Angiogenesis and Tumor Targeting Research Unit, San Raffaele Scientific Institute, Milan, Italy.
Cancer Cell. 2011 Apr 12;19(4):512-26. doi: 10.1016/j.ccr.2011.02.005.
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.
浸润性髓样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（ANG2），一种 TIE2 配体和由激活的内皮细胞（ECs）表达的血管生成因子，可使肿瘤血管退化，并抑制晚期、转移性 MMTV-PyMT 乳腺肿瘤和 RIP1-Tag2 胰腺胰岛细胞瘤的进展。ANG2 阻断并不抑制 MRC1(+)表达 TIE2 的巨噬细胞（TEMs）的募集，但阻碍了它们对 Tie2 的上调、与血管的关联以及在肿瘤中恢复血管生成的能力。TEMs 中条件性 Tie2 基因敲低足以减少肿瘤血管生成。我们的研究结果支持这样一种模型，即 ANG2-TIE2 轴介导 TEMs 和 ECs 之间的细胞间相互作用，这些相互作用对肿瘤血管生成很重要，可以作为靶点诱导有效的抗肿瘤反应。
