Role of Macrophage Targeting in the Antitumor Activity of Trabectedin

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• 作者：Giovanni Germano¹ ; Roberta Frapolli² ; ¹⁰ ; Cristina Belgiovine¹ ; ¹⁰ ; Achille Anselmo¹ ; Samantha Pesce¹ ; Manuela Liguori¹ ; Eugenio Erba² ; Sarah Uboldi² ; Massimo Zucchetti² ; Fabio Pasqualini¹ ; Manuela Nebuloni³ ; Nico van Rooijen⁵ ; Roberta Mortarini⁶ ; Luca Beltrame² ; Sergio Marchini² ; Ilaria Fuso Nerini² ; Roberta Sanfilippo⁷ ; Paolo G. Casali⁷ ; Silvana Pilotti⁸ ; Carlos M. Galmarini⁹ ; Andrea Anichini⁶ ; Alberto Mantovani¹ ; ⁴ ; Maurizio D&rsquo ; Incalci² ; ^{maurizio.dincalci@marionegri.it} ; Paola Allavena¹ ; ^{paola.allavena@humanitasresearch.it}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：11 February, 2013
• 年：2013
• 卷：23
• 期：2
• 页码：249-262
• 全文大小：2155 K

文摘

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Summary

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.