Metalloproteinases in Multiple Myeloma: Production of Matrix Metalloproteinase-9 (MMP-9), Activation of proMMP-2, and Induction of MMP-1 by Myeloma Cells

Barillé, Sophie; Akhoundi, Camelia; Collette, Mathieu; Mellerin, Marie-Paule; Rapp, Maryse; Harousseau, Jean‐Luc; Bataille, Régis; Amiot, Martine

doi:10.1182/blood.v90.4.1649

Cited by 161 publications

(51 citation statements)

References 36 publications

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“…When the MMP‐9 production of this cell line was analyzed, no MMP‐9 activity was observed. This agrees with the data of Barillé et al ,11 who compared the conditioned media of primary myeloma cells (patient SBN‐1) and of the cell line (SBN‐1) established from these myeloma cells. The SBN‐1 cell line, which was immortalized for almost 1 year, had no detectable MMP‐9 activity compared to fresh myeloma cells, which produce a significant amount of MMP‐9.…”

Section: Discussionsupporting

confidence: 92%

“…Several studies have demonstrated a role of MMPs in cancer. MMP production was demonstrated in MM 11, 14, 28. We used the 5T33MM mouse model to investigate the production of MMP‐9 (gelatinase B) in MM.…”

Section: Discussionmentioning

confidence: 99%

“…, transendothelial migration, invasion, osteolytic lesions and angiogenesis 10. Barillé et al 11 demonstrated MMP‐9 production by human MM cells. MMP‐9 is involved in transendothelial migration and invasion 12, 13.…”

mentioning

confidence: 99%

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Upregulation of matrix metalloproteinase‐9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells

Valckenborgh¹,

Bâkkus²,

Munaut

et al. 2002

Intl Journal of Cancer

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MM is a B-cell malignancy mainly characterized by monoclonal expansion of plasma cells in the BM, presence of paraprotein in serum and occurrence of osteolytic bone lesions. MMPs are a family of proteolytic enzymes that can contribute to cancer growth, invasion, angiogenesis, bone degradation and other processes important in the pathogenesis of MM. We investigated MMP-9 production in the 5T33MM murine model. Expression of MMP-9 protein in supernatant and cell extracts was analyzed by gelatin zymography. The in vitro, stroma-independent variant 5T33MMvt showed no protein expression of MMP-9 in contrast to in vivo growing MM cells, 5T33MMvv. However, when 5T33MMvt cells were injected into naive mice and isolated after tumor take (5T33MMvt-vv), they secreted a significant amount of MMP-9. These results were confirmed by specific staining of cytospins with an anti-MMP-9 antibody. The MMP-9 production by 5T33MMvt-vv cells disappeared when the cells were recultured in vitro. These data demonstrated that upregulation of MMP-9 occurs in vivo and that this process is dependent on the microenvironment. Key words: multiple myeloma; matrix metalloproteinase-9; bone marrow; stromal cell; endothelial cell MMPs are a family of zinc-dependent endopeptidases involved in the degradation of many components of the ECM and the basement membrane. 1,2 Depending on their substrate specificity and structure, members of the MMP family can be divided into subgroups of collagenases (MMP-1, -8, -13), stromelysins (MMP-3, -10, -11, -7), gelatinases (MMP-2, -9), membrane-type MMPs and other MMPs. 2,3 MMPs are secreted as inactive proenzymes and activated extracellularly by proteolytic cleavage. MMP production is regulated at the level of transcription, secretion and/or activation. 3,4 All MMPs are inhibited by specific TIMPs, including TIMP-1, -2, -3 and -4. TIMP-1 and TIMP-2 bind tigthly with, respectively, pro-MMP-9 and pro-MMP-2 to regulate their activity. 5 The balance between MMP and TIMP levels determines the net proteolytic activity. This equilibrium is highly regulated in physiologic conditions, e.g., wound healing and embryogenesis, 3 but is disturbed in pathologic circumstances, e.g., rheumatoid arthritis, multiple sclerosis and cancer. 6 -9 MM is a B-cell cancer mainly characterized by proliferation of malignant plasma cells in the BM, presence of a monoclonal serum immunoglobulin and occurence of osteolytic lesions. The disease occurs at older ages and remains incurable despite progress in treatment. Therefore, new approaches for therapy are necessary. The hypothesis is that MMPs are involved in a number of events underlying MM progression, e.g., transendothelial migration, invasion, osteolytic lesions and angiogenesis. 10 Barillé et al. 11 demonstrated MMP-9 production by human MM cells. MMP-9 is involved in transendothelial migration and invasion. 12,13 This suggests a role of the protease in the homing of MM cells to the BM, which implicates transendothelial migration and invasion of MM cells in the BM. Coculture of malig...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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Upregulation of matrix metalloproteinase‐9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells

Valckenborgh¹,

Bâkkus²,

Munaut

et al. 2002

Intl Journal of Cancer

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“…Most of studies in haematologic neoplasia concerning MMPs are in vitro studies. In multiple myelomas, increased activity of MMPs can cause the excessive bone marrow resorption and result in spreading the myeloma cells (17–19).…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in Hodgkin's and non-Hodgkin's lymphoma

Hazar

Polat

Seyrek

et al. 2004

International Journal of Clinical Practice

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Matrix metalloproteinases (MMPs) are responsible for the degradation of extracellular matrix and have an important role in tumour metastases. We investigated the role of MMP-2 and MMP-9 in Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). The serum samples of patients with HD (n = 12), NHL (n = 30) and healthy control (n = 22) were analysed for MMP-2 and MMP-9. An immunoassay method was used for the determination of MMP-2 and MMP-9 levels. No statistical significance was found between HD and NHL groups for levels of MMP-2. There were no relation between MMP-2, MMP-9 levels and clinical characteristics of patients. The mean MMP-9 levels were found to be 555.6 +/- 140 ng/ml, 446.6 +/- 53.6 ng/ml and 111.2 +/- 10.3 ng/ml in HD, NHL and control groups, respectively. Our results suggest that MMP-9 levels are substantially increased in HD and NHL when compared with controls and may probably be used for distinguishing the benign diseases from malign lymphomas.

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“…Besides its implication in the inflammatory processes, the relationship between glucocorticoid resistance, HDACs regulation and gene expression modulation can also be of importance for tumor cell progression (23). In multiple myeloma, the MMP-9 plays a critical role in tumor invasion (24)(25)(26). However, the impact of new therapeutics…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylases meet microRNA-associated MMP-9 expression regulation in glucocorticoid-sensitive and -resistant cell lines

Hentati-Kallel

Jan

Bernard

et al. 2016

International Journal of Oncology

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Glucocorticoids are largely used in the treatment of inflammatory pathologies and/or hematological malignancies and regulate the expression of a variety of genes involved in inflammation or metastasis such as matrix metalloproteinases (MMP). Long-term exposure to glucocorticoids can result in failure of responsiveness, which is often associated with an unwanted gene expression. Epigenetic mechanisms are involved in gene expression modulated after development of glucocorticoid resistance but how these mechanisms take place must be further studied. The effects of HDAC inhibitors (HDACi) in a context of glucocorticoid resistance are still not well understood and need to be further investigated. We hypothesized that acquired glucocorticoid resistance associated to HDACi could disturbs epigenetic landscape, especially miR expression, leading to a modulation of MMP-9 gene expression and/or protein secretion, described as largely involved in bone remodeling and tumor invasion in multiple myeloma. To this aim, we used sensitive RPMI-8226 cell line and its dexamethasone- and methylprednisolone-resistant derivatives. The resistant cell lines displayed an 'open chromatin' and an MMP-9 overexpression comparatively to the sensitive cell line. HDACi treatment with MS-275 increased even more MMP-9 overexpression not only at an mRNA level but also at the protein level. We showed that MMP-9 expression regulation was not directly linked with HAT/HDAC balance alterations but rather with the deregulation of MMP-9-targeting miRs. Then, we first demonstrated that miR‑149 downregulation was directly involved in the MMP-9 overexpression following a chronic glucocorticoid exposure and that MS-275 could amplify this overexpression by inhibition of miR‑149 expression and miR‑520c overexpression. Taken together, these results indicate that the use of HDACi in a context of acquired glucocorticoid resistance could modify the epigenetic landscape, highlighting the importance of taking the glucocorticoid response status into consideration in treatment with HDACi.

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Metalloproteinases in Multiple Myeloma: Production of Matrix Metalloproteinase-9 (MMP-9), Activation of proMMP-2, and Induction of MMP-1 by Myeloma Cells

Cited by 161 publications

References 36 publications

Upregulation of matrix metalloproteinase‐9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells

Upregulation of matrix metalloproteinase‐9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells

Prognostic value of matrix metalloproteinases (MMP-2 and MMP-9) in Hodgkin's and non-Hodgkin's lymphoma

Histone deacetylases meet microRNA-associated MMP-9 expression regulation in glucocorticoid-sensitive and -resistant cell lines

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