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.

Role of macrophage targeting in the antitumor activity of trabectedin / G. Germano, R. Frapolli, C. Belgiovine, A. Anselmo, S. Pesce, M. Liguori, E. Erba, S. Uboldi, M. Zucchetti, F. Pasqualini, M. Nebuloni, N. van Rooijen, R. Mortarini, L. Beltrame, S. Marchini, I. Fuso Nerini, R. Sanfilippo, P.G. Casali, S. Pilotti, C.M. Galmarini, A. Anichini, A. Mantovani, M. D'Incalci, P. Allavena. - In: CANCER CELL. - ISSN 1535-6108. - 23:2(2013 Feb 11), pp. 249-262. [10.1016/j.ccr.2013.01.008]

Role of macrophage targeting in the antitumor activity of trabectedin

M. Liguori;M. Nebuloni;P.G. Casali;
2013

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.
animals ; antineoplastic agents, alkylating ; apoptosis ; blotting, Western ; carcinoma, Lewis lung ; caspase 8 ; cell proliferation ; dioxoles ; female ; fibrosarcoma ; flow cytometry ; humans ; immunoenzyme techniques ; macrophages ; mice ; monocytes ; myeloid cells ; neovascularization, pathologic ; ovarian neoplasms ; phagocytes ; signal transduction ; tetrahydroisoquinolines ; tumor cells, cultured
Settore MED/08 - Anatomia Patologica
Settore MED/04 - Patologia Generale
Settore MED/06 - Oncologia Medica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/227963
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