Bone marrow mesenchymal stem cells are abnormal in multiple myeloma

Recent literature suggested that cells of the microenvironment of tumors could be abnormal as well. To address this hypothesis in multiple myeloma (MM), we studied bone marrow mesenchymal stem cells (BMMSCs), the only long-lived cells of the bone marrow microenvironment, by gene expression profiling and phenotypic and functional studies in three groups of individuals: patients with MM, patients with monoclonal gamopathy of undefined significance (MGUS) and healthy age-matched subjects. Gene expression profile independently classified the BMMSCs of these individuals in a normal and in an MM group. MGUS BMMSCs were interspersed between these two groups. Among the 145 distinct genes differentially expressed in MM and normal BMMSCs, 46% may account for a tumor-microenvironment cross-talk. Known soluble factors implicated in MM pathophysiologic features (i.e. IL (interleukin)-6, DKK1) were revealed and new ones were found which are involved in angiogenesis, osteogenic differentiation or tumor growth. In particular, GDF15 was found to induce dose-dependent growth of MOLP-6, a stromal cell-dependent myeloma cell line. Functionally, MM BMMSCs induced an overgrowth of MOLP-6, and their capacity to differentiate into an osteoblastic lineage was impaired. Thus, MM BMMSCs are abnormal and could create a very efficient niche to support the survival and proliferation of the myeloma cells.

[1]  Elise C. Kohn,et al.  The microenvironment of the tumour–host interface , 2001, Nature.

[2]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Wei-Min Liu,et al.  Analysis of high density expression microarrays with signed-rank call algorithms , 2002, Bioinform..

[4]  R. Bataille,et al.  Single versus double autologous stem-cell transplantation for multiple myeloma. , 2003, The New England journal of medicine.

[5]  Yingdong Zhao,et al.  Common cancer biomarkers. , 2006, Cancer research.

[6]  J. Kench,et al.  The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. , 2005, Cancer research.

[7]  K. Kinzler,et al.  MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  F. Dammacco,et al.  Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease , 2003, British journal of haematology.

[9]  G. Ahmann,et al.  Comparison of interleukin-1 beta expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. , 1999, Blood.

[10]  Jun Yao,et al.  Distinct epigenetic changes in the stromal cells of breast cancers , 2005, Nature Genetics.

[11]  大島 隆志.  Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2 , 2005 .

[12]  K. Tarte,et al.  Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. , 2003, Blood.

[13]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[14]  I. Reid,et al.  The phospholipids sphingosine-1-phosphate and lysophosphatidic acid prevent apoptosis in osteoblastic cells via a signaling pathway involving G(i) proteins and phosphatidylinositol-3 kinase. , 2002, Endocrinology.

[15]  H. Moses,et al.  Stromal fibroblasts in cancer initiation and progression , 2004, Nature.

[16]  D. Prockop,et al.  A Crosstalk Between Myeloma Cells and Marrow Stromal Cells Stimulates Production of DKK1 and Interleukin‐6: A Potential Role in the Development of Lytic Bone Disease and Tumor Progression in Multiple Myeloma , 2006, Stem cells.

[17]  F. Dammacco,et al.  Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignant plasma cells , 2004, British journal of haematology.

[18]  D. Prockop,et al.  An Alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction. , 2004, Analytical biochemistry.

[19]  K. Lunetta,et al.  Abnormalities of bone marrow mesenchymal cells in multiple myeloma patients , 2001, Cancer.

[20]  P. Carmeliet,et al.  Host plasminogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner. , 2005, Neoplasia.

[21]  B. Klein,et al.  Human recombinant dimeric IL-6 binds to its receptor as detected by anti-IL-6 monoclonal antibodies. , 1991, Molecular immunology.

[22]  P. Carmeliet,et al.  Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth , 2004, Oncogene.

[23]  R. Hromas,et al.  Cutting Edge: IL-17D, a Novel Member of the IL-17 Family, Stimulates Cytokine Production and Inhibits Hemopoiesis1 , 2002, The Journal of Immunology.

[24]  Ana M Soto,et al.  The stroma as a crucial target in rat mammary gland carcinogenesis , 2004, Journal of Cell Science.

[25]  M. Jourdan,et al.  Hyaluronic Acid Induces Survival and Proliferation of Human Myeloma Cells through an Interleukin-6-mediated Pathway Involving the Phosphorylation of Retinoblastoma Protein* , 2001, The Journal of Biological Chemistry.

[26]  K. Unsicker,et al.  Expression of a novel member of the TGF-β superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues , 1999, Cell and Tissue Research.

[27]  J. Rossi,et al.  Interleukin‐1 in multiple myeloma: producer cells and their role in the control of IL‐6 production , 1998, British journal of haematology.

[28]  S. Colla,et al.  Angiogenic Switch in Multiple Myeloma , 2004, Hematology.

[29]  P. Marchisio,et al.  Characterization of bone marrow stromal cells from multiple myeloma. , 1994, Leukemia research.

[30]  K. Unsicker,et al.  Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways* , 2003, The Journal of Biological Chemistry.

[31]  B. Klein,et al.  Insulin-like growth factor induces the survival and proliferation of myeloma cells through an interleukin-6-independent transduction pathway. , 2000 .

[32]  J. Rossi,et al.  A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. , 1996, The New England journal of medicine.

[33]  Paul J. Williams,et al.  Cell–cell contact between marrow stromal cells and myeloma cells via VCAM-1 and α4β1-integrin enhances production of osteoclast-stimulating activity , 2000 .

[34]  J. Zaunders,et al.  Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells. , 2003, Cancer research.

[35]  J. D. Vos,et al.  Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells , 2005, Oncogene.

[36]  J. Weiner,et al.  Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[37]  K. Kinzler,et al.  Serum Macrophage Inhibitory Cytokine 1 as a Marker of Pancreatic and Other Periampullary Cancers , 2004, Clinical Cancer Research.

[38]  G. Frantz,et al.  WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. , 2004, The American journal of pathology.

[39]  A. Zannettino,et al.  Elevated Serum Levels of Stromal-Derived Factor-1α Are Associated with Increased Osteoclast Activity and Osteolytic Bone Disease in Multiple Myeloma Patients , 2005 .

[40]  R. Kirchmair,et al.  Attraction of human monocytes by the neuropeptide secretoneurin , 1993, FEBS letters.

[41]  K. Anderson,et al.  Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. , 1993, Blood.

[42]  I. Reid,et al.  Lysophosphatidic acid is an osteoblast mitogen whose proliferative actions involve G(i) proteins and protein kinase C, but not P42/44 mitogen-activated protein kinases. , 2001, Endocrinology.

[43]  T. Yoneda,et al.  Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4)beta(1)-integrin enhances production of osteoclast-stimulating activity. , 2000, Blood.

[44]  T. Hideshima,et al.  Novel therapies for multiple myeloma , 2003, British journal of haematology.

[45]  J. Jaubert,et al.  Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[46]  M. Oken,et al.  Characterization of hyaluronan synthase expression and hyaluronan synthesis in bone marrow mesenchymal progenitor cells: predominant expression of HAS1 mRNA and up-regulated hyaluronan synthesis in bone marrow cells derived from multiple myeloma patients. , 2002, Blood.

[47]  B. Naume,et al.  Lack of IL‐1 secretion from human myeloma cells highly purified by immunomagnetic separation , 1993, British journal of haematology.

[48]  G. Gaidano,et al.  'Role of bone marrow stromal cells in the growth of human multiple myeloma. , 1991, Blood.

[49]  P. Richardson,et al.  Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications , 2001, Leukemia.

[50]  Myeloma bone disease. , 2005, Best practice & research. Clinical haematology.

[51]  Pierre Corvol,et al.  Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. , 2003, The American journal of pathology.

[52]  G. Ahmann,et al.  Comparison of interleukin-1 beta expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. , 1999, Blood.

[53]  I. Reid,et al.  Lysophosphatidic Acid Is an Osteoblast Mitogen Whose Proliferative Actions Involve Gi Proteins and Protein Kinase C, But Not P42/44 Mitogen-Activated Protein Kinases. , 2001, Endocrinology.

[54]  The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. , 2000 .

[55]  C. Delloye,et al.  In vitro growth and osteoblastic differentiation of human bone marrow stromal cells supported by autologous plasma. , 2004, Bone.

[56]  F. Zhan,et al.  The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. , 2003, The New England journal of medicine.

[57]  J. Rossi,et al.  A Prospective, Randomized Trial of Autologous Bone Marrow Transplantation and Chemotherapy in Multiple Myeloma , 1996 .

[58]  K. Tarte,et al.  Microarray‐based understanding of normal and malignant plasma cells , 2006, Immunological reviews.

[59]  Advances in Biology and Therapy of Multiple Myeloma , 2003 .

[60]  B. Klein,et al.  Interleukin‐6 dependence of advanced malignant plasma cell dyscrasias , 1992, Cancer.

[61]  D. Prockop,et al.  The Wnt Signaling Inhibitor Dickkopf-1 Is Required for Reentry into the Cell Cycle of Human Adult Stem Cells from Bone Marrow* , 2003, Journal of Biological Chemistry.

[62]  B. Klein,et al.  Interleukin-6 in human multiple myeloma. , 1995, Blood.