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.