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Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-09-16 , DOI: 10.4049/jimmunol.2000185
Kayla J Steinberger 1, 2, 3 , Mary A Forget 4, 5 , Andrey A Bobko 2, 6 , Nicole E Mihalik 2, 6 , Marieta Gencheva 1, 2 , Julie M Roda 4 , Sara L Cole 4, 7 , Xiaokui Mo 4, 8 , E Hannah Hoblitzell 1, 2 , Randall Evans 4 , Amy C Gross 4 , Leni Moldovan 4 , Clay B Marsh 2 , Valery V Khramstov 1, 2, 6, 9 , Timothy D Eubank 2, 3, 6, 10
Affiliation  

Key Points HIF-α subunits differentially regulate Tie2 expression on macrophages. Myeloid HIF-1α deficiency enhances tumor oxygenation and chemotherapeutic response. 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-1αfl/fl/LysMcre, or HIF-2αfl/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-1αfl/fl/LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2αfl/fl/LysMcre mice. Proangiogenic TEMs in macrophage HIF-2α–deficient tumors presented significantly more CD31+ microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of proangiogenic TEMs in macrophage HIF-1α–deficient tumors presented significantly less microvessel density but tumor vessels that were more functional as lectin injection revealed more perfusion, and functional electron paramagnetic resonance analysis revealed more oxygen in those tumors. Macrophage HIF-1α–deficient tumors also responded significantly to chemotherapy. These data introduce a previously undescribed and counterintuitive prohypoxia role for proangiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2α.

中文翻译:

缺氧诱导因子 α 亚基调节 Tie2 表达巨噬细胞,影响小鼠乳腺癌中的肿瘤氧和灌注

关键点 HIF-α 亚基差异调节巨噬细胞上的 Tie2 表达。髓系 HIF-1α 缺乏可增强肿瘤氧合和化疗反应。表达 Tie2 的单核细胞/巨噬细胞 (TEM) 是一种独特的促血管生成单核细胞亚群,它们被选择性地招募到乳腺癌肿瘤中。由于实体肿瘤的缺氧性质,我们研究了氧气是否通过缺氧诱导转录因子 HIF-1α 和 HIF-2α 调节缺氧肿瘤微环境中的 TEM 功能。我们将 PyMT 乳腺肿瘤细胞原位植入同基因 LysMcre、HIF-1αfl/fl/LysMcre 或 HIF-2αfl/fl/LysMcre 小鼠的乳腺脂肪垫中,并评估了肿瘤 TEM 群体。小鼠组中肿瘤巨噬细胞的百分比没有差异。相比之下,与对照和 HIF-2αfl/fl/LysMcre 小鼠相比,HIF-1αfl/fl/LysMcre 小鼠的肿瘤 TEM 百分比显着降低。巨噬细胞 HIF-2α 缺陷肿瘤中的促血管生成 TEM 表现出明显更高的 CD31+ 微血管密度,但会加剧缺氧和组织坏死。巨噬细胞 HIF-1α 缺陷肿瘤中促血管生成 TEM 数量减少,微血管密度显着降低,但由于凝集素注射而功能更强的肿瘤血管显示更多灌注,功能性电子顺磁共振分析显示这些肿瘤中的氧气更多。巨噬细胞 HIF-1α 缺陷肿瘤也对化疗有显着反应。这些数据为乳腺癌中的促血管生成 TEM 引入了先前未描述的和违反直觉的缺氧作用,这部分被 HIF-2α 抑制。
更新日期:2020-09-16
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