Abstract
Abstract The breast tumor microenvironment greatly influences tumor progression and modulates the migratory abilities of both cancer cells and macrophages, especially M2 macrophages, at the tumor site. The pleiotropic inflammatory cytokine TNFα through interactions with TNFR promotes macrophage migration and tumor cell apoptosis. The shedding of TNFR increases the concentration of sTNFR within the tumor microenvironment. We determined whether sTNFR modulates the trafficking of specific macrophage subtypes in the tumor microenvironment. Concentrations of TNFα, sTNFR1 and sTNFR2 secreted by 4T1 and NMuMG mammary epithelial cells, stroma mesenchymal stem cells, and adipocyte-derived cells were measured by cytokine arrays and ELISA. The migration of murine monocytes cultured in media promoting preferential expression of M0, M1, or M2 phenotypes toward tumor or stroma cell conditioned media (CM) was determined by transwell assays. The effects of conditioned media obtained following treatment with the sheddase inhibitor TAPI-0 on cell migration were also assessed. The concentrations of sTNFR2 secreted were drastically higher in the CMs from 4T1 cells compared to NMuMG cells (p<0.05). In addition, adipocytes secreted markedly more sTNF2 compared to D1 mesenchymal stem cells (p<0.05). sTNFR2 concentrations were significantly decreased in the presence of a sheddase inhibitor (p<0.05). The transwell migration of M2 phenotype macrophages toward 4T1-CM was significantly greater than the migration of M0 or M1 phenotype macrophages (p<0.05). Furthermore, only the migration of the M2 macrophage subtype following TAPI-0 treatment toward 4T1 CM was markedly higher (p<0.05). These results strongly suggest a role for sTNFR secreted by tumor cells and adipocytes in the infiltration of M2 phenotype macrophages within the tumor microenvironment. Whether selective prevention of sTNFR shedding may have therapeutic benefit for breast cancer patients remains to be determined. This work was supported by grants from the Department of Defense Era of Hope program (BC044778) and the National Science Foundation EFRI program (CBE0736007). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 455. doi:10.1158/1538-7445.AM2011-455
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