Skip to main content

Advertisement

SpringerLink
Log in

Targeting the interplay between myeloma cells and the bone marrow microenvironment in myeloma

  • Progress in Hematology
  • Understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Cellular interplay in the bone marrow (BM) microenvironment in multiple myeloma (MM) mediates MM growth and the formation of bone-destructive lesions. MM cells show enhanced osteoclastogenesis, and stimulate angiogenesis in concert with BM stromal cells and osteoclasts, whereas they suppress osteoblastic differentiation, leading to devastating bone destruction and the rapid loss of bone. Importantly, osteoclasts, vascular endothelial cells, and BM stromal cells with defective osteoblastic differentiation create a cellular microenvironment suitable for MM growth and survival and confer a drug resistance to MM cells, which can be construed as the “MM niche”. Therefore, the MM niche must be targeted and disrupted to improve the efficacy of anti-tumor treatment and prevent the progression of bone disease in MM. Clarifying molecular mechanisms leading to the formation of the MM niche along with bone disease will help in the development of novel approaches targeting the interplay between MM cells and the BM microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Abildgaard N, Brixen K, Kristensen JE, Eriksen EF, Nielsen JL, Heickendorff L. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pre-treatment levels of S-ICTP and U-Ntx are predictive for early progression of the bone disease during standard chemotherapy. Br J Haematol. 2003;120:235–42.

    Article  CAS  PubMed  Google Scholar 

  2. Fonseca R, Trendle MC, Leong T, Kyle RA, Oken MM, Kay NE, et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients. Br J Haematol. 2000;109:24–9.

    Article  CAS  PubMed  Google Scholar 

  3. Terpos E, Szydlo R, Apperley JF, Hatjiharissi E, Politou M, Meletis J, et al. Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index. Blood. 2003;102:1064–9.

    Article  CAS  PubMed  Google Scholar 

  4. Miyamoto A, Kunisada T, Hemmi H, Yamane T, Yasuda H, Miyake K, et al. Establishment and characterization of an immortal macrophage-like cell line inducible to differentiate to osteoclasts. Biochem Biophys Res Commun. 1998;242:703–9.

    Article  CAS  PubMed  Google Scholar 

  5. Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K, et al. RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1998;253:395–400.

    Article  CAS  PubMed  Google Scholar 

  6. Hsu H, Lacey DL, Dunstan CR, Solovyev I, Colombero A, Timms E, et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci USA. 1999;96:3540–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA. 2000;97:1566–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006;12:17–25.

    Article  CAS  PubMed  Google Scholar 

  9. Pearse RN, Sordillo EM, Yaccoby S, Wong BR, Liau DF, Colman N, et al. Multiple myeloma disrupts the TRANCE/osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression. Proc Natl Acad Sci USA. 2001;98:11581–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Giuliani N, Rizzoli V, Roodman GD. Multiple myeloma bone disease: pathophysiology of osteoblast inhibition. Blood. 2006;108:3992–6.

    Article  CAS  PubMed  Google Scholar 

  11. Sezer O, Heider U, Zavrski I, Kuhne CA, Hofbauer LC. RANK ligand and osteoprotegerin in myeloma bone disease. Blood. 2003;101:2094–8.

    Article  CAS  PubMed  Google Scholar 

  12. Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009;23:435–41.

    Article  CAS  PubMed  Google Scholar 

  13. Choi SJ, Cruz JC, Craig F, Chung H, Devlin RD, Roodman GD, et al. Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood. 2000;96:671–5.

    CAS  PubMed  Google Scholar 

  14. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD. Macrophage inflammatory protein-1 alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappa B ligand. Blood. 2001;97:3349–53.

    Article  CAS  PubMed  Google Scholar 

  15. Abe M, Hiura K, Wilde J, Moriyama K, Hashimoto T, Ozaki S, et al. Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma. Blood. 2002;100:2195–202.

    CAS  PubMed  Google Scholar 

  16. Hashimoto T, Abe M, Oshima T, Shibata H, Ozaki S, Inoue D, et al. Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma. Br J Haematol. 2004;125:38–41.

    Article  CAS  PubMed  Google Scholar 

  17. Kim MS, Magno CL, Day CJ, Morrison NA. Induction of chemokines and chemokine receptors CCR2b and CCR4 in authentic human osteoclasts differentiated with RANKL and osteoclast like cells differentiated by MCP-1 and RANTES. J Cell Biochem. 2006;97:512–8.

    Article  CAS  PubMed  Google Scholar 

  18. Drew M, Barker HF, Ball J, Pearson C, Cook G, Franklin I. Very late antigen (VLA) expression by normal and neoplastic human plasma cells; including an assessment of antibodies submitted to the Vth International Workshop on Leucocyte Differentiation Antigens using human myeloma cell lines. Leuk Res. 1996;20:619–24.

    Article  CAS  PubMed  Google Scholar 

  19. Sanz-Rodriguez F, Ruiz-Velasco N, Pascual-Salcedo D, Teixido J. Characterization of VLA-4-dependent myeloma cell adhesion to fibronectin and VCAM-1. Br J Haematol. 1999;107:825–34.

    Article  CAS  PubMed  Google Scholar 

  20. 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;96:1953–60.

    CAS  PubMed  Google Scholar 

  21. Mori Y, Shimizu N, Dallas M, Niewolna M, Story B, Williams PJ, et al. Anti-alpha4 integrin antibody suppresses the development of multiple myeloma and associated osteoclastic osteolysis. Blood. 2004;104:2149–54.

    Article  CAS  PubMed  Google Scholar 

  22. Abe M, Hiura K, Ozaki S, Kido S, Matsumoto T. Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA-4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production. J Bone Miner Metab. 2009;27:16–23.

    Article  CAS  PubMed  Google Scholar 

  23. Giuliani N, Bataille R, Mancini C, Lazzaretti M, Barille S. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Blood. 2001;98:3527–33.

    Article  CAS  PubMed  Google Scholar 

  24. Zannettino AC, Farrugia AN, Kortesidis A, Manavis J, To LB, Martin SK, et al. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res. 2005;65:1700–9.

    Article  CAS  PubMed  Google Scholar 

  25. Hjertner O, Torgersen ML, Seidel C, Hjorth-Hansen H, Waage A, Borset M, et al. Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease. Blood. 1999;94:3883–8.

    CAS  PubMed  Google Scholar 

  26. Lee JW, Chung HY, Ehrlich LA, Jelinek DF, Callander NS, Roodman GD, et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood. 2004;103:2308–15.

    Article  CAS  PubMed  Google Scholar 

  27. Kukreja A, Radfar S, Sun BH, Insogna K, Dhodapkar MV. Dominant role of CD47-thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease. Blood. 2009;114:3413–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Giuliani N, Colla S, Sala R, Moroni M, Lazzaretti M, La Monica S, et al. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Blood. 2002;100:4615–21.

    Article  CAS  PubMed  Google Scholar 

  29. Dhodapkar KM, Barbuto S, Matthews P, Kukreja A, Mazumder A, Vesole D, et al. Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17–1 cells) enriched in the bone marrow of patients with myeloma. Blood. 2008;112:2878–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Noonan K, Marchionni L, Anderson J, Pardoll D, Roodman GD, Borrello I A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma. Blood. 2010;116:3554–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43.

    Article  CAS  PubMed  Google Scholar 

  32. Moon RT, Brown JD, Torres M. WNTs modulate cell fate and behavior during vertebrate development. Trends Genet. 1997;13:157–62.

    Article  CAS  PubMed  Google Scholar 

  33. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.

    Article  CAS  PubMed  Google Scholar 

  34. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286–305.

    Article  CAS  PubMed  Google Scholar 

  35. Miller JR, Hocking AM, Brown JD, Moon RT. Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene. 1999;18:7860–72.

    Article  CAS  PubMed  Google Scholar 

  36. 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;349:2483–94.

    Article  CAS  PubMed  Google Scholar 

  37. 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 interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells. 2006;24:986–91.

    Article  CAS  PubMed  Google Scholar 

  38. Oyajobi BO, Garrett IR, Gupta A, Flores A, Esparza J, Munoz S, et al. Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease. Br J Haematol. 2007;139:434–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Haaber J, Abildgaard N, Knudsen LM, Dahl IM, Lodahl M, Thomassen M, et al. Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis. Br J Haematol. 2008;140:25–35.

    CAS  PubMed  Google Scholar 

  40. Kaiser M, Mieth M, Liebisch P, Oberlander R, Rademacher J, Jakob C, et al. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma. Eur J Haematol. 2008;80:490–4.

    Article  CAS  PubMed  Google Scholar 

  41. Qiang YW, Chen Y, Stephens O, Brown N, Chen B, Epstein J, et al. Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood. 2008;112:196–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dun X, Jiang H, Zou J, Shi J, Zhou L, Zhu R, et al. Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma. Mol Cancer. 2010;9:247.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. 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;106:3160–5.

    Article  CAS  PubMed  Google Scholar 

  44. Feliers D, Woodruff K, Abboud S. Potential role of insulin-like growth factor binding protein-4 in the uncoupling of bone turnover in multiple myeloma. Br J Haematol. 1999;104:715–22.

    Article  CAS  PubMed  Google Scholar 

  45. Li B, Shi M, Li J, Zhang H, Chen B, Chen L, et al. Elevated tumor necrosis factor-alpha suppresses TAZ expression and impairs osteogenic potential of Flk-1+ mesenchymal stem cells in patients with multiple myeloma. Stem Cells Dev. 2007;16:921–30.

    Article  CAS  PubMed  Google Scholar 

  46. Ehrlich LA, Chung HY, Ghobrial I, Choi SJ, Morandi F, Colla S, et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma. Blood. 2005;106:1407–14.

    Article  CAS  PubMed  Google Scholar 

  47. Giuliani N, Colla S, Morandi F, Lazzaretti M, Sala R, Bonomini S, et al. Myeloma cells block RUNX2/CBFA1 activity in human bone marrow osteoblast progenitors and inhibit osteoblast formation and differentiation. Blood. 2005;106:2472–83.

    Article  CAS  PubMed  Google Scholar 

  48. Standal T, Abildgaard N, Fagerli UM, Stordal B, Hjertner O, Borset M, et al. HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood. 2007;109:3024–30.

    CAS  PubMed  Google Scholar 

  49. Takeuchi K, Abe M, Hiasa M, Oda A, Amou H, Kido S, et al. TGF-beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS One. 2010;5:e9870.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Vallet S, Mukherjee S, Vaghela N, Hideshima T, Fulciniti M, Pozzi S, et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA. 2010;107:5124–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol. 2011;21:139–46.

    Article  CAS  PubMed  Google Scholar 

  52. Lemaire M, Deleu S, De Bruyne E, Van Valckenborgh E, Menu E, Vanderkerken K, et al. The microenvironment and molecular biology of the multiple myeloma tumor. Adv Cancer Res. 2011;110:19–42.

    Article  CAS  PubMed  Google Scholar 

  53. Klein B, Seckinger A, Moehler T, Hose D. Molecular pathogenesis of multiple myeloma: chromosomal aberrations, changes in gene expression, cytokine networks, and the bone marrow microenvironment. Recent Results Cancer Res. 2011;183:39–86.

    Article  PubMed  Google Scholar 

  54. Anderson KC, Carrasco RD. Pathogenesis of myeloma. Annu Rev Pathol. 2011;6:249–74.

    Article  CAS  PubMed  Google Scholar 

  55. Shain KH, Yarde DN, Meads MB, Huang M, Jove R, Hazlehurst LA, et al. Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res. 2009;69:1009–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dalton WS. The tumor microenvironment: focus on myeloma. Cancer Treat Rev. 2003;29(Suppl 1):11–9.

    Article  CAS  PubMed  Google Scholar 

  57. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS. Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood. 1999;93:1658–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Landowski TH, Olashaw NE, Agrawal D, Dalton WS. Cell adhesion-mediated drug resistance (CAM-DR) is associated with activation of NF-kappa B (RelB/p50) in myeloma cells. Oncogene. 2003;22:2417–21.

    Article  CAS  PubMed  Google Scholar 

  59. Yaccoby S, Wezeman MJ, Henderson A, Cottler-Fox M, Yi Q, Barlogie B, et al. Cancer and the microenvironment: myeloma–osteoclast interactions as a model. Cancer Res. 2004;64:2016–23.

    Article  CAS  PubMed  Google Scholar 

  60. Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T, et al. Osteoclasts enhance myeloma cell growth and survival via cell–cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood. 2004;104:2484–91.

    Article  CAS  PubMed  Google Scholar 

  61. Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103:689–94.

    Article  CAS  PubMed  Google Scholar 

  62. Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C, et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004;103:3148–57.

    Article  CAS  PubMed  Google Scholar 

  63. Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P, et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood. 2005;106:1021–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Abe M, Kido S, Hiasa M, Nakano A, Oda A, Amou H, et al. BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma. Leukemia. 2006;20:1313–5.

    Article  CAS  PubMed  Google Scholar 

  65. Yaccoby S, Pennisi A, Li X, Dillon SR, Zhan F, Barlogie B, et al. Atacicept (TACI-Ig) inhibits growth of TACI(high) primary myeloma cells in SCID-hu mice and in coculture with osteoclasts. Leukemia. 2008;22:406–13.

    Article  CAS  PubMed  Google Scholar 

  66. Ge Y, Zhan F, Barlogie B, Epstein J, Shaughnessy J Jr, Yaccoby S. Fibroblast activation protein (FAP) is upregulated in myelomatous bone and supports myeloma cell survival. Br J Haematol. 2006;133:83–92.

    Article  CAS  PubMed  Google Scholar 

  67. Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Kimlinger TK, et al. Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression. Blood. 2004;104:1159–65.

    Article  CAS  PubMed  Google Scholar 

  68. Bhatti SS, Kumar L, Dinda AK, Dawar R. Prognostic value of bone marrow angiogenesis in multiple myeloma: use of light microscopy as well as computerized image analyzer in the assessment of microvessel density and total vascular area in multiple myeloma and its correlation with various clinical, histological, and laboratory parameters. Am J Hematol. 2006;81:649–56.

    Article  PubMed  Google Scholar 

  69. Jakob C, Sterz J, Zavrski I, Heider U, Kleeberg L, Fleissner C, et al. Angiogenesis in multiple myeloma. Eur J Cancer. 2006;42:1581–90.

    Article  CAS  PubMed  Google Scholar 

  70. Corre J, Mahtouk K, Attal M, Gadelorge M, Huynh A, Fleury-Cappellesso S, et al. Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007;21:1079–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Tanaka Y, Abe M, Hiasa M, Oda A, Amou H, Nakano A, et al. Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: a role for vascular endothelial cell growth factor and osteopontin. Clin Cancer Res. 2007;13:816–23.

    Article  CAS  PubMed  Google Scholar 

  72. Takafuji V, Forgues M, Unsworth E, Goldsmith P, Wang XW. An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma. Oncogene. 2007;26:6361–71.

    Article  CAS  PubMed  Google Scholar 

  73. Cackowski FC, Anderson JL, Patrene KD, Choksi RJ, Shapiro SD, Windle JJ, et al. Osteoclasts are important for bone angiogenesis. Blood. 2009;115:140–9.

    Article  PubMed  CAS  Google Scholar 

  74. Croucher PI, Shipman CM, Lippitt J, Perry M, Asosingh K, Hijzen A, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood. 2001;98:3534–40.

    Article  CAS  PubMed  Google Scholar 

  75. Yaccoby S, Pearse RN, Johnson CL, Barlogie B, Choi Y, Epstein J. Myeloma interacts with the bone marrow microenvironment to induce osteoclastogenesis and is dependent on osteoclast activity. Br J Haematol. 2002;116:278–90.

    Article  PubMed  Google Scholar 

  76. Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, et al. Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res. 2003;18:482–92.

    Article  CAS  PubMed  Google Scholar 

  77. Dhodapkar MV, Singh J, Mehta J, Fassas A, Desikan KR, Perlman M, et al. Anti-myeloma activity of pamidronate in vivo. Br J Haematol. 1998;103:530–2.

    Article  CAS  PubMed  Google Scholar 

  78. Kondo H, Mori A. Anti-tumor activity of pamidronate in human multiple myeloma. Leuk Lymphoma. 2002;43:919–21.

    Article  PubMed  Google Scholar 

  79. Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, et al. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2006;66:6675–82.

    Article  CAS  PubMed  Google Scholar 

  80. Lund T, Soe K, Abildgaard N, Garnero P, Pedersen PT, Ormstrup T, et al. First-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitro. Eur J Haematol. 1111;85:290–9.

    Article  CAS  Google Scholar 

  81. Lee SE, Min CK, Yahng SA, Cho BS, Eom KS, Kim YJ, et al. Bone scan images reveal increased osteoblastic function after bortezomib treatment in patients with multiple myeloma. Eur J Haematol. 1111;86:83–6.

    Article  Google Scholar 

  82. Delforge M, Terpos E, Richardson PG, Shpilberg O, Khuageva NK, Schlag R, et al. Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial in multiple myeloma. Eur J Haematol. 1111;86:372–84.

    Article  CAS  Google Scholar 

  83. Zangari M, Aujay M, Zhan F, Hetherington KL, Berno T, Vij R, et al. Alkaline phosphatase variation during carfilzomib treatment is associated with best response in multiple myeloma patients. Eur J Haematol. 1111;86:484–7.

    Article  CAS  Google Scholar 

  84. Zangari M, Esseltine D, Lee CK, Barlogie B, Elice F, Burns MJ, et al. Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma. Br J Haematol. 2005;131:71–3.

    Article  CAS  PubMed  Google Scholar 

  85. Ozaki S, Tanaka O, Fujii S, Shigekiyo Y, Miki H, Choraku M, et al. Therapy with bortezomib plus dexamethasone induces osteoblast activation in responsive patients with multiple myeloma. Int J Hematol. 2007;86:180–5.

    Article  CAS  PubMed  Google Scholar 

  86. Yaccoby S, Wezeman MJ, Zangari M, Walker R, Cottler-Fox M, Gaddy D, et al. Inhibitory effects of osteoblasts and increased bone formation on myeloma in novel culture systems and a myelomatous mouse model. Haematologica. 2006;91:192–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD Jr. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo. Blood. 2007;109:2106–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Heath DJ, Chantry AD, Buckle CH, Coulton L, Shaughnessy JD Jr, Evans HR, et al. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res. 2009;24:425–36.

    Article  CAS  PubMed  Google Scholar 

  89. Edwards CM, Edwards JR, Lwin ST, Esparza J, Oyajobi BO, McCluskey B, et al. Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo. Blood. 2008;111:2833–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chantry AD, Heath D, Mulivor AW, Pearsall S, Baud’huin M, Coulton L, et al. Inhibiting activin-A signaling stimulates bone formation and prevents cancer-induced bone destruction in vivo. J Bone Miner Res. 1002;25:2633–46.

    Article  CAS  Google Scholar 

  91. Qiang YW, Shaughnessy JD Jr, Yaccoby S. Wnt3a signaling within bone inhibits multiple myeloma bone disease and tumor growth. Blood. 2008;112:374–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Fulciniti M, Tassone P, Hideshima T, Vallet S, Nanjappa P, Ettenberg SA, et al. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma. Blood. 2009;114:371–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Maeda S, Hayashi M, Komiya S, Imamura T, Miyazono K. Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. EMBO J. 2004;23:552–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Matsumoto T, Abe M TGF-beta-related mechanisms of bone destruction in multiple myeloma. Bone 2011;48:129–34.

    Article  CAS  PubMed  Google Scholar 

  95. Lotinun S, Pearsall RS, Davies MV, Marvell TH, Monnell TE, Ucran J, et al. A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys. Bone. 1082;46:1082–8.

    Article  CAS  Google Scholar 

  96. Li X, Pennisi A, Yaccoby S. Role of decorin in the antimyeloma effects of osteoblasts. Blood. 2008;112:159–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dai Y, Yang Y, MacLeod V, Yue X, Rapraeger AC, Shriver Z, et al. HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo. J Biol Chem. 2005;280:40066–73.

    Article  CAS  PubMed  Google Scholar 

  98. Teplyuk NM, Haupt LM, Ling L, Dombrowski C, Mun FK, Nathan SS, et al. The osteogenic transcription factor Runx2 regulates components of the fibroblast growth factor/proteoglycan signaling axis in osteoblasts. J Cell Biochem. 2009;107:144–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Menu E, van Valckenborgh E, van Camp B, Vanderkerken K. The role of the insulin-like growth factor 1 receptor axis in multiple myeloma. Arch Physiol Biochem. 2009;115:49–57.

    Article  CAS  PubMed  Google Scholar 

  100. Sprynski AC, Hose D, Caillot L, Reme T, Shaughnessy JD Jr, Barlogie B, et al. The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood. 2009;113:4614–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Asano J, Nakano A, Oda A, Amou H, Hiasa M, Takeuchi K, et al. The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells. Leukemia. 2011;25:1182–88.

    Article  CAS  PubMed  Google Scholar 

  102. Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Henze C, Loffler D, Koczan D, et al. Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood. 2004;103:242–51.

    Article  CAS  PubMed  Google Scholar 

  103. van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, et al. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989;56:673–82.

    Article  PubMed  Google Scholar 

  104. Allen JD, Verhoeven E, Domen J, van der Valk M, Berns A. Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene. 1997;15:1133–41.

    Article  CAS  PubMed  Google Scholar 

  105. Isaac M, Siu A, Jongstra J The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms. Drug Resist Updat. 2011;19.

  106. Xie Y, Xu K, Linn DE, Yang X, Guo Z, Shimelis H, et al. The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells. J Biol Chem. 2008;283:3349–56.

    Article  CAS  PubMed  Google Scholar 

  107. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood. 2006;107:4053–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. McMillin DW, Ooi M, Delmore J, Negri J, Hayden P, Mitsiades N, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009;69:5835–42.

    Article  CAS  PubMed  Google Scholar 

  109. Hammerman PS, Fox CJ, Birnbaum MJ, Thompson CB. Pim and Akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood. 2005;105:4477–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-aid for Scientific (C) from the Ministry of Education, Culture, Science and Sports of Japan, a Grant-in-aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, and National Cancer Center Research and Development Fund.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Masahiro Abe

Authors
  1. Masahiro Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masahiro Abe.

About this article

Cite this article

Abe, M. Targeting the interplay between myeloma cells and the bone marrow microenvironment in myeloma. Int J Hematol 94, 334–343 (2011). https://doi.org/10.1007/s12185-011-0949-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-011-0949-x

Keywords

Search

Navigation