Abstract 1424: Inhibition of M-CSF or MCP-1 expression in tumor cells reduces tumor growth and lung metastasis in a murine mammary cancer model.

Abstract

Abstract Tumor-associated macrophages, which are derived from the infiltration of circulating bone marrow-derived monocytes, consist primarily of a polarized M2 macrophage population and are associated with poor prognosis in various cancers. We previously observed that solid tumor growth and lung metastasis were enhanced when 4T1 mammary carcinoma cells were injected with M2 macrophages into the mammary fat pad of BALB/c mice. Cancer cell proliferation and macrophage infiltration were markedly increased when M2 macrophages were co-injected with 4T1 cells. In the present study, we explored the mechanisms underlying the crosstalk between 4T1 cells and M2 macrophages in tumor microenvironment. The results of in vitro experiments revealed that the migration of monocytes and the secretion of many cytokines including macrophage-colony stimulating factor (M-CSF) and monocyte chemotactic protein-1 (MCP-1) were increased when 4T1 cells were co-cultured with M2 macrophages, as compared to when the 4T1 cells were cultured alone. The mRNA expression of M-CSF and MCP-1 increased in 4T1 cells when 4T1 cells were co-cultured with M2 macrophages. To investigate the potential roles of M-CSF and MCP-1 in tumor growth and metastasis, 4T1 cells were infected with M-CSF, MCP-1, or control shRNA lentivirus particles and selected with puromycin. 4T1 cells infected with M-CSF shRNA did not grow or metastasize to the lung when injected into the mammary fat pads of BALB/c mice. Inhibition of MCP-1 expression in tumor cells also suppressed 4T1 tumor growth and metastasis, however, the degree of inhibition was much smaller than that of M-CSF inhibition. M-CSF knockdown decreased M2 macrophage (mouse mannose receptor+) population, whereas MCP-1 knockdown decreased the number of both M1 and M2 macrophages in tumor tissues. Taken together, these results indicate that M-CSF and MCP-1 are produced by the crosstalk between 4T1 cells and M2 macrophages, and these cytokines play important roles in mammary tumor progression. Citation Format: Han Jin Cho, Jung Han Yoon Park. Inhibition of M-CSF or MCP-1 expression in tumor cells reduces tumor growth and lung metastasis in a murine mammary cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1424. doi:10.1158/1538-7445.AM2013-1424