Abstract
CD68+ tumor-associated macrophages (TAMs) are pro-tumorigenic, pro-angiogenic and are associated with decreased survival rates in patients with cancer, including breast cancer. Non-specific models of macrophage ablation reduce the number of TAMs and limit the development of mammary tumors. However, the lack of specificity and side effects associated with these models compromise their reliability. We hypothesized that specific and controlled macrophage depletion would provide precise data on the effects of reducing TAM numbers on tumor development. In this study, the MacLow mouse model of doxycycline-inducible and selective CD68+ macrophage depletion was crossed with the murine mammary tumor virus (MMTV)-Polyoma virus middle T antigen (PyMT) mouse model of spontaneous ductal breast adenocarcinoma to generate the PyMT-MacLow line. In doxycycline-treated PyMT-MacLow mice, macrophage numbers were decreased in areas surrounding tumors by 43%. Reducing the number of macrophages by this level delayed tumor progression, generated less proliferative tumors, decreased the vascularization of carcinomas and down-regulated the expression of many pro-angiogenic genes. These results demonstrate that depleting CD68+ macrophages in an inducible and selective manner delays the development of mammary tumors and that the PyMT-MacLow model is a useful and unique tool for studying the role of TAMs in breast cancer.
Highlights
Macrophages are extremely versatile cells found in every tissue of the body, whose functions are often required for organism development, maintenance of tissue homeostasis and immunity [1]
We found that nearly 100% of CD11b+F4/80+ tumor associated macrophage (TAM) express CD68 (Fig 1)
We established the Polyoma virus middle T antigen (PyMT)-macrophage Low (MacLow) model as novel tool to study the role of macrophages during breast cancer progression
Summary
Macrophages are extremely versatile cells found in every tissue of the body, whose functions are often required for organism development, maintenance of tissue homeostasis and immunity [1]. Macrophages are important in cancer biology, where they are referred to as tumor-associated macrophages (TAMs). Determining the role of CD68 positive cells in breast tumor development specific funding for this work: SBC, SD and TAN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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