Macrophages are abundant in the tumor microenvironment and enhance malignancy through their promotion of angiogenesis and invasion at the primary tumor site as well as extravasation, target organ seeding and persistent growth at distant metastatic sites. To determine the origin and recruitment of tumor associated macrophages, different populations of monocytes were FACS sorted and adoptively transferred into mice bearing MMTV-PyMT induced mouse mammary tumors with or without spontaneous pulmonary metastases. Ly6C+ inflammatory monocytes were preferentially recruited to pulmonary metastases but not primary tumors in a CCL2 (also known as MCP1) dependent manner. Human inflammatory monocytes were also preferentially recruited to pulmonary metastases of human breast cancer cells in immuno-compromised mice in a CCL2 dependent manner. These inflammatory monocytes promote tumor cell trans-endothelial migration in vitro, a process that is abrogated by an anti-CCL2 neutralizing antibody. Neutralizing CCL2 in vivo blocks the recruitment of metastasis associated macrophages and their direct interaction with metastasizing tumor cells, leading to inhibition of tumor cell extravasation and metastatic seeding. Inhibition of tumor cell-derived CCL2 inhibits their metastatic seeding. Secretory factors from inflammatory monocytes were identified to mediate their metastasis-promoting function in vitro and in vivo. Both CCL2 expression and macrophage infiltration are correlated with poor prognosis in human breast cancer. Our data strongly suggest that recruitment of Ly6C+ inflammatory monocytes is the mechanistic link between these two clinical associations and suggests new therapeutic targets for treating metastatic breast disease.

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 2842. doi:10.1158/1538-7445.AM2011-2842