Tumor Hypoxia Does Not Drive Differentiation of Tumor-Associated Macrophages but Rather Fine-Tunes the M2-like Macrophage Population
Tumor Hypoxia Does Not Drive Differentiation of Tumor-Associated Macrophages but Rather Fine-Tunes the M2-like Macrophage Population
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DOI：
10.1158/0008-5472.can-13-1196
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Van Ginderachter, Jo A.
中科院分区：
文献类型：
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作者：
Laoui, Damya;Van Overmeire, Eva;Van Ginderachter, Jo A.
肿瘤相关巨噬细胞()暴露在肿瘤中的多种微环境信号中，这些微环境信号共同赋予这些细胞具有促肿瘤活性。缺氧，是由于组织不良的血管系统导致的氧供需不平衡造成的，通常是实体肿瘤的一个显著特征。然而，肿瘤缺氧在多大程度上调节体内的表型尚不清楚。在这里，我们发现小鼠肺癌的髓样浸润液包含两个形态不同的CD11b(Hi)F4/80(Hi)Ly6C(Lo)亚群，命名为MHC-IIlo和MHC-IIhi，这两个亚群都来自肿瘤浸润性Ly6C(Hi)单核细胞。MHC-IILO表达较高水平的典型M2标志物，且居住在较低氧区。因此，与MHC-IIHI相比，MHC-IIlo含有更高的低氧调控基因的基因水平。为了评估体内低氧对这些特征的影响，我们将癌细胞接种到Pro羟基酶结构域2(PHD2)单倍体缺陷的小鼠中，导致了更好的氧合肿瘤。有趣的是，减少肿瘤缺氧并没有改变亚群的相对丰度，也没有改变其M2标记的表达，但特异性地降低了MHC-IIlo亚群中缺氧敏感基因的表达和血管生成活性。在PHD2(+/+)->；PHD2(+/-)骨髓嵌合体中同样的观察也表明组织了更好的氧化微环境。总之，我们的结果表明，缺氧不是亚群分化的主要驱动因素，而是特异性地微调了类M2 MHC-IIlo的表型。(C)2013年AACR。
Tumor-associated macrophages (TAM) are exposed to multiple microenvironmental cues in tumors, which collaborate to endow these cells with protumoral activities. Hypoxia, caused by an imbalance in oxygen supply and demand because of a poorly organized vasculature, is often a prominent feature in solid tumors. However, to what extent tumor hypoxia regulates the TAM phenotype in vivo is unknown. Here, we show that the myeloid infiltrate in mouse lung carcinoma tumors encompasses two morphologically distinct CD11b(hi)F4/80(hi)Ly6C(lo) TAM subsets, designated as MHC-IIlo and MHC-IIhi TAM, both of which were derived from tumor-infiltrating Ly6C(hi) monocytes. MHC-IIlo TAM express higher levels of prototypical M2 markers and reside in more hypoxic regions. Consequently, MHC-IIlo TAM contain higher mRNA levels for hypoxia-regulated genes than their MHC-IIhi counterparts. To assess the in vivo role of hypoxia on these TAM features, cancer cells were inoculated in prolyl hydroxylase domain 2 (PHD2)-haplodeficient mice, resulting in better-oxygenated tumors. Interestingly, reduced tumor hypoxia did not alter the relative abundance of TAM subsets nor their M2 marker expression, but specifically lowered hypoxia-sensitive gene expression and angiogenic activity in the MHC-IIlo TAM subset. The same observation in PHD2(+/+) -> PHD2(+/-) bone marrow chimeras also suggests organization of a better-oxygenized microenvironment. Together, our results show that hypoxia is not a major driver of TAM subset differentiation, but rather specifically fine-tunes the phenotype of M2-like MHC-IIlo TAM. (C)2013 AACR.