Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells.
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.
Germano
Giovanni
G
Department of Immunology and Inflammation, IRCCS Istituto Clinico Humanitas, Rozzano, Italy.
Frapolli
Roberta
R
Simone
Matteo
M
Tavecchio
Michele
M
Erba
Eugenio
E
Pesce
Samantha
S
Pasqualini
Fabio
F
Grosso
Federica
F
Sanfilippo
Roberta
R
Casali
Paolo G
PG
Gronchi
Alessandro
A
Virdis
Emanuela
E
Tarantino
Eva
E
Pilotti
Silvana
S
Greco
Angela
A
Nebuloni
Manuela
M
Galmarini
Carlos Maria
CM
Tercero
Juan Carlos
JC
Mantovani
Alberto
A
D'Incalci
Maurizio
M
Allavena
Paola
P
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis / Q000276:immunology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004149:Dioxoles / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D018208:Liposarcoma, Myxoid / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D000683:Serum Amyloid P-Component / Q000096:biosynthesis; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*; D000077606:Trabectedin; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D000099153:Pentraxins; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018906:Antineoplastic Agents, Alkylating; D002097:C-Reactive Protein; D018932:Chemokine CCL2; D004149:Dioxoles; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D000683:Serum Amyloid P-Component; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D042461:Vascular Endothelial Growth Factor A; D000099153:Pentraxins; C067980:CD68 antigen, human; D000097382:CD68 Molecule