Abstract
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.
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References
Liotta LA, Kohn EC . The microenvironment of the tumour–host interface. Nature 2001; 411: 375–379.
Bhowmick NA, Neilson EG, Moses HL . Stromal fibroblasts in cancer initiation and progression. Nature 2004; 432: 332–337.
Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C . The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004; 117: 1495–1502.
Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 2004; 6: 17–32.
Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 1996; 335: 91–97.
Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349: 2495–2502.
Berenson JR . Myeloma bone disease. Best Pract Res Clin Haematol 2005; 18: 653–672.
Silvestris F, Cafforio P, Tucci M, Grinello D, Dammacco F . Upregulation of osteoblast apoptosis by malignant plasma cells: a role in myeloma bone disease. Br J Haematol 2003; 122: 39–52.
Silvestris F, Cafforio P, Calvani N, Dammacco F . Impaired osteoblastogenesis in myeloma bone disease: role of upregulated apoptosis by cytokines and malignant plasma cells. Br J Haematol 2004; 126: 475–486.
Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483–2494.
Oshima T, Abe M, Asano J, Hara T, Kitazoe K, Sekimoto E et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2. Blood 2005; 106: 3160–3165.
Mahtouk K, Hose D, Reme T, De Vos J, Jourdan M, Moreaux J et al. Expression of EGF-family receptors and amphiregulin in multiple myeloma Amphiregulin is a growth factor for myeloma cells. Oncogene 2005; 24: 3512–3524.
Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC . Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 1993; 82: 3712–3720.
Zhang XG, Bataille R, Widjenes J, Klein B . Interleukin-6 dependence of advanced malignant plasma cell dyscrasias. Cancer 1992; 69: 1373–1376.
Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT et al. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications. Leukemia 2001; 15: 1950–1961.
Michigami T, Shimizu N, Williams PJ, Niewolna M, Dallas SL, Mundy GR 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. Blood 2000; 96: 1953–1960.
Barille-Nion S, Barlogie B, Bataille R, Bergsagel PL, Epstein J, Fenton RG et al. Advances in biology and therapy of multiple myeloma. Hematology 2003, 248–278.
Hayashi T, Hideshima T, Anderson KC . Novel therapies for multiple myeloma. Br J Haematol 2003; 120: 10–17.
Gregoretti MG, Gottardi D, Ghia P, Bergui L, Merico F, Marchsio PC et al. Characterization of bone marrow stromal cells from multiple myeloma. Leuk Res 1994; 18: 675–682.
Caligaris-Cappio F, Bergui L, Gregoretti MG, Gaidano G, Gaboli M, Schena M et al. Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 1991; 77: 2688–2693.
Wallace SR, Oken MM, Lunetta KL, Panoskaltsis-Mortari A, Masellis AM . Abnormalities of bone marrow mesenchymal stem cells in multiple myeloma patients. Cancer 2001; 91: 1219–1230.
Calabro A, Oken MM, Hascall VC, Masellis AM . Characterization of hyaluronan synthetase 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. Blood 2002; 100: 2578–2585.
Vincent T, Jourdan M, Sy MS, Klein B, Mechti N . Hyaluronic acid induces survival and proliferation of human myeloma cells through an interleukin-6-mediated pathway involving the phosphorylation of retinoblastoma protein. J Biol Chem 2001; 276: 14728–14736.
Zhang XG, Gaillard JP, Robillard N, Lu ZY, Gu ZJ, Jourdan M et al. Reproducible obtaining of human myeloma cell lines as a model for tumor stem cell study in human multiple myeloma. Blood 1994; 83: 3654–3663.
Harashima A, Matsuo Y, Nishizaki C, Kozuka T, Fukuda S, Sezaki T et al. Human bone marrow stroma-dependent myeloma sister cell lines MOLP-6 and MOLP-7 derived from a patient with multiple myeloma. Human Cell 2000; 13: 43–54.
Schecroun N, Delloye Ch . In vitro growth and osteoblastic differentiation of human bone marrow stromal cells supported by autologous plasma. Bone 2004; 35: 517–524.
Gregory CA, Gunn WG, Peister A, Prockop DJ . An Alizarin red-based assay of mineralization by adherent cells in culture: comparison with cetylpyridinium chloride extraction. Anal Biochem 2004; 329: 77–84.
Wijdenes J, Clement C, Klein B, Morel-Fourrier B, Vita N, Ferrara P et al. Human recombinant dimeric IL-6 binds to its receptor as detected by anti-IL-6 monoclonal antibodies. Mol Immunol 1991; 28: 1183–1192.
Liu WM, Mei R, Di X, Ryder TB, Hubbell E, Dee S et al. Analysis of high density expression microarrays with signed-rank call algorithms. Bioinformatics 2002; 18: 1593–1599.
Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95: 14863–14868.
Tarte K, Zhan F, De Vos J, Klein B, Shaughnessy Jr J . Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. Blood 2003; 102: 592–600.
Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005; 37: 899–905.
De Vos J, Hose D, Reme T, Tarte K, Moreaux J, Mahtouk K et al. Microarray-based understanding of normal and malignant plasma cells. Immunol Rev 2006; 210: 86–104.
Lacy MQ, Donovan KA, Heimbach JK, Ahmann GJ, Lust JA . Comparison of interleukin-1 beta expression by in situ hybridization in monoclonal gammopathy of undetermined significance and multiple myeloma. Blood 1999; 93: 300–305.
Costes V, Portier M, Lu ZY, Rossi JF, Bataille R, Klein B . Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production. Br J Haematol 1998; 103: 1152–1160.
Gunn WG, Conley A, Deininger L, Olson SD, Prockop DJ, Gregory CA . A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and IL-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells 2005; 24: 986–991.
Giuliani N, Colla S, Rizzoli V . Angiogenic switch in multiple myeloma. Hematology 2004; 9: 377–381.
Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J et al. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 2003; 162: 1521–1528.
Bajou K, Maillard C, Jost M, Lijnen RH, Gils A, Declerck P et al. Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene 2004; 23: 6986–6990.
Maillard C, Jost M, Romer MU, Brunner N, Houard X, Lejeune A et al. Host plasminogen activator inhibitor-1 promotes human skin carcinoma progression in a stage-dependent manner. Neoplasia 2005; 7: 57–66.
Reinisch N, Kirchmair R, Kahler CM, Hogue-Angeletti R, Fischer-Colbrie R, Winkler H et al. Attraction of human monocytes by the neuropeptide secretoneurin. FEBS Lett 1993; 334: 41–44.
Starnes T, Broxmeyer HE, Robertson MJ, Hromas R . Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J Immunol 2002; 169: 642–646.
Jaubert J, Jaubert F, Martin N, Washburn LL, Lee BK, Eicher EM et al. Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proc Natl Acad Sci USA 1999; 96: 10278–10283.
French DM, Kaul RJ, D'Souza AL, Crowley CW, Bao M, Frantz GD et al. WISP-1 is an osteoblastic regulator expressed during skeletal development and fracture repair. Am J Pathol 2004; 165: 855–867.
Grey A, Banovic T, Naot D, Hill B, Callon K, Reid I 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. Endocrinology 2001; 142: 1098–1106.
Grey A, Chen Q, Callon K, Xu X, Reid IR, Cornish J . 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. Endocrinology 2002; 143: 4755–4763.
Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J . Requirement for the LPA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci USA 2000; 97: 13384–13389.
Böttner M, Suter-Crazzolara C, Schober A, Unsicker K . Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF15/MIC-1) in adult rat tissues. Cell Tissue Res 1999; 297: 103–110.
Moore AG, Brown DA, Fairlie WD, Bauskin AR, Brown PK, Munier ML et al. The transforming growth factor-β superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab 2000; 85: 4781–4788.
Koopmann J, Buckhaults P, Brown DA, Zahurak ML, Sato N, Fukushima N et al. Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers. Clin Cancer Res 2004; 10: 2386–2392.
Brown DA, Ward RL, Buckhaults P, Liu T, Romans KE, Hawkins NJ et al. MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma. Clin Cancer Res 2003; 9: 2642–2650.
Basil CF, Zhao Y, Zavaglia K, Jin P, Panelli MC, Voiculescu S et al. Common cancer biomarkers. Cancer Res 2006; 66: 2953–2961.
Subramaniam S, Strelau J, Unsicker K . Growth differentiation factor-15 prevents low potassium-induced cell death of cerebellar granule neurons by differential regulation of Akt and ERK pathways. J Biol Chem 2003; 278: 8904–8912.
Liu T, Bauskin AR, Zaunders J, Brown DA, Pankhurst S, Russell PJ et al. Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells. Cancer Res 2003; 63: 5034–5040.
Acknowledgements
Author contributions: CJ and MK performed the experiments and participated in the writing of the paper. AM participated in the design of the research and the writing of the paper. GM contributed to new analytical tools and gave technical assistance with the experiments. HA collected bone marrow samples and clinical data. FS gave technical assistance with the experiments. DC and LP collected bone marrow samples and clinical data. KB participated in the design of the research and the writing of the paper. RT performed the bioinformatic studies and participated in the writing of the paper. BP participated in the design of the research and wrote the paper. Financial support: This study was supported by a grant from the region Midi-Pyrénées (Programme Multidisciplinaire De Thérapie Génique Et Cellulaire En Midi-Pyrénées), by EFS-PM and by the Ligue Nationale Contre Le Cancer (B Klein, équipe Labellisée).
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This work was done at: EFS-PM and INSERM U475
Supplementary information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
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Corre, J., Mahtouk, K., Attal, M. et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia 21, 1079–1088 (2007). https://doi.org/10.1038/sj.leu.2404621
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DOI: https://doi.org/10.1038/sj.leu.2404621
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