5 × 10⁶ cells/mL). Lung metastasis was evaluated by the number of colonies, the weight of the lung, and the number of MDSCs (CD11b⁺Gr1⁺ cells) in the lung. RESULTS:Intravenous injections of RM9, a murine prostate cancer cell line to WT mice revealed that lung metastasis and accumulation of MDCSs were suppressed with treatments with a Gr1 antibody, a COX-2 inhibitor, and an mPGES-1 inhibitor. Lung metastasis and accumulation of CD11b⁺Gr1⁺MDSCs were suppressed in mPGES-1KO mice. The mRNA level of stromal cell-derived factor-1 (SDF-1) in the lung and the number of accumulated SDF-1-expressing CD11b⁺Gr1⁺ MDSCs were elevated at an early stage in lung metastasis of C-X-C chemokine receptor type 4 (CXCR4)-expressing RM9 in an mPGES-1-dependent manner. The number of CXCR4-expressing CD11b⁺Gr1⁺MDSCs in WT mice was higher than that in mPGES-1KO mice. RM9 lung metastasis and accumulation of CD11b⁺Gr1⁺MDSCs were suppressed by CXCR4 antibody in WT mice but not in mPGES-1KO. WT mice transplanted with mPGES-1 KO bone marrow (BM) showed a significant reduction in lung metastasis and accumulation of CD11b⁺Gr1⁺MDSCs. CONCLUSION:These results suggest that mPGES-1 enhances tumor metastasis by inducing accumulation of BM-derived MDSCs. Selective mPGES-1 inhibitors might, therefore, represent valuable therapeutic tools for the suppression of tumor metastasis.

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