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首页> 外文期刊>The journal of clinical investigation >TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice
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TIE2-expressing macrophages limit the therapeutic efficacy of the vascular-disrupting agent combretastatin A4 phosphate in mice

机译：表达TIE2的巨噬细胞限制了血管破坏剂康普他汀A4磷酸酯在小鼠中的治疗效果

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摘要

Vascular-disrupting agents (VDAs) such as combretastatin A4 phosphate (CA4P) selectively disrupt blood vessels in tumors and induce tumor necrosis. However, tumors rapidly repopulate after treatment with such compounds. Here, we show that CA4P-induced vessel narrowing, hypoxia, and hemorrhagic necrosis in murine mammary tumors were accompanied by elevated tumor levels of the chemokine CXCL12 and infiltration by proangiogenic TIE2-expressing macrophages (TEMs). Inhibiting TEM recruitment to CA4P-treated tumors either by interfering pharmacologically with the CXCL12/CXCR4 axis or by genetically depleting TEMs in tumor-bearing mice markedly increased the efficacy of CA4P treatment. These data suggest that TEMs limit VDA-induced tumor injury and represent a potential target for improving the clinical efficacy of VDA-based therapies.
机译：血管破坏剂（VDA），例如磷酸康维他汀A4（CA4P）有选择地破坏肿瘤中的血管并诱导肿瘤坏死。然而，在用此类化合物治疗后，肿瘤迅速繁殖。在这里，我们显示，CA4P诱导的小鼠乳腺肿瘤中的血管狭窄，缺氧和出血坏死伴有趋化因子CXCL12的肿瘤水平升高和表达促血管生成TIE2的巨噬细胞（TEM）的浸润。通过药理学上干扰CXCL12 / CXCR4轴或通过遗传消耗TEM在荷瘤小鼠中抑制TEM招募到CA4P治疗的肿瘤，可显着提高CA4P治疗的疗效。这些数据表明，TEM限制了VDA诱导的肿瘤损伤，并代表了改善基于VDA的疗法的临床疗效的潜在目标。

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