Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1.
Angiogenesis is critical for the growth and proliferation of tumors as well as for normal development. We now describe a novel role for histidine-rich glycoprotein (HRGP) in the modulation of angiogenesis. HRGP is a plasma protein that circulates in relatively high concentrations (1.5 microM), but has no known function in vivo. We have shown previously that HRGP binds with high affinity to thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that is a potent inhibitor of angiogenesis. The antiangiogenic activity of TSP-1 is mediated by the binding of properdin-like type I repeats to the receptor CD36. We found that binding of HRGP to TSP-1 was similarly mediated by TSP type I repeats. HRGP colocalized with TSP-1 in the stroma of human breast cancer specimens, and this interaction masked the antiangiogenic epitope of TSP-1. In assays performed in vitro of endothelial cell migration and tube formation, and in vivo corneal angiogenesis assays, HRGP inhibited the antiangiogenic effect of TSP-1. These studies suggest that HRGP can modulate the antiangiogenic activity of TSP-1, and identify a potential mechanism of resistance to the antiangiogenic effect of TSP-1.
Simantov
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Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA. rsimant@mail.med.cornell.edu
Febbraio
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Crombie
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Asch
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Nachman
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Silverstein
R L
RL
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000098:blood supply / Q000209:etiology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid; D019700:Thrombospondin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000099053:Histidine-Rich Glycoprotein
D006023:Glycoproteins; D011506:Proteins; D019700:Thrombospondin 1; D000099053:Histidine-Rich Glycoprotein