CD36-mediated activation of endothelial cell apoptosis by an N-terminal recombinant fragment of thrombospondin-2 inhibits breast cancer growth and metastasis in vivo |
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Authors: | Manuel Koch Fadi Hussein Andreas Woeste Carsten Gründker Karl Frontzek Günter Emons Thomas Hawighorst |
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Institution: | 1.Institute for Oral and Musculoskeletal Biology, Department of Dermatology, Center for Biochemistry, Center for Molecular Medicine Cologne, Medical Faculty,University of Cologne,Cologne,Germany;2.Department of Gynecology and Obstetrics,University Medical Center G?ttingen, Georg-August-University G?ttingen,G?ttingen,Germany |
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Abstract: | Thus far the clinical benefits seen in breast cancer patients treated with drugs targeting the vascular endothelial growth
factor (VEGF) pathway are only modest. Consequently, additional antiangiogenic approaches for treatment of breast cancer need
to be investigated. Thrombospondin-2 (TSP-2) has been shown to inhibit tumor growth and angiogenesis with a greater potency
than the related molecule TSP-1. The systemic effects of TSP-2 on tumor metastasis and the underlying molecular mechanisms
of the antiangiogenic activity of TSP-2 have remained poorly understood. We generated a recombinant fusion protein consisting
of the N-terminal region of TSP-2 and the IgG-Fc1 fragment (N-TSP2-Fc) and could demonstrate that the antiangiogenic activity
of N-TSP2-Fc is dependent on the CD36 receptor. We found that N-TSP2-Fc inhibited VEGF-induced tube formation of human dermal
microvascular endothelial cells (HDMEC) on matrigel in vitro and that concurrent incubation of anti-CD36 antibody with N-TSP2-Fc
resulted in tube formation that was comparable to untreated control. N-TSP2-Fc potently induced apoptosis of HDMEC in vitro
in a CD36-dependent manner. Moreover, we could demonstrate a CD36 receptor-mediated loss of mitochondrial membrane potential
and activation of caspase-3 in HDMEC in vitro. Daily intraperitoneal injections of N-TSP2-Fc resulted in a significant inhibition
of the growth of human MDA-MB-435 and MDA-MB-231 tumor cells grown in the mammary gland of immunodeficient nude mice and in
reduced tumor vascularization. Finally, increased serum concentrations of N-TSP2-Fc significantly inhibited regional metastasis
to lymph nodes and distant metastasis to lung as shown by quantitative real-time alu PCR. These results identify N-TSP2-Fc as a potent systemic inhibitor of tumor metastasis and provide strong evidence for
an important role of the CD36 receptor in mediating the antiangiogenic activity of TSP-2. |
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