Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

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.

Detaljer

Författare
  • Giovanni Germano
  • Roberta Frapolli
  • Matteo Simone
  • Michele Tavecchio
  • Eugenio Erba
  • Samantha Pesce
  • Fabio Pasqualini
  • Federica Grosso
  • Roberta Sanfilippo
  • Paolo G Casali
  • Alessandro Gronchi
  • Emanuela Virdis
  • Eva Tarantino
  • Silvana Pilotti
  • Angela Greco
  • Manuela Nebuloni
  • Carlos Maria Galmarini
  • Juan Carlos Tercero
  • Alberto Mantovani
  • Maurizio D'Incalci
  • Och 1 andra
  • Paola Allavena
Externa organisationer
  • Mario Negri Institute for Pharmacological Research
Forskningsområden

Nyckelord

Originalspråkengelska
Sidor (från-till)2235-44
Antal sidor10
TidskriftCancer Research
Volym70
Utgivningsnummer6
StatusPublished - 2010 mar 15
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa