Macrophage Functions in Early Dissemination and Dormancy of Breast Cancer
Technical Report,01 Sep 2015,31 Aug 2016
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI NEW YORK NEW YORK United States
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This research project focuses on the role of macrophages in early dissemination and dormancy. We hypothesized that macrophages are actively recruited by pre-malignant ErbB2 overexpressing cancer cells and that these intra-epithelial macrophages then produce factors that induce an EMT and thereby facilitate early dissemination. We further hypothesized that bone marrow but not lung macrophages produce TGF2, BMP7 and other factors that instruct DCCs to enter dormancy. In funding year 1 we provided evidence that early ErbB2 lesions, but not healthy mammary tissue, produced CCL2 in an NFkB dependent manner and thereby recruited resident macrophages inside the duct. Intra-ductal macrophages secretedWnt1 and thereby induced an EMT in early ErbB2 cancer cells. Depletion of macrophages - but only before overt advanced tumors appeared - drastically reduced early dissemination and surprisingly the onset of metastasis even after macrophages repopulated the overt tumor tissue. We also proposed that cancer cells that disseminated early play a long-term causal role in metastasis development. In funding year 2 we demonstrated that bone resident macrophages inhibit proliferation of disseminated tumor cells and are responsible for less efficient metastasis formation. When bone resident macrophages are coinjected with breast cancer cells in an experimental metastasis assay in vivo, this significantly reduced lung metastasis formation, demonstrating that resident macrophages can decide over the fate of disseminated tumor cells. We further revealed that bone resident macrophages produce TGF2, a factor known to be able to induce dormancy. In contrast, lung resident macrophages produce only low amounts of TGF2 and seem to inhibit TGF2 production in the lung microenvironment. Overall, these results demonstrate that tissue resident macrophages are highly specific in their function and can decide over the fate of disseminated tumor cells.
- Anatomy and Physiology
- Medicine and Medical Research