High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3139-3146 ◽  
Author(s):  
Carina Seidel ◽  
Magne Børset ◽  
Øyvind Hjertner ◽  
Dianjun Cao ◽  
Niels Abildgaard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Osteosarcoma Cell ◽  
Heparin Binding ◽  
Myeloma Cells ◽  
Hepatocyte Growth

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 μg/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.

High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3139-3146 ◽  
Author(s):  
Carina Seidel ◽  
Magne Børset ◽  
Øyvind Hjertner ◽  
Dianjun Cao ◽  
Niels Abildgaard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Cell Line ◽  
Osteosarcoma Cell ◽  
Heparin Binding ◽  
Myeloma Cells ◽  
Hepatocyte Growth

Abstract 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 μg/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.

Hepatocyte Growth Factor (HGF) Induces Interleukin-11 Secretion From Osteoblasts: A Possible Role for HGF in Myeloma-Associated Osteolytic Bone Disease

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3883-3888 ◽  
Author(s):  
Øyvind Hjertner ◽  
Maria Lyngaas Torgersen ◽  
Carina Seidel ◽  
Henrik Hjorth-Hansen ◽  
Anders Waage ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Line ◽  
Bone Disease ◽  
Myeloma Cell ◽  
Physical Contact ◽  
Myeloma Cell Line ◽  
Myeloma Cells ◽  
Hepatocyte Growth ◽  
Interleukin 11

Multiple myeloma is associated with unbalanced bone remodeling causing lytic bone lesions. Interleukin-11 (IL-11) promotes osteoclast formation and inhibits osteoblast activity and may, thus, be one factor involved in cancer-induced bone destruction. We have previously shown that myeloma cells produce hepatocyte growth factor (HGF). We now report that HGF induces IL-11 secretion from human osteoblast-like cells and from the osteosarcoma cell lines Saos-2 and HOS. In coculture experiments, both the myeloma cell line JJN-3 and primary myeloma cells from 3 patients induced IL-11 secretion from osteoblasts, whereas no induction was observed with the non-HGF producing myeloma cell line OH-2. Enhanced IL-11 induction was observed with physical contact between osteoblasts and myeloma cells as compared with experiments in which contact was prohibited by tissue inserts. Anti-HGF serum strongly reduced the myeloma cell-induced IL-11 secretion. Furthermore, we show that JJN-3 cells express HGF on the cell-surface. Removal of surface-bound HGF on JJN-3 cells reduced IL-11 production induced in cocultures. Transforming growth factor β1 and IL-1 potentiated the effect of HGF on IL-11 secretion, whereas an additive effect was observed with tumor necrosis factor. Thus, myeloma-derived HGF can influence the bone marrow environment both as a soluble and a surface-bound factor. Furthermore, HGF emerges as a possible factor involved in myeloma bone disease by its ability to induce IL-11.

Identification of Basophils as Source of Hepatocyte Growth Factor (HGF) In CML: a Potential Trigger of Disease Acceleration.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1202-1202
Author(s):  
Sabine Cerny-Reiterer ◽  
Karl J. Aichberger ◽  
Harald Herrmann ◽  
Gregor Hoermann ◽  
Barbara Peter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Line ◽  
Research Funding ◽  
K562 Cells ◽  
Leukemic Cells ◽  
Mrna Levels ◽  
Ku812 Cells ◽  
Hepatocyte Growth

Abstract Abstract 1202 Chronic myeloid leukemia (CML) is a myeloproliferative disorder in which BCR/ABL leads to enhanced survival of leukemic cells. Several different angiogenic molecules, including vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), have been implicated in the pathogenesis of CML. Enhanced production of these pro-angiogenic molecules in CML may be associated with disease acceleration. However, little is known so far about the exact origin of these growth factors and about mechanisms underlying their production and secretion in CML cells. In the current study, we analyzed the cellular distribution of HGF and its receptor c-MET in CML cells, and explored the mechanism of expression of HGF in BCR/ABL-transformed cells. As assessed by immunostaining of bone marrow sections and isolated blood and bone marrow samples, the HGF protein was found to be expressed in a subset of leukemic cells in all patients tested. In addition, CML cells were found to express HGF mRNA and c-MET mRNA. In consecutive experiments, we were able to show that basophils are the primary source of HGF in CML. In particular, highly enriched sorted CD203c+ CML basophils were found to express substantial amounts of HGF mRNA as well as the HGF protein. Correspondingly, leukemic cell samples obtained from patients with accelerated phase CML were found to contain higher HGF mRNA levels compared to cells obtained from patients in chronic phase or blast phase CML. Finally, HGF mRNA and the HGF protein were detectable in the basophil-committed CML cell line KU812, but not in the more immature Ph+ cell line K562. We next asked whether expression of HGF in CML cells depends on BCR/ABL. To address this question, Ba/F3 cells with doxycycline-inducible expression of BCR/ABL were employed. However, BCR/ABL failed to induce expression of HGF mRNA or the HGF protein in Ba/F3 cells. Correspondingly, the BCR/ABL-blocker imatinib was found to inhibit expression of VEGF mRNA, but did not inhibit HGF mRNA expression in KU812 cells. Next, we examined the expression of c-MET in CML cells. c-MET mRNA was found to be expressed in KU812 and K562 cells, in highly enriched CD34+/CD38- CML stem cells, and less abundantly in more mature CD34+/CD38+ CML cells and CML basophils. The c-MET inhibitor MSC-2156119J-15 (Merck-Serono Darmstadt, Germany) was found to counteract growth of primary CML cells, K562 cells, and KU812 cells with comparable IC50 values (0.5-1.0 μM). In summary, our data suggest that HGF is a BCR/ABL-independent basophil-derived mediator in CML. Basophils and basophil-derived mediators may play a more active role in CML-acceleration as has been considered previously. Whether targeting of HGF or/and c-MET is an effective approach to block acceleration in CML remains to be elucidated. Disclosures: Valent: Novartis: Honoraria, Research Funding; Merck-Serono: Research Funding.

Hepatocyte Growth Factor (HGF) Induces Interleukin-11 Secretion From Osteoblasts: A Possible Role for HGF in Myeloma-Associated Osteolytic Bone Disease

Blood ◽  
1999 ◽  
Vol 94 (11) ◽  
pp. 3883-3888 ◽  
Author(s):  
Øyvind Hjertner ◽  
Maria Lyngaas Torgersen ◽  
Carina Seidel ◽  
Henrik Hjorth-Hansen ◽  
Anders Waage ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Cell Line ◽  
Bone Disease ◽  
Myeloma Cell ◽  
Physical Contact ◽  
Myeloma Cell Line ◽  
Myeloma Cells ◽  
Hepatocyte Growth ◽  
Interleukin 11

Abstract Multiple myeloma is associated with unbalanced bone remodeling causing lytic bone lesions. Interleukin-11 (IL-11) promotes osteoclast formation and inhibits osteoblast activity and may, thus, be one factor involved in cancer-induced bone destruction. We have previously shown that myeloma cells produce hepatocyte growth factor (HGF). We now report that HGF induces IL-11 secretion from human osteoblast-like cells and from the osteosarcoma cell lines Saos-2 and HOS. In coculture experiments, both the myeloma cell line JJN-3 and primary myeloma cells from 3 patients induced IL-11 secretion from osteoblasts, whereas no induction was observed with the non-HGF producing myeloma cell line OH-2. Enhanced IL-11 induction was observed with physical contact between osteoblasts and myeloma cells as compared with experiments in which contact was prohibited by tissue inserts. Anti-HGF serum strongly reduced the myeloma cell-induced IL-11 secretion. Furthermore, we show that JJN-3 cells express HGF on the cell-surface. Removal of surface-bound HGF on JJN-3 cells reduced IL-11 production induced in cocultures. Transforming growth factor β1 and IL-1 potentiated the effect of HGF on IL-11 secretion, whereas an additive effect was observed with tumor necrosis factor. Thus, myeloma-derived HGF can influence the bone marrow environment both as a soluble and a surface-bound factor. Furthermore, HGF emerges as a possible factor involved in myeloma bone disease by its ability to induce IL-11.

scholarly journals Dissociation of Heparan Sulfate and Receptor Binding Domains of Hepatocyte Growth Factor Reveals That Heparan Sulfate-c-Met Interaction Facilitates Signaling

2001 ◽  
Vol 276 (35) ◽  
pp. 32977-32983 ◽  
Author(s):  
Jeffrey S. Rubin ◽  
Regina M. Day ◽  
Diane Breckenridge ◽  
Nese Atabey ◽  
William G. Taylor ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Heparan Sulfate ◽  
Receptor Binding ◽  
Binding Domains ◽  
Hepatocyte Growth

Abstract 1340: Disruption of a Hepatocyte Growth Factor/c-Met Receptor Autocrine Loop Severely Impairs the Potency of Pluripotent Adipose Stromal Cells

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Liying Cai ◽  
Brian H Johnstone ◽  
Zhong Liang ◽  
Dmitry Traktuev ◽  
Todd G Cook ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Rank Order ◽  
Residual Activity ◽  
Autocrine Loop ◽  
Major Mode ◽  
Factor C ◽  
Hepatocyte Growth

Background Paracrine stimulation of endogenous repair, rather than direct tissue regeneration, is increasingly accepted as a major mode of therapeutic stem and progenitor cell action; yet, this principle has not been fully established in vivo . Adipose-derived stem cells (ASCs) secrete many factors and promote reperfusion and tissue repair in ischemia models. RNA interference was used to silence the expression of the abundant protein, hepatocyte growth factor (HGF), to determine its contribution to ASC potency in vivo . Methods and Results Dual-cassette lentiviral vectors, expressing GFP and either a small hairpin RNA (shRNA) specific for HGF mRNA (shHGF) or a control sequence (shCtrl), were used to stably transduce ASCs (ASC-shHGF or ASC-shCtrl). ASC-shHGF secreted 5-fold less HGF, which resulted in a reduced ability of these cells to promote survival, proliferation and migration of mature and progenitor endothelial cells in vitro ( p <0.01). HGF knockdown also severely impaired the ability of ASCs to promote reperfusion in a mouse hindlimb ischemia model. Perfusion of the ischemic leg at 15 d in mice treated with ASC-Ctrl was 84±4%, compared to only 69±5% for ASC-shHGF ( p <0.05). Even so, ASC-shHGF retained residual activity as indicated by greater reperfusion ( p <0.05) than with saline treatment (58±6%). Capillary densities in ischemic tissues from each group followed a similar rank order (ASC-Ctrl>ASC-shHGF>saline) ( p <0.05 between each group). While there was no difference in total GFP + cells in ischemic limbs at 5 d after infusion, indicating similar homing potentials, 3-fold fewer ASC-shHGF were present in ischemic tissues at 15 d compared to ASC-shCtrl ( p <0.01). This was accompanied by an increase in TUNEL-positive ASC-shHGF cells (61 ± 0.1%) compared to ASC-Ctrl (41% ± 3.2%) in ischemic tissues at 5 d ( p <0.01); suggesting that attenuated potency of ASC-shHGF was related to reduced survival in ischemic tissues. Conclusions These results indicate that secretion of HGF is critically important for ASC potency. In addition to promoting endogenous repair, the data suggest that an important effect of HGF is autocrine promotion of ASC survival in ischemic tissue. Enhanced donor cell survival is an important goal for increasing the efficacy of cell therapy.

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