Role of Macrophage Targeting in the Antitumor Activity of Trabectedin
Role of Macrophage Targeting in the Antitumor Activity of Trabectedin
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DOI：
10.1016/j.ccr.2013.01.008
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发表时间：
2013-02-11
期刊：
影响因子：
50.3
通讯作者：
Allavena, Paola
中科院分区：
文献类型：
--
作者：
Germano, Giovanni;Frapolli, Roberta;Allavena, Paola
人们对巨噬细胞作为癌症治疗靶点产生了广泛的兴趣。在这里，我们证明曲贝替定（一种最近批准的化疗剂）仅在单核吞噬细胞中诱导快速凋亡。在四种小鼠肿瘤模型中，曲贝替定引起血液、脾脏和肿瘤中单核细胞/巨噬细胞的选择性耗竭，并伴随血管生成的减少。通过使用曲贝替定耐药肿瘤细胞和骨髓细胞转移或耗竭实验，我们证明对单核吞噬细胞的细胞毒性是其抗肿瘤活性的关键组成部分。在接受治疗的肿瘤患者中观察到单核细胞耗竭，包括肿瘤相关巨噬细胞。 Trabectedin 激活 caspase-8 依赖性细胞凋亡；单核细胞相对于中性粒细胞和淋巴细胞的选择性是由于信号传导和诱饵 TRAIL 受体的差异表达。这种意想不到的特性可以在不同的治疗策略中得到利用。
There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.