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Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription factors HIF-1α and HIF-2α, regulates TEM function in the hypoxic tumor microenvironment. We orthotopically implanted PyMT breast tumor cells into the mammary fat pads of syngeneic LysMcre, HIF-1α fl/fl/LysMcre, or HIF-2α fl/fl/LysMcre mice and evaluated the tumor TEM population. There was no difference in the percentage of tumor macrophages among the mouse groups. In contrast, HIF-1α fl/fl/LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2α fl/fl/LysMcre mice. Proangiogenic TEMs in macrophage HIF-2α–deficient tumors presented significantly more CD31+ microvessel density but exacerbated hypoxia …