The role of the bone marrow microenvironment in multiple myeloma

Department of Pathology, University of Antwerp (UA), Belgium.
Histology and histopathology (Impact Factor: 2.1). 11/2005; 20(4):1227-50.
Source: PubMed


Multiple myeloma (MM) is a malignant disease that results from an excess of monotypic plasma cells in the bone marrow (BM). This malignancy is characterised by complex karyotypic aberrancies. In 60% of all MM there are recurrent primary translocations involving the heavy chain gene locus. The MM cells strongly interact with the BM microenvironment, which is composed of endothelial cells, stromal cells, osteoclasts, osteoblasts, immune cells, fat cells and the extracellular matrix. This interaction is responsible for the specific homing in the BM, the proliferation and survival of the MM cells, the resistance of MM cells to chemotherapy, the development of osteolysis, immunodeficiency and anaemia. New therapeutic agents target both the MM, as well as the interaction MM cell - BM microenviroment.

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    • "Addition of RANKL has been shown to induce OC differentiation and bone resorption activity in vitro[30,31]. BMSCs, osteoblasts and activated T cells express and release RANKL to the bone marrow microenvironment [32,33]. Moreover, MM cells stimulate BMSC production and release of RANKL and other cytokines, such as MIP-1α, VEGF, TNFα, MCP-1, stromal cell-derived factor-1, IL-3, and IL-7, into the bone marrow microenvironment, and in turn these cytokines enhance OC differentiation and activity in a RANKL-dependent or -independent manner[34-36]. "
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    ABSTRACT: Multiple myeloma (MM) cells are responsible for aberrant osteoclast (OC) activation. However, when cocultured monocytes, but not OC precursors, with MM cells, we made a novel observation that MM cells inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced increase of OC differentiation, OC gene expression, signaling pathways and bone resorption activity. Our results showed that MM cells produced multiple inhibitory cytokines of osteoclastogenesis, such as IL-10, which activated STAT3 signaling and induce OC inhibition. However, cocultures of bone marrow stromal cells (BMSCs) reversed MM-induced OC inhibition. We found that MM cells increased production of MCP-1 from BMSCs and BMSC-derived MCP-1 enhanced OC formation. Mechanistic studies showed that IL-10 downregulated RANK expression in monocytes and thus, inhibited RANKL-induced OC formation. In contrast, MCP-1 upregulated RANK expression and thus, enhanced OC formation. Overall, our studies for the first time demonstrated that MM cell have inhibitory effects on osteoclastogenesis by producing inhibitory cytokines. Our results further indicate that activation of osteoclastogenesis in bone marrow requests the crosstalk of MM cells, BMSCs and their produced cytokines. Thus, our studies provide evidences that targeting bone marrow microenvironmental cells and/or cytokines may be a new approach to treating MM bone destruction.
    PLoS ONE 12/2013; 8(12):e82453. DOI:10.1371/journal.pone.0082453 · 3.23 Impact Factor
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    • "The “MM niche” is composed of osteoblasts, osteoclasts, vascular endothelial cells, stromal cells, adipocytes, and extracellular matrix (ECM) proteins [2]. MM cells are thought to be maintained by these various stromal cells [3], which regulate their survival, proliferation and apoptosis. However, the cellular and anatomical features of stromal cells have not been thoroughly examined in the MM. "
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    ABSTRACT: The interaction with bone marrow (BM) plays a crucial role in pathophysiological features of multiple myeloma (MM), including cell proliferation, chemoresistance, and bone lesion progression. To characterize the MM-BM interactions, we utilized an in vivo experimental model for human MM in which a GFP-expressing human MM cell line is transplanted into NOG mice (the NOG-hMM model). Transplanted MM cells preferentially engrafted at the metaphyseal region of the BM endosteum and formed a complex with osteoblasts and osteoclasts. A subpopulation of MM cells expressed VE-cadherin after transplantation and formed endothelial-like structures in the BM. CD138(+) myeloma cells in the BM were reduced by p53-dependent apoptosis following administration of the nitrogen mustard derivative bendamustine to mice in the NOG-hMM model. Bendamustine maintained the osteoblast lining on the bone surface and protected extracellular matrix structures. Furthermore, bendamustine suppressed the growth of osteoclasts and mesenchymal cells in the NOG-hMM model. Since VE-cadherin(+) MM cells were chemoresistant, hypoxic, and HIF-2α-positive compared to the VE-cadherin(-) population, VE-cadherin induction might depend on the oxygenation status. The NOG-hMM model described here is a useful system to analyze the dynamics of MM pathophysiology, interactions of MM cells with other cellular compartments, and the utility of novel anti-MM therapies.
    PLoS ONE 02/2012; 7(2):e30557. DOI:10.1371/journal.pone.0030557 · 3.23 Impact Factor
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    • "Multiple myeloma disease progression has been recognised as the result of different acquired changes in plasma-cell behaviour (self-sufficiency in growth signals, evasion of apoptosis and acquisition of invasive and spreading capacities) combined with an evolving crosstalk between myeloma cells and different cell types within the BM microenvironment (Hanahan and Weinberg, 2000; Mueller and Fusenig, 2004; Sirohi and Powles, 2004). Myeloma cells activate fibroblasts to secrete different growth factors, endothelial cells to initiate an angiogenic response, they stimulate immune and inflammatory cells and finally disrupt the balance between osteoblasts and osteoclasts, which results in osteolysis (Roodman, 2002; De Raeve and Vanderkerken, 2005). "
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    ABSTRACT: Aplidin is an antitumour drug, currently undergoing phase II evaluation in different haematological and solid tumours. In this study, we analysed the antimyeloma effects of Aplidin in the syngeneic 5T33MM model, which is representable for the human disease. In vitro, Aplidin inhibited 5T33MMvv DNA synthesis with an IC(50) of 3.87 nM. On cell-cycle progression, the drug induced an arrest in transition from G0/G1 to S phase, while Western blot showed a decreased cyclin D1 and CDK4 expression. Furthermore, Aplidin induced apoptosis by lowering the mitochondrial membrane potential, by inducing cytochrome c release and by activating caspase-9 and caspase-3. For the in vivo experiment, 5T33MM-injected C57Bl/KaLwRij mice were intraperitoneally treated with vehicle or Aplidin (90 microg kg(-1) daily). Chronic treatment with Aplidin was well tolerated and reduced serum paraprotein concentration by 42% (P<0.001), while BM invasion with myeloma cells was decreased by 35% (P<0.001). Aplidin also reduced the myeloma-associated angiogenesis to basal values. This antiangiogenic effect was confirmed in vitro and explained by inhibition of endothelial cell proliferation and vessel formation. These data indicate that Aplidin is well tolerated in vivo and its antitumour and antiangiogenic effects support the use of the drug in multiple myeloma.
    British Journal of Cancer 06/2008; 98(12):1966-74. DOI:10.1038/sj.bjc.6604388 · 4.84 Impact Factor
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