Antitumor and Anti-inflammatory Effects of Trabectedin on Human Myxoid Liposarcoma Cells
Antitumor and Anti-inflammatory Effects of Trabectedin on Human Myxoid Liposarcoma Cells
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DOI：
10.1158/0008-5472.can-09-2335
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发表时间：
2010-03-15
期刊：
影响因子：
11.2
通讯作者：
Allavena, Paola
中科院分区：
文献类型：
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作者：
Germano, Giovanni;Frapolli, Roberta;Allavena, Paola
肿瘤环境中存在的炎症介质可能促进癌症进展，被认为是新型生物疗法的有希望的目标。我们之前报道过，海洋抗肿瘤药物曲贝替定（trabectedin）能够下调免疫细胞中特定细胞因子/趋化因子的产生，该药物于 2007 年在欧洲获批用于治疗软组织肉瘤，并于 2009 年在欧洲获批用于治疗卵巢癌。粘液样脂肪肉瘤 (MLS) 患者（一种以表达致癌转录物 FUS-CHOP 为特征的亚型）对曲贝替定高度敏感。该药物在低纳摩尔浓度下对 MLS 细胞系具有显着的抗增殖作用。我们测试了曲贝替定也可以影响癌细胞产生的炎症介质的假设。在这里，我们发现 MLS 表达多种细胞因子、趋化因子和生长因子（CCL2、CCL3、CCL5、CXCL8、CXCL12、MIF、VEGF、SPARC）以及炎症和基质结合蛋白五聚蛋白 3 (PTX3)，它们构建了显着的炎症环境。在体外，用非细胞毒性浓度的曲贝替定治疗可选择性抑制 MLS 原代肿瘤培养物和/或细胞系产生 CCL2、CXCL8、IL-6、VEGF 和 PTX3。人 MLS 异种移植小鼠模型显示曲贝替定治疗后 CCL2、CXCL8、CD68+ 浸润巨噬细胞、CD31+ 肿瘤血管显着减少，PTX3 部分减少。在几个治疗周期后切除的患者肿瘤样本中观察到类似的结果，表明体外观察到的结果可能具有体内相关性。总之，曲贝替定在脂肪肉瘤中具有双重作用：除了直接抑制生长外，它还通过减少关键炎症介质的产生来影响肿瘤微环境。癌症研究； 70(6)； 2235-44。 (C) 2010 AACR。
Inflammatory mediators present in the tumor milieu may promote cancer progression and are considered promising targets of novel biological therapies. We previously reported that the marine antitumor agent trabectedin, approved in Europe in 2007 for soft tissue sarcomas and in 2009 for ovarian cancer, was able to downmodulate the production of selected cytokines/chemokines in immune cells. Patients with myxoid liposarcoma (MLS), a subtype characterized by the expression of the oncogenic transcript FUS-CHOP, are highly responsive to trabectedin. The drug had marked antiproliferative effects on MLS cell lines at low nanomolar concentrations. We tested the hypothesis that trabectedin could also affect the inflammatory mediators produced by cancer cells. Here, we show that MLS express several cytokines, chemokines, and growth factors (CCL2, CCL3, CCL5, CXCL8, CXCL12, MIF, VEGF, SPARC) and the inflammatory and matrix-binder protein pentraxin 3 (PTX3), which build up a prominent inflammatory environment. In vitro treatment with noncytotoxic concentrations of trabectedin selectively inhibited the production of CCL2, CXCL8, IL-6, VEGF, and PTX3 by MLS primary tumor cultures and/or cell lines. A xenograft mouse model of human MLS showed marked reduction of CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decrease of PTX3 after trabectedin treatment. Similar findings were observed in a patient tumor sample excised after several cycles of therapy, indicating that the results observed in vitro might have in vivo relevance. In conclusion, trabectedin has dual effects in liposarcoma: in addition to direct growth inhibition, it affects the tumor microenvironment by reducing the production of key inflammatory mediators. Cancer Res; 70(6); 2235-44. (C) 2010 AACR.