Oncogenes and Tumor Suppressors miR-155–Deficient Bone Marrow Promotes Tumor Metastasis

Infiltration of immune cells in primary tumors and metastatic sites is known to influence tumor progression and metastasis. Macrophages represent themost abundant immune cells in the tumormicroenvironment, and evidence has shown thatmacrophages promote seeding, extravasation, and persistent growth of tumor cells atmetastatic sites. miR-155 plays an essential role in immune cell development/function, and its aberrant expression is associated with lymphomas and several solid tumor types.However, it is unknown howmiR-155 expression in immune cells affects solid tumor growth and metastasis. To this end, bone marrow transplantation was performed using miR-155– deficient mice as bone marrow donors and wild-type (WT) mice as recipients, and the chimeric mice were inoculated with tumor cells. We demonstrate that bone marrow lacking miR-155 significantly enhanced lung metastasis without a substantial effect on primary tumor growth. Relative to mice with WT bone marrow, miR155–deficient bone marrow accumulated more macrophages in the spleen and lungs. Further analysis revealed that miR-155–deficient macrophages in metastatic sites exhibited a tumor-promoting M2 phenotype. In vitro study suggested that miR-155–null macrophages were prone to M2 polarization upon incubation with tumor cell– conditioned medium, due to elevated expression of C/EBPb, an identified miR-155 target. These data, for the first time, demonstrate that miR-155 in host immune cells plays a vital role in modulating solid tumor metastasis by affecting the recruitment and polarization of bone marrow–derived macrophages. Implications: Targeted inhibition of miR-155 delays tumor development but inhibition in host immune cells may encourage metastasis. Mol Cancer Res; 11(8); 923–36. 2013 AACR.