Angiopoietin-2 Regulates Gene Expression in TIE2-Expressing Monocytes and Augments Their Inherent Proangiogenic Functions
Angiopoietin-2 Regulates Gene Expression in TIE2-Expressing Monocytes and Augments Their Inherent Proangiogenic Functions
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DOI：
10.1158/0008-5472.can-10-0012
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Lewis, Claire E.
中科院分区：
文献类型：
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作者：
Coffelt, Seth B.;Tal, Andrea O.;Lewis, Claire E.
表达Tie2的单核/巨噬细胞是肿瘤中高度促血管生成的髓系细胞亚群。在这里，我们表明，循环中的人TEM已经被预先编程为更具血管生成能力，并且比TIE2(-)单核细胞表达更高水平的前血管生成基因，如基质金属蛋白酶-9(MMP9)、VEGFA、COX-2和Wnt5A。此外，血管生成素-2(Ang-2)显著增强TEM的促血管生成活性，并增加胸苷磷酸化酶(TP)和组织蛋白酶B(CTSB)这两种促血管生成酶的表达。在TEM中，Ang-2还上调了三种“交替激活的”(或类似M2的)巨噬细胞标志物：白介素10、甘露糖受体(MRC1)和CCL17。为了研究Ang-2对肿瘤中TEM表型和功能的影响，我们使用了血管内皮细胞特异性高表达Ang-2的双转基因(DT)小鼠模型。与野生型(WT)小鼠相比，在这些Ang-2 DT小鼠中生长的同种肿瘤血管更多，含有更多的TEM。在两种类型的肿瘤中，MMP9和MRC1的表达主要局限于肿瘤的TEM，而不是TIE2(-)巨噬细胞。此外，肿瘤TEM在Ang-2DT肿瘤中的MRC1、TP和CTSB表达水平高于WT肿瘤。综上所述，我们的数据显示，尽管循环中的TEM天生就是促血管生成的，但暴露于肿瘤来源的Ang-2会刺激这些细胞表现出更广泛的促进肿瘤的表型。因此，Ang-2-TEM轴可能代表了抗血管生成癌症治疗的新靶点。癌症资源；70(13)；5270-80。(C)2010年AACR。
TIE2-expressing monocytes/macrophages (TEM) are a highly proangiogenic subset of myeloid cells in tumors. Here, we show that circulating human TEMs are already preprogrammed in the circulation to be more angiogenic and express higher levels of such proangiogenic genes as matrix metalloproteinase-9 (MMP-9), VEGFA, COX-2, and WNT5A than TIE2(-) monocytes. Additionally, angiopoietin-2 (ANG-2) markedly enhanced the proangiogenic activity of TEMs and increased their expression of two proangiogenic enzymes: thymidine phosphorylase (TP) and cathepsin B (CTSB). Three "alternatively activated" (or M2-like) macrophage markers were also upregulated by ANG-2 in TEMs: interleukin-10, mannose receptor (MRC1), and CCL17. To investigate the effects of ANG-2 on the phenotype and function of TEMs in tumors, we used a double-transgenic (DT) mouse model in which ANG-2 was specifically overexpressed by endothelial cells. Syngeneic tumors grown in these ANG-2 DT mice were more vascularized and contained greater numbers of TEMs than those in wild-type (WT) mice. In both tumor types, expression of MMP-9 and MRC1 was mainly restricted to tumor TEMs rather than TIE2(-) macrophages. Furthermore, tumor TEMs expressed higher levels of MRC1, TP, and CTSB in ANG-2 DT tumors than WT tumors. Taken together, our data show that although circulating TEMs are innately proangiogenic, exposure to tumor-derived ANG-2 stimulates these cells to exhibit a broader, tumor-promoting phenotype. As such, the ANG-2-TEM axis may represent a new target for antiangiogenic cancer therapies. Cancer Res; 70(13); 5270-80. (C) 2010 AACR.