Role of macrophage targeting in the antitumor activity of trabectedin
Giovanni Germano, Roberta Frapolli, Cristina Belgiovine, Achille Anselmo, Samantha Pesce, Manuela Liguori, Eugenio Erba, Sarah Uboldi, Massimo Zucchetti, Fabio Pasqualini, Manuela Nebuloni, Nico van Rooijen, Roberta Mortarini, Luca Beltrame, Sergio Marchini, Ilaria Fuso Nerini, Roberta Sanfilippo, Paolo G Casali, Silvana Pilotti, Carlos M Galmarini, Andrea Anichini, Alberto Mantovani, Maurizio D'Incalci, Paola Allavena, Giovanni Germano, Roberta Frapolli, Cristina Belgiovine, Achille Anselmo, Samantha Pesce, Manuela Liguori, Eugenio Erba, Sarah Uboldi, Massimo Zucchetti, Fabio Pasqualini, Manuela Nebuloni, Nico van Rooijen, Roberta Mortarini, Luca Beltrame, Sergio Marchini, Ilaria Fuso Nerini, Roberta Sanfilippo, Paolo G Casali, Silvana Pilotti, Carlos M Galmarini, Andrea Anichini, Alberto Mantovani, Maurizio D'Incalci, Paola Allavena
Abstract
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Source: PubMed