scholarly journals Bone marrow endothelial cells increase the invasiveness of human multiple myeloma cells through upregulation of MMP-9: evidence for a role of hepatocyte growth factor

Leukemia ◽  
2004 ◽  
Vol 18 (5) ◽  
pp. 976-982 ◽  
Author(s):  
I Vande Broek ◽  
K Asosingh ◽  
V Allegaert ◽  
X Leleu ◽  
T Facon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Myeloma Cells ◽  
Human Multiple Myeloma ◽  
Hepatocyte Growth

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.

scholarly journals The Serine Protease Matriptase Acts As a Tumour Suppressor in Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Ida Steiro ◽  
Pegah Abdollahi ◽  
Magne Børset ◽  
Tobias S. Slørdahl
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Serine Protease ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Tumour Suppressor ◽  
Hepatocyte Growth

Both in newly diagnosed multiple myeloma (MM) and during progression of the disease, malignant plasma cells are found circulating in peripheral blood as well as in the bone marrow (BM). The disseminated nature of MM is strongly dependent on the interplay between the cancer cells and the BM microenvironment, promoting myeloma cell migration in the BM. Matriptase (ST14), a type-II transmembrane serine protease primarily found in epithelial tissues, is overexpressed in a variety of human malignancies and is sufficient to induce tumour formation in mice. Frequently, a concomitant reduction in the levels of its cognate inhibitor hepatocyte growth factor activator inhibitor (HAI)-1 (SPINT1) is observed in carcinomas, while expression and function of the related inhibitor HAI-2 (SPINT2) is yet to be clarified. Dysregulated expression causing increased matriptase proteolytic activity has been associated with cancer growth, survival and metastasis. Here, we show for the first time a role of matriptase as a possible tumour suppressor in myeloma pathogenesis. Gene expression analysis of primary cells from MM patients (n=24) and human myeloma cell lines (n=8) revealed highly variable levels of matriptase, HAI-1 and HAI-2. This observation prompted us to investigate the functional role of matriptase in vitro. We showed that stable overexpression of matriptase in INA-6, a MM cell line with no endogenous ST14 expression, reduced migration by more than 50% in response to the combination of the pro-migratory cytokines stromal cell-derived factor-1 alpha (SDF-1α) and hepatocyte growth factor (HGF, Fig. 1A). Conversely, stable knockdown of matriptase in two MM cell lines with high endogenous matriptase expression (RPMI-8226 and JJN-3) significantly enhanced migration in vitro. Mechanistically, matriptase overexpression blocked activation of Src kinase (Fig. 1B), well-known as a critical player in metastasis formation promoting cancer cell motility, invasiveness and angiogenesis. In agreement with our result, previous studies have demonstrated the activation of Src family kinases (SFK) downstream SDF-1/CXCR4-signaling. Finally, we performed survival analyses in the public available MMRF CoMMpass trial database (release version IA14). Low ST14 expression was associated with significant worse overall survival (P=0.05, Fig. 1C) and progression-free survival (P=0.02, Fig. 1D). Altogether, our data are in marked contrast to the role ascribed to matriptase in epithelial and certain non-epithelial tumours as an oncogenic protein and an unfavourable prognostic marker. In conclusion, these findings suggest a novel role of matriptase as a tumour suppressor in MM pathogenesis. Disclosures Slørdahl: Celgene: Consultancy; Janssen and Celgene: Honoraria.

scholarly journals Hepatocyte growth factor and its receptor c-met in multiple myeloma

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3998-4004 ◽  
Author(s):  
M Borset ◽  
H Hjorth-Hansen ◽  
C Seidel ◽  
A Sundan ◽  
A Waage
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Mononuclear Cells ◽  
Primary Cultures ◽  
Enzyme Linked Immunosorbent Assay ◽  
Myeloma Cells ◽  
The Mean ◽  
Hepatocyte Growth ◽  
Normal Controls

We have examined whether the hepatocyte growth factor (HGF)/c-met receptor-ligand pair is expressed in freshly isolated and highly purified myeloma cells and whether HGF can be found in the sera of myeloma patients. Myeloma cells were purified with an immunomagnetic method using the syndecan 1-specific antibody B-B4. HGF and c-met mRNA in these cells were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). HGF and c-met proteins were detected by enzyme- linked immunosorbent assay (ELISA) and Western blot, respectively. Serum from 13 myeloma patients was obtained at diagnosis and the levels of HGF were determined by ELISA. HGF and c-met mRNA were expressed in all examined samples (n = 7). HGF was detected in the supernatants of 17 of 20 primary cultures of myeloma cells, whereas bone marrow mononuclear cells from normal controls did not produce detectable amounts of HGF (n = 3). The mean HGF level in serum of myeloma patients at diagnosis was more than fourfold higher than the mean level in normal controls. Possible implications of HGF/c-met expression for the pathophysiology of multiple myeloma are discussed.

Upregulation of MMP-2 & 9 by Co-Culture of Human Myeloma Cell Lines and Endothelial Cells May Be Responsible for Protection Against Cytotoxic Drugs.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5080-5080
Author(s):  
Shankaranarayana Paneesha ◽  
Raghu Adya ◽  
Hemali Khanji ◽  
Ed Leung ◽  
C. Vijayasekar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endothelial Cells ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Human Myeloma Cell

Abstract Multiple myeloma is a clonal lymphoproliferative disorder characterised by the proliferation of plasma cells in the bone marrow. Inspite of good initial response, it is associated with universal relapse. We hypothesise this is due to sanctuary provided to myeloma cells by the endothelium. Matrix metalloproteinases (MMPs) are shown play a role in cell growth, invasion, angiogenesis, metastasis and bone degradation. We show here the protection offered by endothelial cells to human myeloma cell lines in in-vitro co-culture with upregulation of MMP-2 & 9 and the role of GM6001 MMP inhibitor (Ilomastat) in overcoming this protection. Human myeloma cell lines (H929, RPMI 8226, U266 & JJN3) with or without endothelial cells (human umbilical vein endothelial cells and EaHy 926 cell line) in-vitro co-culture were treated with melphalan, dexamethasone, arsenic trioxide and Ilomastat. Cytotoxicity/proliferation were assessed by the alamarBlue™ assay (Serotec) and validated by Annexin V-FITC apoptosis detection Kit (Calbiochem) and BrDU proliferation assay (BD Pharmingen™). Gelatin Zymography was used to demonstrate activity of MMP-2 & 9 in the supernatant. MMP-2 and 9 mRNA expression was quantified by Real Time Quantitative PCR (ROCHE). Co-culture of human myeloma cell lines with endothelial cells lead to increase in the proliferation of myeloma cell lines and also protected them from the cytotoxicity of chemotherapeutic agents. MMP-2 & 9 activity was upregulated by the co-culture. MMP-2 mRNA expression in human myeloma cell lines increased following 4 hr co-culture. Treatments with Ilomastat lead to the suppression of proliferation in co-culture in a dose dependent manner, associated with a reduction of MMP-2 and 9 activity. Our study shows endothelial cells offer protection to human myeloma cell lines in the presence of cytotoxic agents. This may result in the sanctuary of myeloma cells in bone marrow leading to ultimate relapse of disease. Our study also demonstrates the upregulation of MMP-2 and 9 by co-culture and increased cytotoxicity achieved by the inhibition of MMPs. Further studies are needed to determine the exact role of MMPs in myeloma biology as MMP inhibition may be an interesting therapeutic target and help in averting relapse in multiple myeloma.

scholarly journals Hepatocyte growth factor pathway upregulation in the bone marrow microenvironment in multiple myeloma is associated with lytic bone disease

2013 ◽  
Vol 161 (3) ◽  
pp. 373-382 ◽  
Author(s):  
Ida B. Kristensen ◽  
Jacob H. Christensen ◽  
Maria B. Lyng ◽  
Michael B. Møller ◽  
Lise Pedersen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Bone Disease ◽  
Bone Marrow Microenvironment ◽  
Hepatocyte Growth

scholarly journals Multiple myeloma relapse in the irradiated liver: involvement of hepatocyte growth factor akin to that after hepatocyte transplantation

2012 ◽  
Vol 11 (4) ◽  
pp. 271-273
Author(s):  
Akiko Uetake ◽  
Atsuya Takeda ◽  
Naoyuki Shigematsu ◽  
Eiji Ikeda ◽  
Minako Kametaka ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Plasma Cells ◽  
Growth Factor Receptor ◽  
Immunohistochemical Analysis ◽  
Left Lobe ◽  
Hepatocyte Growth Factor Receptor ◽  
Hepatocyte Growth

AbstractWe described a rare case of multiple myeloma in a 60-year-old man, in whom relapse limited to the irradiated area in the left lobe of the liver developed following radiotherapy for lesions in 11th and 12th thoracic spines. Immunohistochemical analysis revealed expression of hepatocyte growth factor (HGF) and hepatocyte growth factor receptor (c-Met) in the hepatocytes in the irradiated area of the liver. We speculate that the malignant plasma cells might have proliferated in response to local increase of HGF production in the irradiated liver. The role of HGF in the extraosseous spread of multiple myeloma and also under the experimental condition of hepatic transplantation is discussed.

NK4, an Antagonist of Hepatocyte Growth Factor (HGF), Inhibits Growth of Multiple Myeloma Cells In Vitro and In Vivo: A Mouse Model for Molecular Targeting of Angiogenic Growth Factor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 637-637 ◽  
Author(s):  
Yutaka Hattori ◽  
Wenlin Du ◽  
Taketo Yamada ◽  
Kunio Matsumoto ◽  
Toshikazu Nakamura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Scid Mice ◽  
Response To Therapy ◽  
Molecular Targeting ◽  
Angiogenic Growth Factors ◽  
Myeloma Cells ◽  
Hepatocyte Growth

Abstract Background and rationale: Recent study showed that bone marrow angiogenesis and angiogenic growth factors including hepatocyte growth factor (HGF) are associated with pathogenesis and disease activity of multiple myeloma. In our experience, plasma concentration of HGF significantly elevated in 30 % of patients with clinically active myeloma and declined along with response to therapy. Thus, HGF signaling is considered to play a role in progression of myeloma and is a potential therapeutic target. The aim of this study is to establish a novel therapy targeting HGF and the receptor, c-MET, using NK4 molecule which is an HGF-antagonist consisting of N-terminal kringle domain of HGF. Results: 1) Among eleven myeloma cell lines established from Japanese patients, two lines, KMS11 and 34, secreted HGF while c-MET is expressed in all eleven cells. 2) 10nM of NK4 protein significantly inhibited growth of the two HGF-producing cells in vitro. NK4 protein showed additive anti-myeloma effect to dexamethasone (Dex) in Dex-sensitive KMS11 cells, and is also effective for growth suppression of Dex-resistant KMS 34 cells. 3) NK4 significantly reduced phosphorylation of ERK1/2 while no significant effect on STAT3 activation. 4) Adenoviral vector carrying NK4 cDNA (Ad-NK4) was injected in femoral muscle of lcr/scid mice. Pharmacokinetic study showed that NK4 proteins were detected in plasma, liver, lung and kidney up to three weeks and attained a maximum level at day 10–14. 5) Ad-NK4 injection to tumor-bearing lcr-SCID mice significantly inhibited growth of subcutaneous tumor derived from KMS11 and 34 cells compared with empty vector injection (n=10, p<. 05). Co-injection of Ad-NK4 and Dex revealed synergistic or additive anti-tumor effect in mice bearing KMS11 tumor. Anti-myeloma effect of Ad-NK4 is also confirmed by histopathological examination. Conclusion: Above results directly showed that HGF/c-MET signal plays an important role in progression of myeloma cells producing HGF. Molecular targeting of HGF by NK4 is considered as a novel approach for the treatment of myeloma via independent mechanism of glucocorticoid therapy.

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