Targeting the ANG2/TIE2 Axis Inhibits Tumor Growth and Metastasis by Impairing Angiogenesis and Disabling Rebounds of Proangiogenic Myeloid Cells
Targeting the ANG2/TIE2 Axis Inhibits Tumor Growth and Metastasis by Impairing Angiogenesis and Disabling Rebounds of Proangiogenic Myeloid Cells
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DOI：
10.1016/j.ccr.2011.02.005
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发表时间：
2011-04-12
期刊：
影响因子：
50.3
通讯作者：
De Palma, Michele
中科院分区：
文献类型：
--
作者：
Mazzieri, Roberta;Pucci, Ferdinando;De Palma, Michele
肿瘤浸润骨髓细胞传递促血管生成程序，抵消抗血管生成治疗的疗效。在这里，我们表明，阻断血管生成素-2（ANG 2），一种由活化的内皮细胞（EC）表达的TIE 2配体和血管生成因子，可使肿瘤血管系统消退，并抑制晚期转移性MMTV-PyMT乳腺癌和RIP 1-Tag 2胰腺胰岛素瘤的进展。ANG 2阻断并不能抑制表达MRC 1（+）TIE 2的巨噬细胞（TEM）的募集，但阻碍了它们上调Tie 2、与血管的结合以及恢复肿瘤血管生成的能力。TEM中的条件性Tie 2基因敲低足以减少肿瘤血管生成。我们的研究结果支持一种模型，其中ANG 2-TIE 2轴介导TEM和EC之间的细胞间相互作用，这对肿瘤血管生成很重要，并且可以靶向诱导有效的抗肿瘤反应。
Tumor-infiltrating myeloid cells convey proangiogenic programs that counteract the efficacy of antiangiogenic therapy. Here, we show that blocking angiopoietin-2 (ANG2), a TIE2 ligand and angiogenic factor expressed by activated endothelial cells (ECs), regresses the tumor vasculature and inhibits progression of late-stage, metastatic MMTV-PyMT mammary carcinomas and RIP1-Tag2 pancreatic insulinomas. ANG2 blockade did not inhibit recruitment of MRC1(+) TIE2-expressing macrophages (TEMs) but impeded their upregulation of Tie2, association with blood vessels, and ability to restore angiogenesis in tumors. Conditional Tie2 gene knockdown in TEMs was sufficient to decrease tumor angiogenesis. Our findings support a model wherein the ANG2-TIE2 axis mediates cell-to-cell interactions between TEMs and ECs that are important for tumor angiogenesis and can be targeted to induce effective antitumor responses.