Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

Romina Dossi; Roberta Frapolli; Silvana Di Giandomenico; Lara Paracchini; Fabio Bozzi; Silvia Brich; Vittoria Castiglioni; Patrizia Borsotti; Dorina Belotti; Sarah Uboldi; Roberta Sanfilippo; Eugenio Erba; Raffaella Giavazzi; Sergio Marchini; Silvana Pilotti; Maurizio D'Incalci; Giulia Taraboletti

doi:10.1002/ijc.29023

journal article Jun 19, 2014

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

Romina Dossi Roberta Frapolli Silvana Di Giandomenico Lara Paracchini Fabio Bozzi Silvia Brich Vittoria Castiglioni Patrizia Borsotti Dorina Belotti Sarah Uboldi Roberta Sanfilippo Eugenio Erba Raffaella Giavazzi

Sergio Marchini Silvana Pilotti Maurizio D'Incalci Giulia Taraboletti

International Journal of Cancer Vol. 136 No. 3 pp. 721-729 · Wiley

View at Publisher Save 10.1002/ijc.29023

Abstract

Trabectedin is a marine natural product, approved in Europe for the treatment of soft tissue sarcoma and relapsed ovarian cancer. Clinical and experimental evidence indicates that trabectedin is particularly effective against myxoid liposarcomas where response is associated to regression of capillary networks. Here, we investigated the mechanism of the antiangiogenic activity of trabectedin in myxoid liposarcomas. Trabectedin directly targeted endothelial cells, impairing functions relying on extracellular matrix remodeling (invasion and branching morphogenesis) through the upregulation of the inhibitors of matrix metalloproteinases TIMP‐1 and TIMP‐2. Increased TIMPs synthesis by the tumor microenvironment following trabectedin treatment was confirmed in xenograft models of myxoid liposarcoma. In addition, trabectedin upregulated tumor cell expression of the endogenous inhibitor thrombospondin‐1 (TSP‐1, a key regulator of angiogenesis‐dependent dormancy in sarcoma), in in vivo models of myxoid liposarcomas, in vitro cell lines and primary cell cultures from patients' myxoid liposarcomas. Chromatin Immunoprecipitation analysis showed that trabectedin displaced the master regulator of adipogenesis C/EBPβ from the TSP‐1 promoter, indicating an association between the up‐regulation of TSP‐1 and induction of adipocytic differentiation program by trabectedin. We conclude that trabectedin inhibits angiogenesis through multiple mechanisms, including directly affecting endothelial cells in the tumor microenvironment—with a potentially widespread activity—and targeting tumor cells' angiogenic activity, linked to a tumor‐specific molecular alteration.

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Details

Published: Jun 19, 2014
Vol/Issue: 136(3)
Pages: 721-729
License: View

Authors

R

Romina Dossi

Tumor Angiogenesis Unit, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Bergamo Italy

R

Roberta Frapolli

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

S

Silvana Di Giandomenico

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

L

Lara Paracchini

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

F

Fabio Bozzi

Department of Pathology IRCCS‐Istituto Nazionale Tumori Milan Italy

S

Silvia Brich

Department of Pathology IRCCS‐Istituto Nazionale Tumori Milan Italy

V

Vittoria Castiglioni

DIVET, Faculty of Veterinary Medicine University of Milan Milan Italy

P

Patrizia Borsotti

Tumor Angiogenesis Unit, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Bergamo Italy

D

Dorina Belotti

Tumor Angiogenesis Unit, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Bergamo Italy

S

Sarah Uboldi

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

R

Roberta Sanfilippo

Adult Sarcoma Medical Unit IRCCS‐Istituto Nazionale Tumori Milan Italy

E

Eugenio Erba

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

R

Raffaella Giavazzi

Tumor Angiogenesis Unit, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Bergamo Italy

S

Sergio Marchini

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

S

Silvana Pilotti

Department of Pathology IRCCS‐Istituto Nazionale Tumori Milan Italy

M

Maurizio D'Incalci

Laboratory of Cancer Pharmacology, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

G

Giulia Taraboletti

Tumor Angiogenesis Unit, Department of Oncology IRCCS‐Istituto di Ricerche Farmacologiche Mario Negri Bergamo Italy

Funding

Italian Association for Cancer Research (AIRC) Award: 14658

Cite This Article

Romina Dossi, Roberta Frapolli, Silvana Di Giandomenico, et al. (2014). Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1. International Journal of Cancer, 136(3), 721-729. https://doi.org/10.1002/ijc.29023

Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP‐1 and TIMP‐2 and tumor thrombospondin‐1

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