Antitumor and Anti-inflammatory Effects of Trabectedin on Human Myxoid Liposarcoma Cells

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.

A Review of Trabectedin (ET-743): A Unique Mechanism of Action

“…Note that CCL2 plays a major role in monocyte recruitment at tumor sites, whereas IL-6 is a growth factor for several tumors. Similar results were recently seen in a tumor particularly sensitive to trabectedin: myxoid liposarcoma (24). The production of CCL2, CXCL8, IL-6, vascular endothelial growth factor (VEGF), and the matrix binder protein pentraxin 3 (PTX3), by primary cultures or cell lines of myxoid liposarcomas, was selectively inhibited by noncytotoxic concentrations of trabectedin.…”

“…The production of CCL2, CXCL8, IL-6, vascular endothelial growth factor (VEGF), and the matrix binder protein pentraxin 3 (PTX3), by primary cultures or cell lines of myxoid liposarcomas, was selectively inhibited by noncytotoxic concentrations of trabectedin. These findings were further confirmed in a patient-derived myxoid liposarcoma xenograft mouse model in which trabectedin treatment caused a marked reduction in the tumor expression of CCL2/ CXCL8/CD68+ infiltrating macrophages and CD31 tumor vessels (24).…”

The immune network in thyroid cancer

“…14 Targeting macrophages has been shown effective for blocking tumor growth. 115 This experimental approach could be also useful in TC. TC cells and immune cells are a major source of several protumorigenic and proangiogenic cytokines/chemokines.…”

Chemokines in cancer related inflammation

“…Expressed chemokines include CCL2, CCL20, angiogenic CXC ligands, CXCL12 and its receptor CXCR4. Recently, we reported that the oncogenic fusion transcript FUS-CHOP, characteristic of the human myxoid lyposarcoma, trans-activates the chemokines CCL2, CCL5 and CXCL8 [12]. The transcription factor Myc, which is overexpressed in many human tumors, in addition to promoting cell autonomous proliferation, instructs remodelling of the extracellular microenvironment with inflammatory cells and mediators (e.g.…”

“…The registered anti-tumor agent of marine origin Trabectedin, in addition to a strong anti-proliferative effect on cancer cells, is able to downmodulate the production of a wide set of tumor-related chemokine, among which CCL2 and CXCL8 [12,132]. This antiinflammatory effect of Trabectedin, not shared by conventional anti-tumor agents, combined with its action on tumor cells, may represent an ideal therapeutic tool in inflammation-related tumors.…”