The role of the bone marrow microenvironment in multiple myeloma.

Department of Pathology, University of Antwerp (UA), Belgium.
Histology and histopathology (Impact Factor: 2.24). 11/2005; 20(4):1227-50.
Source: PubMed

ABSTRACT 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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    ABSTRACT: Patients with myeloma develop localized and generalized bone loss leading to hypercalcaemia, accelerated osteoporosis, vertebral wedge fractures, other pathological fractures, spinal cord compression and bone pain. Bone loss is mediated by a variety of biological modifiers including osteoclast-activating factors (OAF) and osteoblast (OB) inhibitory factors produced either directly by malignant plasma cells (MPCs) or as a consequence of their interaction with the bone marrow microenvironment (BMM). Raised levels of OAFs such as receptor activator of nuclear factor-kappa B ligand (RANKL), macrophage inflammatory protein 1 alpha, tumour necrosis factor-alpha and interleukin 6 stimulate bone resorption by recruiting additional osteoclasts. Via opposing mechanisms, increases in OB inhibitory factors, such as dickkopf-1 (Dkk-1), soluble frizzled-related protein-3 and hepatocyte growth factor (HGF), suppress bone formation by inhibiting the differentiation and recruitment of OBs. These changes result in an uncoupling of physiological bone remodelling, leading to myeloma bone disease (MBD). Moreover, the altered BMM provides a fertile ground for the growth and survival of MPCs. Current clinical management of MBD is both reactive (to pain and fractures) and preventive, with bisphosphonates (BPs) being the mainstay of pharmacological treatment. However, side effects and uncertainties associated with BPs warrant the search for more targeted treatments for MBD. This review will summarize recent developments in understanding the intimate relationship between MBD and the BMM and the novel ways in which they are being therapeutically targeted.
    British Medical Bulletin 09/2014; 111(1):117-38. DOI:10.1093/bmb/ldu016 · 3.95 Impact Factor
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    ABSTRACT: Multiple myeloma (MM) is a hematologic malignancy of monoclonal plasma cells which remains incurable despite recent advances in therapies. The presence of cancer stem cells (CSCs) has been demonstrated in many solid and hematologic tumors, so the idea of CSCs has been proposed for MM, even if MM CSCs have not been define yet. The existence of myeloma CSCs with clonotypic B and clonotypic non B cells was postulated by many groups. This review aims to focus on these distinct clonotypic subpopulations and on their ability to develop and sustain MM. The bone marrow microenvironment provides to MM CSCs self-renewal, survival and drug resistance thanks to the presence of normal and cancer stem cell niches. The niches and CSCs interact each other through adhesion molecules and the interplay between ligands and receptors activates stemness signaling (Hedgehog, Wnt and Notch pathways). MM CSCs are also supposed to be responsible for drug resistance that happens in three steps from the initial cancer cell homing microenvironment-mediated to development of microenvironment-independent drug resistance. In this review, we will underline all these aspects of MM CSCs.
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    ABSTRACT: 160 J Jo ou ur rn na al l o of f C Ca an nc ce er r 2015; 6(2): 160-168. doi: 10.7150/jca.10873 © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License ( licenses/by-nc-nd/3.0/). Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Abstract The bone marrow microenvironment plays a key role in the stimulation of growth and survival of multiple myeloma (MM) cells. We investigated whether membrane microfragments (MFBs) exert a stimulatory effect on mesenchymal stem cell (MSC) gene expression or differentiation. MSCs from patients with multiple myeloma (MMBM-MSCs) proliferated at a slower rate than MSCs from healthy volunteers (BM-MSCs), and fewer MMBM-MSCs adhered to the substrate as compared to BM-MSCs. Phenotypic analysis revealed that MMBM-MSCs and BM-MSCs differed significantly in terms of their CD166 and CXCR4 expressions. In conclusion, our comparative analysis of mes-enchymal cells from MM patients and healthy volunteers revealed differences in the genetic and phenotypic profiles of these two populations, their potential for osteodifferentiation, and ex-pression of surface antigens. Moreover, we showed that membrane MFBs may alter the genetic profile of MSCs, leading to disorders of their osteodifferentiation, and interact with the WNT pathway via presentation of the DKK-1 protein.
    01/2015; 6(2). DOI:10.7150/jca.10873

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