title: Role of macrophage targeting in the antitumor activity of trabectedin.
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.
authors: Department Immunology and Inflammation, IRCCS Clinical and Research Institute Humanitas, 20089 Rozzano, Milan, Italy.
authors: Giovanni
authors: G
authors: Germano
authors: Roberta
authors: R
authors: Frapolli
authors: Cristina
authors: C
authors: Belgiovine
authors: Achille
authors: A
authors: Anselmo
authors: Samantha
authors: S
authors: Pesce
authors: Manuela
authors: M
authors: Liguori
authors: Eugenio
authors: E
authors: Erba
authors: Sarah
authors: S
authors: Uboldi
authors: Massimo
authors: M
authors: Zucchetti
authors: Fabio
authors: F
authors: Pasqualini
authors: Manuela
authors: M
authors: Nebuloni
authors: Nico
authors: N
authors: van Rooijen
authors: Roberta
authors: R
authors: Mortarini
authors: Luca
authors: L
authors: Beltrame
authors: Sergio
authors: S
authors: Marchini
authors: Ilaria
authors: I
authors: Fuso Nerini
authors: Roberta
authors: R
authors: Sanfilippo
authors: Paolo G
authors: PG
authors: Casali
authors: Silvana
authors: S
authors: Pilotti
authors: Carlos M
authors: CM
authors: Galmarini
authors: Andrea
authors: A
authors: Anichini
authors: Alberto
authors: A
authors: Mantovani
authors: Maurizio
authors: M
authors: D'Incalci
authors: Paola
authors: P
authors: Allavena
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D049109:Cell Proliferation; D004149:Dioxoles / Q000627:therapeutic use*; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000627:therapeutic use*; D000077606:Trabectedin; D014407:Tumor Cells, Cultured
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D053181:Caspase 8; D000077606:Trabectedin