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

Germano, Giovanni; Frapolli, Roberta; Simone, Matteo; Tavecchio, Michele LU ; Erba, Eugenio; Pesce, Samantha; Pasqualini, Fabio; Grosso, Federica; Sanfilippo, Roberta and Casali, Paolo G, et al. (2010) In Cancer Research 70(6). p.44-2235
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... (More)

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.

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keywords
Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Antineoplastic Agents, Alkylating, C-Reactive Protein, Cell Cycle, Cell Death, Cell Line, Tumor, Chemokine CCL2, Dioxoles, Humans, Immunohistochemistry, Inflammation Mediators, Interleukin-6, Interleukin-8, Liposarcoma, Myxoid, Macrophages, Mice, Serum Amyloid P-Component, Tetrahydroisoquinolines, Vascular Endothelial Growth Factor A, Xenograft Model Antitumor Assays, Journal Article, Research Support, Non-U.S. Gov't
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Cancer Research
volume
70
issue
6
pages
10 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:77950231708
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-09-2335
language
English
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f8128a1f-4fbf-41b4-8845-0f97afc9daad
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2017-03-07 09:12:05
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2018-12-02 04:48:43
@article{f8128a1f-4fbf-41b4-8845-0f97afc9daad,
  abstract     = {<p>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.</p>},
  author       = {Germano, Giovanni and Frapolli, Roberta and Simone, Matteo and Tavecchio, Michele and Erba, Eugenio and Pesce, Samantha and Pasqualini, Fabio and Grosso, Federica and Sanfilippo, Roberta and Casali, Paolo G and Gronchi, Alessandro and Virdis, Emanuela and Tarantino, Eva and Pilotti, Silvana and Greco, Angela and Nebuloni, Manuela and Galmarini, Carlos Maria and Tercero, Juan Carlos and Mantovani, Alberto and D'Incalci, Maurizio and Allavena, Paola},
  issn         = {1538-7445},
  keyword      = {Animals,Antigens, CD,Antigens, Differentiation, Myelomonocytic,Antineoplastic Agents, Alkylating,C-Reactive Protein,Cell Cycle,Cell Death,Cell Line, Tumor,Chemokine CCL2,Dioxoles,Humans,Immunohistochemistry,Inflammation Mediators,Interleukin-6,Interleukin-8,Liposarcoma, Myxoid,Macrophages,Mice,Serum Amyloid P-Component,Tetrahydroisoquinolines,Vascular Endothelial Growth Factor A,Xenograft Model Antitumor Assays,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {03},
  number       = {6},
  pages        = {44--2235},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-09-2335},
  volume       = {70},
  year         = {2010},
}