High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity.
Syndecan-1 is a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells. Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. Previous studies have demonstrated elevated levels of syndecan-1 and HGF in the serum of patients with myeloma, both of negative prognostic value for the disease. Here we show that the median concentrations of syndecan-1 (900 ng/mL) and HGF (6 ng/mL) in the marrow compartment of patients with myeloma are highly elevated compared with healthy controls and controls with other diseases. We show that syndecan-1 isolated from the marrow of patients with myeloma seems to exist in an intact form, with glucosaminoglycan chains. Because HGF is a heparan-sulfate binding cytokine, we examined whether it interacted with soluble syndecan-1. In supernatants from myeloma cells in culture as well as in pleural effusions from patients with myeloma, HGF existed in a complex with soluble syndecan-1. Washing myeloma cells with purified soluble syndecan-1 could effectively displace HGF from the cell surface, suggesting that soluble syndecan-1 can act as a carrier for HGF in vivo. Finally, using a sensitive HGF bioassay (interleukin-11 production from the osteosarcoma cell line Saos-2) and intact syndecan-1 isolated from the U-266 myeloma cell line, we found that the presence of high concentrations of syndecan-1 (more than 3 microg/mL) inhibited the HGF effect, whereas lower concentrations potentiated it. HGF is only one of several heparin-binding cytokines associated with myeloma. These data indicate that soluble syndecan-1 may participate in the pathology of myeloma by modulating cytokine activity within the bone marrow.
Seidel
C
C
Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway. carinas@medisin.ntnu.no
Børset
M
M
Hjertner
O
O
Cao
D
D
Abildgaard
N
N
Hjorth-Hansen
H
H
Sanderson
R D
RD
Waage
A
A
Sundan
A
A
D001707:Biopsy, Needle; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology*; D001859:Bone Neoplasms; D002462:Cell Membrane / Q000473:pathology; D017077:Culture Media, Conditioned; D005434:Flow Cytometry; D017228:Hepatocyte Growth Factor / Q000032:analysis* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D017370:Interleukin-11 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000302:isolation & purification / Q000494:pharmacology; D009101:Multiple Myeloma / Q000473:pathology*; D012516:Osteosarcoma; D011509:Proteoglycans / Q000032:analysis* / Q000302:isolation & purification / Q000494:pharmacology; D012016:Reference Values; D053668:Syndecan-1; D053667:Syndecans; D014407:Tumor Cells, Cultured
D017077:Culture Media, Conditioned; D017370:Interleukin-11; D008562:Membrane Glycoproteins; D011509:Proteoglycans; C508241:SDC1 protein, human; D053668:Syndecan-1; D053667:Syndecans; D017228:Hepatocyte Growth Factor