Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1063-1069 ◽  
Author(s):  
Luciana Teofili ◽  
Anna Laura Di Febo ◽  
Francesco Pierconti ◽  
Nicola Maggiano ◽  
Maurizio Bendandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymph Node ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Hodgkin Disease ◽  
Healthy Individuals ◽  
Serum Samples ◽  
Bone Marrow Biopsies ◽  
Barr Virus ◽  
Hepatocyte Growth

Abstract The receptor for hepatocyte growth factor (HGF) is a transmembrane tyrosine kinase that is encoded by the proto-oncogene c-met. Recently, c-MET was detected in Reed-Sternberg (RS) cells from Epstein-Barr virus–positive (EBV+) Hodgkin disease (HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease. In all 45 lymph node and 12 bone marrow samples examined, RS cells expressed c-MET but not HGF+. These results were independent of the EBV infection. Interestingly, several HGF+ dendritic-reticulum cells were found scattered around c-MET+ RS cells. The mean ± SEM serum HGF levels in HD patients at diagnosis and at the time of relapse were 1403 ± 91 (95% confidence interval [CI], 1221-1585) and 1497 ± 242 pg/mL (95% CI, 977-2017), respectively. HGF values were significantly higher than those of healthy individuals (665 ± 28 pg/mL; 95% CI, 600-721; and P < .001 for both groups of patients) and of HD patients in remission (616 ± 49 pg/mL; 95% CI, 517-714; andP < .001 for both groups of patients). A significant correlation was found between serum HGF levels and B symptoms at diagnosis (P = .014). In conclusion, this study indicates that HGF and c-MET constitute an additional signaling pathway between RS cells and the reactive cellular background, thereby affecting adhesion, proliferation, and survival of RS cells. Furthermore, the serum concentration of HGF in HD patients may be a useful tool in monitoring the status of disease.

scholarly journals Hepatocyte Growth Factor Is Constitutively Produced by Human Bone Marrow Stromal Cells and Indirectly Promotes Hematopoiesis

Blood ◽  
1997 ◽  
Vol 89 (5) ◽  
pp. 1560-1565 ◽  
Author(s):  
Kenji Takai ◽  
Junichi Hara ◽  
Kunio Matsumoto ◽  
Gaku Hosoi ◽  
Yuko Osugi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Gm Csf ◽  
Tumor Growth Factor ◽  
Cd34 Cells ◽  
Factor Α ◽  
Hepatocyte Growth

Bone marrow (BM) stromal cells are required for normal hematopoiesis. A number of soluble factors secreted by these cells that mediate hematopoiesis have been characterized. However, the mechanism of hematopoiesis cannot be explained solely by these known factors, and the existence of other, still unknown stromal factors has been postulated. We showed that hepatocyte growth factor (HGF ) is one such cytokine produced by human BM stromal cells. BM stromal cells were shown to constitutively produce HGF and also to express the c-MET/HGF receptor. The production of HGF was enhanced by addition of heparin and phorbol ester. Dexamethasone and tumor growth factor-β (TGF-β) inhibited the production of HGF. Interleukin-1α (IL-1α) tumor necrosis factor-α (TNF-α), and N6,2′-o-dibutyryl-adenosine-3′:5′-cyclic monophosphate (dbc-AMP) showed no obvious influence on HGF production. Western blot analysis of HGF derived from BM stromal cells showed two bands at 85 and 28 kD corresponding to native and variant HGF, respectively. Addition of recombinant HGF significantly promoted the formation of burst-forming unit-erythroid (BFU-E) and colony-forming unit-granulocyte erythroid macrophage (CFU-GEM) by BM mononuclear cells in the presence of erythropoietin and granulocyte-macrophage colony-stimulating factor (GM-CSF ), but the formation of CFU-GM was not modified. However, HGF had no effects on colony formation by purified CD34+ cells. Within BM mononuclear cells, c-MET was expressed on a proportion of cells (CD34−, CD33+, CD13+, CD14+, and CD15+), but was not found on CD34+ cells. We conclude that HGF is constitutively produced by BM stromal cells and that it enhances hematopoiesis. In addition, expression of c-MET on the stromal cells suggests the presence of an autocrine mechanism, operating through HGF, among stromal cells.

Characterization of a functional relationship between hepatocyte growth factor and mouse bone marrow-derived mast cells

1999 ◽  
Vol 65 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Christine C. Fehlner-Gardiner ◽  
Henian Cao ◽  
Linda Jackson-Boeters ◽  
Toshikazu Nakamura ◽  
Bruce E. Elliott ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Mast Cells ◽  
Hepatocyte Growth Factor ◽  
Functional Relationship ◽  
Mouse Bone Marrow ◽  
Hepatocyte Growth

Working Toward Better Tissue Repair Therapies: Exposure of MSC to Hypoxic Conditions In Vitro Increases Levels of the Hepatocyte Growth Factor Receptor c-met, Improves Motility, and Induces Phosphorylation of the Pro-Survival Protein AKT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2313-2313
Author(s):  
Ivana Rosova ◽  
Todd E. Meyerrose ◽  
Jan A. Nolta
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Liver Damage ◽  
Tissue Damage ◽  
Cardiac Ischemia ◽  
Hypoxic Conditions ◽  
Hepatocyte Growth

Abstract Necrosis, apoptosis, and fibrosis are characteristics of tissue damage/injuries such as cardiac ischemia and liver damage. In most instances, a loss of blood supply due to death of endothelial cells results, creating a hypoxic environment at the damage sites. In addition, a flux of growth factors and chemokines are induced as a “rescue” signal to recruit exogenous and/or proximal stem cells into proliferation and differentiation. One such soluble factor reported to have both mitogenic and motogenic effect on stem cells for liver and cardiac regeneration is the hepatocyte growth factor (HGF), also known as “scatter factor”. Our lab has previously demonstrated that administration of HGF in vivo following human hematopoietic stem cell transplantation into an immune deficient mouse model of liver injury greatly enhances recruitment of human stem cells to sites of liver damage (Wang et al, Blood 2003). In the current studies, we addressed the role of HGF in promoting human bone marrow-derived mesenchymal stem cells (MSC) to sites of tissue damage such as liver or cardiac ischemia. In addition to exploiting the beneficial effect of HGF, we also evaluated the possible additive effect of hypoxia in stem cell regeneration based on the following hypothesis - that exposure of MSC to hypoxic conditions prior to transplantation will enhance the levels of c-met and amplify the signaling cascades downstream of HGF/c-met. To answer the question of whether MSCs have increased motility in hypoxic conditions, human bone marrow derived MSC were cultured in hypoxic (2 to 3% oxygen) vs. normoxic conditions (20–21% O2) in the presence or absence of 25ng/ml HGF, and scratch tests were performed to assess the scattering potential of MSC. There was an increase in total c-met protein, by immunohistochemical analysis, and increased migration of MSC under hypoxic conditions with HGF, as compared to normoxic conditions with HGF. Protein studies were designed to measure c-met induction/stabilization and downstream signals following ligand binding. By immunoprecipitation followed by immunoblotting with specific phosphorylation antibodies, we showed that hypoxic conditions + HGF stimulation induced a higher level of total cellular phosphotyrosine activity in MSC. Downstream of HGF/c-met, we observed an amplification of AKT phosphorylation when comparing HGF stimulation under normoxic vs. hypoxic conditions. In contrast, MAPK phosphorylation was moderately, but not significantly, different between hypoxic vs. normoxic conditions. Our data from these functional and molecular studies suggest that pre-treatment of MSC under hypoxic conditions might not only increase c-met to enhance HGF-mediated chemotactic recruitment to sites of tissue damage but may also enhance the survival of these stem cells upon arrival at the damaged site, through increasing the levels of phosphorylation of the pro-survival protein AKT.

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.

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