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Prepublished online as a Blood First Edition Paper on August 28, 2003; DOI 10.1182/blood-2003-03-0893.
Submitted March 24, 2003
Accepted August 18, 2003
Thrombospondin-1 as a scavenger for matrix-associated fibroblast growth factor-2
Barbara Margosio, Daniela Marchetti, Veronica Vergani, Raffaella Giavazzi, Marco Rusnati, Marco Presta, and Giulia Taraboletti*
Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, Italy
Department of Biomedical Sciences and Biotechnology, University of Brescia School of Medicine, Brescia, Italy
* Corresponding author; email: taraboletti{at}marionegri.it.
The antiangiogenic factor thrombospondin-1 (TSP-1) binds with high affinity to several heparin-binding angiogenic factors, including FGF-2, VEGF, HGF/SF. The aim of this study was to investigate whether TSP-1 affects FGF-2 association with the extracellular matrix (ECM) and its bioavailability. TSP-1 prevented the binding of free FGF-2 to endothelial cell ECM. It also promoted the mobilization of matrix-bound FGF-2, generating a TSP-1/FGF-2 complex. The region of TSP-1 responsible for these activities was located within the 140 kDa, anti-angiogenic and FGF-2 binding fragment, while the 25 kDa, heparin-binding fragment was inactive. Matrix-released FGF-2/TSP-1 complex had a reduced ability to bind to and induce proliferation of endothelial cells. TSP-1 depleted the ECM laid by FGF-2-overproducing tumor cells of its FGF-2-dependent mitogenic activity for endothelial cells. Besides FGF-2, TSP-1 also inhibited VEGF and HGF/SF binding to the ECM and mobilized them from the ECM. Our study shows that TSP-1 acts as a scavenger for matrix-associated angiogenic factors, affecting their location, bioavailability and function.
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