Matrix metalloproteinases-1 and -2, and tissue inhibitor of metalloproteinase-2 production is abnormal in bone marrow stromal cells of multiple myeloma patients

Zdzisińska, Barbara; Walter‐Croneck, Adam; Kandefer‐Szerszeń, Martyna

doi:10.1016/j.leukres.2008.04.001

Cited by 29 publications

(36 citation statements)

References 29 publications

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“…The differentially upregulated genes in List I were functionally linked to: i) a chemokine/cytokine response, since these molecules have effectively been implicated in several aspects of MM biology (myeloma cell proliferation and survival, homing and/or drug resistance, angiogenesis, OC precursor recruitment and bone destruction) [1, 2, 28]; ii) an immune and inflammatory response, which could be related to the reported diminished immunomodulatory potential of pMSCs [18]; iii) angiogenesis (e. g. ANGPTL4, FGF2 ) [13, 31]; iv) microenvironment cross-talk, including cell-matrix adhesion (e. g. COL12A1 , ITGB1 ) or integrin-mediated and extracellular matrix remodelation (e. g. ITGA2, ITGAM , VCAM1, MMP1 , MMP3 , MMP9 , MMP12 ) [3, 45, 46]; and v) bone biology and skeletal development [(e. g. SPP1 (osteopontin) [47]]. Manual curation based on the literature, further revealed functions of these deregulated genes related to myeloma growth and drug resistance (e. g. IL6 , CCL3 , HGF , FN1 ) [3, 20, 48], OC formation and/or activation (e. g. CCL3 , CCL20, LIF ) [26, 48, 49] and inhibition of OB differentiation and function (e. g. CCL3 , EREG ) [50, 51].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

et al. 2014

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Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

et al. 2014

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“…Based on evidence that MMP-2 is expressed in the bone marrow of myeloma patients and known roles for MMP-2 in the progression of skeletal malignancies [11, 12, 14, 16, 19], we hypothesized that inhibiting MMP-2 in myeloma would be an effective therapeutic strategy to prevent disease progression. To address this, we created highly specific “bone-seeking” MMP-2 inhibitors (BMMPIs) to target the multiple myeloma-bone microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

et al. 2017

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Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow of myeloma patients. These data provide rationale for selectively inhibiting MMP-2 activity as a multiple myeloma treatment strategy. Given that MMP-2 is systemically expressed, we used novel “bone-seeking” bisphosphonate based MMP-2 specific inhibitors (BMMPIs) to target the skeletal tissue thereby circumventing potential off-target effects of MMP-2 inhibition outside the bone marrow-tumor microenvironment. Using in vivo models of multiple myeloma (5TGM1, U266), we examined the impact of MMP-2 inhibition on disease progression using BMMPIs. Our data demonstrate that BMMPIs can decrease multiple myeloma burden and protect against cancer-induced osteolysis. Additionally, we have shown that MMP-2 can be specifically inhibited in the multiple myeloma-bone microenvironment, underscoring the feasibility of developing targeted and tissue selective MMP inhibitors. Given the well-tolerated nature of bisphosphonates in humans, we anticipate that BMMPIs could be rapidly translated to the clinical setting for the treatment of multiple myeloma.

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“…The latter is a transmembrane proteoglycan strongly expressed by terminally differentiated plasma cells and MM cells that mediates adherence to ECM via binding of type I collagen. The CD138-type I collagen interaction triggers expression of matrix metalloproteinase 1 (MMP-1) which has been shown to be crucial for ECM reabsorption and tumor invasion [52, 59, 60]. …”

Section: The Bone Marrow Microenvironment: a Survival Niche For MMmentioning

confidence: 99%

Cell Trafficking in Multiple Myeloma

Bianchi¹,

Kumar²,

Ghobrial³

et al. 2012

Open J. Hematol.

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Multiple myeloma (MM) is an incurable cancer of terminally differentiated plasma cells (PC) and represents the second most frequent hematologic malignancy in the western world. MM cells localize preferentially to the bone marrow where they interact closely with bone marrow stroma cells (BMSC) and extracellular matrix (ECM) proteins in a reciprocal pro-survival loop. Such a bone marrow niche guarantees a survival advantage for MM cells and has a crucial role in mediating drug resistance to chemotherapy agents. As the name suggests, hallmark characteristic of MM is the ability to localize in multiple, distant bone sites causing disruption of the normal bone architecture and impairment of normal hematopoiesis. The pathogenic mechanisms of MM rely then not only on proliferation of cancerous cells, but also on the ability of myeloma cells to traffic between sites and home to appropriate survival niches. Identifying the mechanisms that regulate the homing of MM cells to the bone marrow, the MM-BMSC interaction and the trafficking of MM cells from the bloodstream to distant bone locations is therefore crucial to design new, more effective therapies capable of overcoming the maladaptive interaction between BMSCs and MM and help in finding a cure for MM.

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Matrix metalloproteinases-1 and -2, and tissue inhibitor of metalloproteinase-2 production is abnormal in bone marrow stromal cells of multiple myeloma patients

Cited by 29 publications

References 29 publications

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Cell Trafficking in Multiple Myeloma

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