Abstract
Reports demonstrate the role of M-CSF (CSF1) in tumor progression in mouse models as well as the prognostic value of macrophage numbers in breast cancer patients. Recently, a subset of CD14+ monocytes expressing the Tie2 receptor, once thought to be predominantly expressed on endothelial cells, has been characterized. We hypothesized that increased levels of CSF1 in breast tumors can regulate differentiation of Tie2- monocytes to a Tie2+ phenotype. We treated CD14+ human monocytes with CSF1 and found a significant increase in CD14+/Tie2+ positivity. To understand if CSF1-induced Tie2 expression on these cells improved their migratory ability, we pre-treated CD14+ monocytes with CSF1 and used Boyden chemotaxis chambers to observe enhanced response to angiopoietin-2 (ANG2), the chemotactic ligand for the Tie2 receptor. We found that CSF1 pre-treatment significantly augmented chemotaxis and that Tie2 receptor upregulation was responsible as siRNA targeting Tie2 receptor abrogated this effect. To understand any augmented angiogenic effect produced by treating these cells with CSF1, we cultured human umbilical vein endothelial cells (HUVECs) with conditioned supernatants from CSF1-pre-treated CD14+ monocytes for a tube formation assay. While supernatants from CSF1-pre-treated TEMs increased HUVEC branching, a neutralizing antibody against the CSF1R abrogated this activity, as did siRNA against the Tie2 receptor. To test our hypothesis in vivo, we treated PyMT tumor-bearing mice with CSF1 and observed an expansion in the TEM population relative to total F4/80+ cells, which resulted in increased angiogenesis. Investigation into the mechanism of Tie2 receptor upregulation on CD14+ monocytes by CSF1 revealed a synergistic contribution from the PI3 kinase and HIF pathways as the PI3 kinase inhibitor LY294002, as well as HIF-1α-deficient macrophages differentiated from the bone marrow of HIF-1αfl/fl/LysMcre mice, diminished CSF1-stimulated Tie2 receptor expression.
Highlights
Macrophage colony-stimulating factor (CSF1) drives the survival and differentiation of monocytes, recruited from the bone marrow, to macrophages [1]
Tie2-expressing monocytes/macrophages (TEMs) are a subset of myeloid cells that function similar to M2, tumor-associated macrophages (TAMs) as their activity increases tumor blood vessel area and metastasis in mouse models of breast cancer[24,26,27]
We hypothesized that because CSF1 can differentiate macrophages with a pro-tumor M2 phenotype, that CSF1 might be differentiating a subpopulation of Tie2expressing monocytes/macrophages (TEMs) that can be recruited by angiopoietins into breast tumors
Summary
Macrophage colony-stimulating factor (CSF1) drives the survival and differentiation of monocytes, recruited from the bone marrow, to macrophages [1]. As transformed cells develop into tumor tissue, ‘‘tumor-helping’’ tumor-associated macrophages (TAMs) facilitate tumor growth and progression through the production of proteases and angiogenic factors [13,14]. Treatment of macrophages with CSF1 up-regulates the potent pro-angiogenic molecule vascular endothelial growth factor (VEGF) which increases endothelial cell proliferation and migration to drive new blood vessel growth [13]. Production of these factors has been demonstrated in solid tumors, such as breast cancer, where CSF1 increases angiogenic branching and blood vessel density. The re-introduction of CSF1 locally into the tumor restores the tumor macrophage population, tumor vessel density, and metastasis [20]
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