Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.
Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.
复制标题
DOI：
10.4049/jimmunol.2000185
复制
发表时间：
2020-10-15
期刊：
影响因子：
--
通讯作者：
Eubank TD
中科院分区：
文献类型：
--
作者：
Steinberger KJ;Forget MA;Bobko AA;Mihalik NE;Gencheva M;Roda JM;Cole SL;Mo X;Hoblitzell EH;Evans R;Gross AC;Moldovan L;Marsh CB;Khramstov VV;Eubank TD
表达tie2的单核细胞（TEMs）是乳腺癌中选择性募集到肿瘤的促血管生成单核细胞的一个独特子集。由于实体肿瘤的缺氧特性，我们研究了氧是否通过缺氧诱导的转录因子HIF-1α和HIF-2α在缺氧肿瘤微环境中调节TEM功能。我们将PyMT乳腺肿瘤细胞原位植入到同系型LysMcre、HIF-1αfl/fl/LysMcre、HIF-2αfl/fl/LysMcre巨噬细胞的乳腺脂肪垫中。与对照组和HIF-2αfl/fl/LysMcre小鼠相比，HIF-1αfl/fl/LysMcre小鼠的肿瘤tem百分比显著降低。巨噬细胞hif -2α缺陷肿瘤的促血管生成tem显示CD31+微血管密度明显增加，但缺氧和组织坏死加剧。巨噬细胞hif -1α-缺陷肿瘤的促血管生成tem数量减少，微血管密度明显降低，但凝集素注射功能更强的肿瘤血管显示更多的灌注，功能EPR分析显示肿瘤中有更多的氧气。巨噬细胞hif -1α-缺陷肿瘤对化疗也有显著反应。这些数据介绍了先前描述的促血管生成tem在乳腺癌中的促缺氧作用，这部分是由HIF-2α抑制的。
Tie2-expressing monocytes (TEMs) are a distinct subset of pro-angiogenic monocytes selectively recruited to tumors in breast cancer. Due to 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 fackmacrophages among the mouse groups. In contrast, HIF-1αfl/fl/LysMcre mice had a significantly smaller percentage of tumor TEMs compared to control and HIF-2αfl/fl/LysMcre mice. Pro-angiogenic TEMs in macrophage HIF-2α-deficient tumors presented significantly more CD31+ microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of pro-angiogenic 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 EPR 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 pro-hypoxia role for pro-angiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2α.
登录
查看更多内容
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
15.9
作者：
Imtiyaz, Hongxia Z.;Williams, Emily P.;Simon, M. Celeste
通讯作者：
Simon, M. Celeste
影响因子：
20.3
作者：
Fantin, Alessandro;Vieira, Joaquim M.;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana
影响因子：
--
作者：
Henke N;Ferreirós N;Geisslinger G;Ding MG;Essler S;Fuhrmann DC;Geis T;Namgaladze D;Dehne N;Brüne B
通讯作者：
Brüne B
影响因子：
--
作者：
Mira E;Carmona-Rodríguez L;Tardáguila M;Azcoitia I;González-Martín A;Almonacid L;Casas J;Fabriás G;Mañes S
通讯作者：
Mañes S