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Bone microenvironment signals in osteosarcoma development

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Abstract

The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome.

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Abbreviations

AKT:

V-Akt murine thymoma viral oncogene homolog

ALDH:

Aldehyde dehydrogenase

BM:

Bone marrow

BMP:

Bone morphogenic proteins

CCL:

Chemokine (C–C Motif) ligands

CSC:

Cancer stem cells

CXCL:

Chemokine (C–X–C Motif) ligands

DKK:

Dickkopf proteins

ECM:

Extracellular matrix

EDN1:

Endothelin 1

EMV:

Extracellular membrane vesicles

EPH:

Erythropoietin-producing hepatoma

ERK:

Extracellular signal-related kinases

FGF:

Fibroblast growth factors

GLI:

Glioma-associated oncogene

GH:

Growth hormone

GP:

Growth plate

HES:

Hairy and enhancer of split

HH:

Hedgehog proteins

HIF:

Hypoxia-inducible factors

IGF:

Insulin-like growth factors

IHH:

Indian hedgehog

IL:

Interleukin

MAPK:

Mitogen-activated protein kinases

MCT:

Monocarboxylate transporter

miRs:

MicroRNAs

MMP:

Matrix metalloproteinases

MSC:

Mesenchymal stem/progenitor cells

mTOR:

Mammalian target of rapamycin

NFkB:

Nuclear factor kB

OPG:

Osteoprotegerin

OS:

Osteosarcoma

PDGF:

Platelet-derived growth factor

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-kinase

PTHrP:

Parathyroid hormone-related peptide

RANK:

Receptor activator of nuclear factor kappa B

RANKL:

RANK ligand

RB:

Retinoblastoma

SOX2:

Sex-determining region Y-box 2

STAT3:

Signal transducer and activator of transcription 3

TGFα/β:

Transforming growth factor α/β

VEGF:

Vascular endothelial growth factors

WIF1:

WNT inhibitory factor 1

WNT:

Wingless-type MMTV integration site family

YAP1:

Yes-associated protein 1

References

  1. Kronenberg HM (2003) Developmental regulation of the growth plate. Nature 423(6937):332–336

    CAS  PubMed  Google Scholar 

  2. Burdan F, Szumilo J, Korobowicz A, Farooquee R, Patel S, Patel A, Dave A, Szumilo M, Solecki M, Klepacz R, Dudka J (2009) Morphology and physiology of the epiphyseal growth plate. Folia Histochem Cytobiol 47(1):5–16

    PubMed  Google Scholar 

  3. Overholtzer M, Rao PH, Favis R, Lu XY, Elowitz MB, Barany F, Ladanyi M, Gorlick R, Levine AJ (2003) The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability. Proc Natl Acad Sci USA 100(20):11547–11552

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki MS, Kotoura Y, Yamamuro T (1994) Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res 54(11):3042–3048

    CAS  PubMed  Google Scholar 

  5. Mutsaers AJ, Walkley CR (2014) Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells? Bone 62:56–63

    PubMed  Google Scholar 

  6. Rodriguez R, Garcia-Castro J, Trigueros C, Garcia Arranz M, Menendez P (2012) Multipotent mesenchymal stromal cells: clinical applications and cancer modeling. Adv Exp Med Biol 741:187–205

    CAS  PubMed  Google Scholar 

  7. Rodriguez R, Rubio R, Menendez P (2012) Modeling sarcomagenesis using multipotent mesenchymal stem cells. Cell Res 22(1):62–77

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Rubio R, Gutierrez-Aranda I, Saez-Castillo AI, Labarga A, Rosu-Myles M, Gonzalez-Garcia S, Toribio ML, Menendez P, Rodriguez R (2013) The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development. Oncogene 32(41):4970–4980

    CAS  PubMed  Google Scholar 

  9. Xiao W, Mohseny AB, Hogendoorn PC, Cleton-Jansen AM (2013) Mesenchymal stem cell transformation and sarcoma genesis. Clin Sarcoma Res 3(1):10

    PubMed Central  PubMed  Google Scholar 

  10. Rubio R, Garcia-Castro J, Gutierrez-Aranda I, Paramio J, Santos M, Catalina P, Leone PE, Menendez P, Rodriguez R (2010) Deficiency in p53 but not retinoblastoma induces the transformation of mesenchymal stem cells in vitro and initiates leiomyosarcoma in vivo. Cancer Res 70(10):4185–4194

    CAS  PubMed  Google Scholar 

  11. Rubio R, Abarrategi A, Garcia-Castro J, Martinez-Cruzado L, Suarez C, Tornin J, Santos L, Astudillo A, Colmenero I, Mulero F, Rosu-Myles M, Menendez P, Rodriguez R (2014) Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells. Stem Cells 32(5):1136–1148

    CAS  PubMed  Google Scholar 

  12. Richardson RB (2014) Age-specific bone tumour incidence rates are governed by stem cell exhaustion influencing the supply and demand of progenitor cells. Mech Ageing Dev 139:31–40

    CAS  PubMed  Google Scholar 

  13. Kirpensteijn J, Timmermans-Sprang EP, van Garderen E, Rutteman GR, Lantinga-van Leeuwen IS, Mol JA (2002) Growth hormone gene expression in canine normal growth plates and spontaneous osteosarcoma. Mol Cell Endocrinol 197(1–2):179–185

    CAS  PubMed  Google Scholar 

  14. Robson H, Siebler T, Shalet SM, Williams GR (2002) Interactions between GH, IGF-I, glucocorticoids, and thyroid hormones during skeletal growth. Pediatr Res 52(2):137–147

    CAS  PubMed  Google Scholar 

  15. Huang J, Ni J, Liu K, Yu Y, Xie M, Kang R, Vernon P, Cao L, Tang D (2012) HMGB1 promotes drug resistance in osteosarcoma. Cancer Res 72(1):230–238

    CAS  PubMed  Google Scholar 

  16. Ek ET, Dass CR, Contreras KG, Choong PF (2007) Inhibition of orthotopic osteosarcoma growth and metastasis by multitargeted antitumor activities of pigment epithelium-derived factor. Clin Exp Metastasis 24(2):93–106

    CAS  PubMed  Google Scholar 

  17. Theriault RL, Theriault RL (2012) Biology of bone metastases. Cancer Control 19(2):92–101

    PubMed  Google Scholar 

  18. Boyce BF, Xing L (2008) Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 473(2):139–146

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Broadhead ML, Clark JC, Myers DE, Dass CR, Choong PF (2011) The molecular pathogenesis of osteosarcoma: a review. Sarcoma 2011:959248

    PubMed Central  PubMed  Google Scholar 

  20. Miyamoto N, Higuchi Y, Mori K, Ito M, Tsurudome M, Nishio M, Yamada H, Sudo A, Kato K, Uchida A, Ito Y (2002) Human osteosarcoma-derived cell lines produce soluble factor(s) that induces differentiation of blood monocytes to osteoclast-like cells. Int Immunopharmacol 2(1):25–38

    CAS  PubMed  Google Scholar 

  21. Kingsley LA, Fournier PG, Chirgwin JM, Guise TA (2007) Molecular biology of bone metastasis. Mol Cancer Ther 6(10):2609–2617

    CAS  PubMed  Google Scholar 

  22. Kuchimaru T, Hoshino T, Aikawa T, Yasuda H, Kobayashi T, Kadonosono T, Kizaka-Kondoh S (2014) Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia. Cancer Sci 105(5):553–559

    CAS  PubMed  Google Scholar 

  23. Lamoureux F, Richard P, Wittrant Y, Battaglia S, Pilet P, Trichet V, Blanchard F, Gouin F, Pitard B, Heymann D, Redini F (2007) Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the “vicious cycle” between tumor cell proliferation and bone resorption. Cancer Res 67(15):7308–7318

    CAS  PubMed  Google Scholar 

  24. Zeng W, Wan R, Zheng Y, Singh SR, Wei Y (2011) Hypoxia, stem cells and bone tumor. Cancer Lett 313(2):129–136

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Avnet S, Longhi A, Salerno M, Halleen JM, Perut F, Granchi D, Ferrari S, Bertoni F, Giunti A, Baldini N (2008) Increased osteoclast activity is associated with aggressiveness of osteosarcoma. Int J Oncol 33(6):1231–1238

    CAS  PubMed  Google Scholar 

  26. Costa-Rodrigues J, Teixeira CA, Fernandes MH (2011) Paracrine-mediated osteoclastogenesis by the osteosarcoma MG63 cell line: is RANKL/RANK signalling really important? Clin Exp Metastasis 28(6):505–514

    CAS  PubMed  Google Scholar 

  27. Itoh K, Udagawa N, Matsuzaki K, Takami M, Amano H, Shinki T, Ueno Y, Takahashi N, Suda T (2000) Importance of membrane- or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by SaOS-4/3 cells expressing recombinant PTH/PTHrP receptors. J Bone Miner Res 15(9):1766–1775

    CAS  PubMed  Google Scholar 

  28. Kinpara K, Mogi M, Kuzushima M, Togari A (2000) Osteoclast differentiation factor in human osteosarcoma cell line. J Immunoassay 21(4):327–340

    CAS  PubMed  Google Scholar 

  29. Costa-Rodrigues J, Fernandes A, Fernandes MH (2011) Reciprocal osteoblastic and osteoclastic modulation in co-cultured MG63 osteosarcoma cells and human osteoclast precursors. J Cell Biochem 112(12):3704–3713

    CAS  PubMed  Google Scholar 

  30. Lee JA, Jung JS, Kim DH, Lim JS, Kim MS, Kong CB, Song WS, Cho WH, Jeon DG, Lee SY, Koh JS (2011) RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma. Pediatr Blood Cancer 56(5):738–743

    PubMed  Google Scholar 

  31. Rousseau J, Escriou V, Lamoureux F, Brion R, Chesneau J, Battaglia S, Amiaud J, Scherman D, Heymann D, Redini F, Trichet V (2011) Formulated siRNAs targeting Rankl prevent osteolysis and enhance chemotherapeutic response in osteosarcoma models. J Bone Miner Res 26(10):2452–2462

    CAS  PubMed  Google Scholar 

  32. Moriceau G, Ory B, Gobin B, Verrecchia F, Gouin F, Blanchard F, Redini F, Heymann D (2010) Therapeutic approach of primary bone tumours by bisphosphonates. Curr Pharm Des 16(27):2981–2987

    CAS  PubMed  Google Scholar 

  33. Heymann D, Ory B, Blanchard F, Heymann MF, Coipeau P, Charrier C, Couillaud S, Thiery JP, Gouin F, Redini F (2005) Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma. Bone 37(1):74–86

    CAS  PubMed  Google Scholar 

  34. Lamoureux F, Moriceau G, Picarda G, Rousseau J, Trichet V, Redini F (2010) Regulation of osteoprotegerin pro- or anti-tumoral activity by bone tumor microenvironment. Biochim Biophys Acta 1805(1):17–24

    CAS  PubMed  Google Scholar 

  35. Picarda G, Trichet V, Teletchea S, Heymann D, Redini F (2012) TRAIL receptor signaling and therapeutic option in bone tumors: the trap of the bone microenvironment. Am J Cancer Res 2(1):45–64

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Lamoureux F, Picarda G, Rousseau J, Gourden C, Battaglia S, Charrier C, Pitard B, Heymann D, Redini F (2008) Therapeutic efficacy of soluble receptor activator of nuclear factor-kappa B-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma. Mol Cancer Ther 7(10):3389–3398

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Cathomas R, Rothermundt C, Bode B, Fuchs B, von Moos R, Schwitter M (2014) RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward? Oncology 88(4):257–260

    PubMed  Google Scholar 

  38. Endo-Munoz L, Cumming A, Rickwood D, Wilson D, Cueva C, Ng C, Strutton G, Cassady AI, Evdokiou A, Sommerville S, Dickinson I, Guminski A, Saunders NA (2010) Loss of osteoclasts contributes to development of osteosarcoma pulmonary metastases. Cancer Res 70(18):7063–7072

    CAS  PubMed  Google Scholar 

  39. Endo-Munoz L, Evdokiou A, Evdokiou A, Saunders NA (2012) The role of osteoclasts and tumour-associated macrophages in osteosarcoma metastasis. Biochim Biophys Acta 1826(2):434–442

    CAS  PubMed  Google Scholar 

  40. Matsuo K, Otaki N (2012) Bone cell interactions through Eph/ephrin: bone modeling, remodeling and associated diseases. Cell Adh Migr 6(2):148–156

    PubMed Central  PubMed  Google Scholar 

  41. Fritsche-Guenther R, Noske A, Ungethum U, Kuban RJ, Schlag PM, Tunn PU, Karle J, Krenn V, Dietel M, Sers C (2010) De novo expression of EphA2 in osteosarcoma modulates activation of the mitogenic signalling pathway. Histopathology 57(6):836–850

    PubMed  Google Scholar 

  42. Abdou AG, Abdel-Wahed MM, Asaad NY, Samaka RM, Abdallaha R (2010) Ephrin A4 expression in osteosarcoma, impact on prognosis, and patient outcome. Indian J Cancer 47(1):46–52

    CAS  PubMed  Google Scholar 

  43. Varelias A, Koblar SA, Cowled PA, Carter CD, Clayer M (2002) Human osteosarcoma expresses specific ephrin profiles: implications for tumorigenicity and prognosis. Cancer 95(4):862–869

    PubMed  Google Scholar 

  44. Garimella R, Washington L, Isaacson J, Vallejo J, Spence M, Tawfik O, Rowe P, Brotto M, Perez R (2014) Extracellular membrane vesicles derived from 143B osteosarcoma cells contain pro-osteoclastogenic cargo: a novel communication mechanism in osteosarcoma bone microenvironment. Transl Oncol 7(3):331–340

    PubMed Central  PubMed  Google Scholar 

  45. Yu L, Guo W, Zhao S, Wang F, Xu Y (2011) Fusion between cancer cells and myofibroblasts is involved in osteosarcoma. Oncol Lett 2(6):1083–1087

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Barcellos-de-Souza P, Gori V, Bambi F, Chiarugi P (2013) Tumor microenvironment: bone marrow-mesenchymal stem cells as key players. Biochim Biophys Acta 1836(2):321–335

    CAS  PubMed  Google Scholar 

  47. Mishra PJ, Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D (2008) Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 68(11):4331–4339

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Zhang L, Tang A, Zhou Y, Tang J, Luo Z, Jiang C, Li X, Xiang J, Li G (2012) Tumor-conditioned mesenchymal stem cells display hematopoietic differentiation and diminished influx of Ca2+. Stem Cells Dev 21(9):1418–1428

    CAS  PubMed  Google Scholar 

  49. Hass R, Otte A (2012) Mesenchymal stem cells as all-round supporters in a normal and neoplastic microenvironment. Cell Commun Signal 10(1):26

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Rodriguez R, Rosu-Myles M, Arauzo-Bravo M, Horrillo A, Pan Q, Gonzalez-Rey E, Delgado M, Menendez P (2014) Human bone marrow stromal cells lose immunosuppressive and anti-inflammatory properties upon oncogenic transformation. Stem Cell Rep 3(4):606–619

    CAS  Google Scholar 

  51. Brune JC, Tormin A, Johansson MC, Rissler P, Brosjo O, Lofvenberg R, von Steyern FV, Mertens F, Rydholm A, Scheding S (2011) Mesenchymal stromal cells from primary osteosarcoma are non-malignant and strikingly similar to their bone marrow counterparts. Int J Cancer 129(2):319–330

    CAS  PubMed  Google Scholar 

  52. Xu WT, Bian ZY, Fan QM, Li G, Tang TT (2009) Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett 281(1):32–41

    CAS  PubMed  Google Scholar 

  53. Bian ZY, Fan QM, Li G, Xu WT, Tang TT (2010) Human mesenchymal stem cells promote growth of osteosarcoma: involvement of interleukin-6 in the interaction between human mesenchymal stem cells and Saos-2. Cancer Sci 101(12):2554–2560

    CAS  PubMed  Google Scholar 

  54. Tu B, Du L, Fan QM, Tang Z, Tang TT (2012) STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer Lett 325(1):80–88

    CAS  PubMed  Google Scholar 

  55. Tu B, Peng ZX, Fan QM, Du L, Yan W, Tang TT (2014) Osteosarcoma cells promote the production of pro-tumor cytokines in mesenchymal stem cells by inhibiting their osteogenic differentiation through the TGF-beta/Smad2/3 pathway. Exp Cell Res 320(1):164–173

    CAS  PubMed  Google Scholar 

  56. Tsukamoto S, Honoki K, Fujii H, Tohma Y, Kido A, Mori T, Tsujiuchi T, Tanaka Y (2012) Mesenchymal stem cells promote tumor engraftment and metastatic colonization in rat osteosarcoma model. Int J Oncol 40(1):163–169

    CAS  PubMed  Google Scholar 

  57. Zhang P, Dong L, Long H, Yang TT, Zhou Y, Fan QY, Ma BA (2014) Homologous mesenchymal stem cells promote the emergence and growth of pulmonary metastases of the rat osteosarcoma cell line UMR-106. Oncol Lett 8(1):127–132

    PubMed Central  PubMed  Google Scholar 

  58. Kido A, Yoshitani K, Shimizu T, Akahane M, Fujii H, Tsukamoto S, Kondo Y, Honoki K, Imano M, Tanaka Y (2012) Effect of mesenchymal stem cells on hypoxia-induced desensitization of beta2-adrenergic receptors in rat osteosarcoma cells. Oncol Lett 4(4):745–750

    PubMed Central  PubMed  Google Scholar 

  59. Bonuccelli G, Avnet S, Grisendi G, Salerno M, Granchi D, Dominici M, Kusuzaki K, Baldini N (2014) Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells. Oncotarget 5(17):7575–7588

    PubMed Central  PubMed  Google Scholar 

  60. Matsuyama S, Iwadate M, Kondo M, Saitoh M, Hanyu A, Shimizu K, Aburatani H, Mishima HK, Imamura T, Miyazono K, Miyazawa K (2003) SB-431542 and Gleevec inhibit transforming growth factor-beta-induced proliferation of human osteosarcoma cells. Cancer Res 63(22):7791–7798

    CAS  PubMed  Google Scholar 

  61. Franchi A, Arganini L, Baroni G, Calzolari A, Capanna R, Campanacci D, Caldora P, Masi L, Brandi ML, Zampi G (1998) Expression of transforming growth factor beta isoforms in osteosarcoma variants: association of TGF beta 1 with high-grade osteosarcomas. J Pathol 185(3):284–289

    CAS  PubMed  Google Scholar 

  62. Kloen P, Gebhardt MC, Perez-Atayde A, Rosenberg AE, Springfield DS, Gold LI, Mankin HJ (1997) Expression of transforming growth factor-beta (TGF-beta) isoforms in osteosarcomas: TGF-beta3 is related to disease progression. Cancer 80(12):2230–2239

    CAS  PubMed  Google Scholar 

  63. Mohseny AB, Cai Y, Kuijjer M, Xiao W, van den Akker B, de Andrea CE, Jacobs R, ten Dijke P, Hogendoorn PC, Cleton-Jansen AM (2012) The activities of Smad and Gli mediated signalling pathways in high-grade conventional osteosarcoma. Eur J Cancer 48(18):3429–3438

    CAS  PubMed  Google Scholar 

  64. Lamora A, Talbot J, Bougras G, Amiaud J, Leduc M, Chesneau J, Taurelle J, Stresing V, Le Deley MC, Heymann MF, Heymann D, Redini F, Verrecchia F (2014) Overexpression of smad7 blocks primary tumor growth and lung metastasis development in osteosarcoma. Clin Cancer Res 20(19):5097–5112

    CAS  PubMed  Google Scholar 

  65. Yang RS, Wu CT, Lin KH, Hong RL, Liu TK, Lin KS (1998) Relation between histological intensity of transforming growth factor-beta isoforms in human osteosarcoma and the rate of lung metastasis. Tohoku J Exp Med 184(2):133–142

    CAS  PubMed  Google Scholar 

  66. Xu S, Yang S, Sun G, Huang W, Zhang Y (2014) Transforming growth factor-beta polymorphisms and serum level in the development of osteosarcoma. DNA Cell Biol 33(11):802–806

    CAS  PubMed  Google Scholar 

  67. Suzuki S, Kulkarni AB (2010) Extracellular heat shock protein HSP90beta secreted by MG63 osteosarcoma cells inhibits activation of latent TGF-beta1. Biochem Biophys Res Commun 398(3):525–531

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Nguyen A, Scott MA, Dry SM, James AW (2014) Roles of bone morphogenetic protein signaling in osteosarcoma. Int Orthop 38(11):2313–2322

    PubMed  Google Scholar 

  69. Luo X, Chen J, Song WX, Tang N, Luo J, Deng ZL, Sharff KA, He G, Bi Y, He BC, Bennett E, Huang J, Kang Q, Jiang W, Su Y, Zhu GH, Yin H, He Y, Wang Y, Souris JS, Chen L, Zuo GW, Montag AG, Reid RR, Haydon RC, Luu HH, He TC (2008) Osteogenic BMPs promote tumor growth of human osteosarcomas that harbor differentiation defects. Lab Invest 88(12):1264–1277

    CAS  PubMed  Google Scholar 

  70. Sotobori T, Ueda T, Myoui A, Yoshioka K, Nakasaki M, Yoshikawa H, Itoh K (2006) Bone morphogenetic protein-2 promotes the haptotactic migration of murine osteoblastic and osteosarcoma cells by enhancing incorporation of integrin beta1 into lipid rafts. Exp Cell Res 312(19):3927–3938

    CAS  PubMed  Google Scholar 

  71. Wang L, Park P, Zhang H, La Marca F, Claeson A, Valdivia J, Lin CY (2011) BMP-2 inhibits the tumorigenicity of cancer stem cells in human osteosarcoma OS99-1 cell line. Cancer Biol Ther 11(5):457–463

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Lv Z, Wang C, Yuan T, Liu Y, Song T, Liu Y, Chen C, Yang M, Tang Z, Shi Q, Weng Y (2014) Bone morphogenetic protein 9 regulates tumor growth of osteosarcoma cells through the Wnt/beta-catenin pathway. Oncol Rep 31(2):989–994

    CAS  PubMed  Google Scholar 

  73. Ma Y, Ren Y, Han EQ, Li H, Chen D, Jacobs JJ, Gitelis S, O’Keefe RJ, Konttinen YT, Yin G, Li TF (2013) Inhibition of the Wnt-beta-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochem Biophys Res Commun 431(2):274–279

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Westendorf JJ, Kahler RA, Schroeder TM (2004) Wnt signaling in osteoblasts and bone diseases. Gene 341:19–39

    CAS  PubMed  Google Scholar 

  75. Zhang A, He S, Sun X, Ding L, Bao X, Wang N (2014) Wnt5a promotes migration of human osteosarcoma cells by triggering a phosphatidylinositol-3 kinase/Akt signals. Cancer Cell Int 14(1):15

    PubMed Central  PubMed  Google Scholar 

  76. Kansara M, Teng MW, Smyth MJ, Thomas DM (2014) Translational biology of osteosarcoma. Nat Rev Cancer 14(11):722–735

    CAS  PubMed  Google Scholar 

  77. Lin CH, Guo Y, Ghaffar S, McQueen P, Pourmorady J, Christ A, Rooney K, Ji T, Eskander R, Zi X, Hoang BH (2013) Dkk-3, a secreted wnt antagonist, suppresses tumorigenic potential and pulmonary metastasis in osteosarcoma. Sarcoma 2013:147541

    PubMed Central  PubMed  Google Scholar 

  78. Tian J, He H, Lei G (2014) Wnt/beta-catenin pathway in bone cancers. Tumour Biol 35(10):9439–9445

    CAS  PubMed  Google Scholar 

  79. Cai Y, Mohseny AB, Karperien M, Hogendoorn PC, Zhou G, Cleton-Jansen AM (2010) Inactive Wnt/beta-catenin pathway in conventional high-grade osteosarcoma. J Pathol 220(1):24–33

    CAS  PubMed  Google Scholar 

  80. Du X, Yang J, Yang D, Tian W, Zhu Z (2014) The genetic basis for inactivation of Wnt pathway in human osteosarcoma. BMC Cancer 14:450

    PubMed Central  PubMed  Google Scholar 

  81. Krause U, Ryan DM, Clough BH, Gregory CA (2014) An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity. Cell Death Dis 5:e1093

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Hassan SE, Bekarev M, Kim MY, Lin J, Piperdi S, Gorlick R, Geller DS (2012) Cell surface receptor expression patterns in osteosarcoma. Cancer 118(3):740–749

    CAS  PubMed  Google Scholar 

  83. Wiedłocha A, Falnes PO, Rapak A, Muñoz R, Klingenberg O, Olsnes S (1996) Stimulation of proliferation of a human osteosarcoma cell line by exogenous acidic fibroblast growth factor requires both activation of receptor tyrosine kinase and growth factor internalization. Mol Cell Biol 16(1):270–280

    PubMed Central  PubMed  Google Scholar 

  84. Basu-Roy U, Seo E, Ramanathapuram L, Rapp TB, Perry JA, Orkin SH, Mansukhani A, Basilico C (2012) Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas. Oncogene 31(18):2270–2282

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Shimizu T, Ishikawa T, Iwai S, Ueki A, Sugihara E, Onishi N, Kuninaka S, Miyamoto T, Toyama Y, Ijiri H, Mori H, Matsuzaki Y, Yaguchi T, Nishio H, Kawakami Y, Ikeda Y, Saya H (2012) Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma. Mol Cancer Res 10(3):454–468

    CAS  PubMed  Google Scholar 

  86. Tingting R, Wei G, Changliang P, Xinchang L, Yi Y (2010) Arsenic trioxide inhibits osteosarcoma cell invasiveness via MAPK signaling pathway. Cancer Biol Ther 10(3):251–257

    PubMed  Google Scholar 

  87. Datsis GA, Berdiaki A, Nikitovic D, Mytilineou M, Katonis P, Karamanos NK, Tzanakakis GN (2011) Parathyroid hormone affects the fibroblast growth factor-proteoglycan signaling axis to regulate osteosarcoma cell migration. FEBS J 278(19):3782–3792

    CAS  PubMed  Google Scholar 

  88. Pollak MN, Polychronakos C, Richard M (1990) Insulin like growth factor I: a potent mitogen for human osteogenic sarcoma. J Natl Cancer Inst 82(4):301–305

    CAS  PubMed  Google Scholar 

  89. Jentzsch T, Robl B, Husmann M, Bode-Lesniewska B, Fuchs B (2014) Worse prognosis of osteosarcoma patients expressing IGF-1 on a tissue microarray. Anticancer Res 34(8):3881–3889

    PubMed  Google Scholar 

  90. Pollak M, Sem AW, Richard M, Tetenes E, Bell R (1992) Inhibition of metastatic behavior of murine osteosarcoma by hypophysectomy. J Natl Cancer Inst 84(12):966–971

    CAS  PubMed  Google Scholar 

  91. Chou AJ, Geller DS, Gorlick R (2008) Therapy for osteosarcoma: where do we go from here? Paediatr Drugs 10(5):315–327

    PubMed  Google Scholar 

  92. Cao Y, Roth M, Piperdi S, Montoya K, Sowers R, Rao P, Geller D, Houghton P, Kolb EA, Gill J, Gorlick R (2014) Insulin-like growth factor 1 receptor and response to anti-IGF1R antibody therapy in osteosarcoma. PLoS One 9(8):e106249

    PubMed Central  PubMed  Google Scholar 

  93. Chen D, Zhang YJ, Zhu KW, Wang WC (2013) A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma. Tumour Biol 34(3):1895–1899

    CAS  PubMed  Google Scholar 

  94. Ohba T, Cates JM, Cole HA, Slosky DA, Haro H, Ando T, Schwartz HS, Schoenecker JG (2014) Autocrine VEGF/VEGFR1 signaling in a subpopulation of cells associates with aggressive osteosarcoma. Mol Cancer Res 12(8):1100–1111

    CAS  PubMed  Google Scholar 

  95. Cho HJ, Lee TS, Park JB, Park KK, Choe JY, Sin DI, Park YY, Moon YS, Lee KG, Yeo JH, Han SM, Cho YS, Choi MR, Park NG, Lee YS, Chang YC (2007) Disulfiram suppresses invasive ability of osteosarcoma cells via the inhibition of MMP-2 and MMP-9 expression. J Biochem Mol Biol 40(6):1069–1076

    CAS  PubMed  Google Scholar 

  96. Mohseny AB, Xiao W, Carvalho R, Spaink HP, Hogendoorn PC, Cleton-Jansen AM (2012) An osteosarcoma zebrafish model implicates Mmp-19 and Ets-1 as well as reduced host immune response in angiogenesis and migration. J Pathol 227(2):245–253

    CAS  PubMed  Google Scholar 

  97. Kang HG, Kim HS, Kim KJ, Oh JH, Lee MR, Seol SM, Han I (2007) RECK expression in osteosarcoma: correlation with matrix metalloproteinases activation and tumor invasiveness. J Orthop Res 25(5):696–702

    CAS  PubMed  Google Scholar 

  98. de Nigris F, Mancini FP, Schiano C, Infante T, Zullo A, Minucci PB, Al-Omran M, Giordano A, Napoli C (2013) Osteosarcoma cells induce endothelial cell proliferation during neo-angiogenesis. J Cell Physiol 228(4):846–852

    PubMed  Google Scholar 

  99. Ren K, Yao N, Wang G, Tian L, Ma J, Shi X, Zhang L, Zhang J, Zhou X, Zhou G, Wu S, Sun X (2014) Vasculogenic mimicry: a new prognostic sign of human osteosarcoma. Hum Pathol 45(10):2120–2129

    PubMed  Google Scholar 

  100. Sampson VB, Gorlick R, Kamara D, Anders Kolb E (2013) A review of targeted therapies evaluated by the pediatric preclinical testing program for osteosarcoma. Front Oncol 3:132

    PubMed Central  PubMed  Google Scholar 

  101. Sulzbacher I, Birner P, Trieb K, Träxler M, Lang S, Chott A (2003) Expression of platelet-derived growth factor-AA is associated with tumor progression in osteosarcoma. Mod Pathol 16(1):66–71

    PubMed  Google Scholar 

  102. Takagi S, Takemoto A, Takami M, Oh-Hara T, Fujita N (2014) Platelets promote osteosarcoma cell growth through activation of the platelet-derived growth factor receptor-Akt signaling axis. Cancer Sci 105(8):983–988

    CAS  PubMed  Google Scholar 

  103. Lo WW, Pinnaduwage D, Gokgoz N, Wunder JS, Andrulis IL (2014) Aberrant hedgehog signaling and clinical outcome in osteosarcoma. Sarcoma 2014:261804

    PubMed Central  PubMed  Google Scholar 

  104. Chan LH, Wang W, Yeung W, Deng Y, Yuan P, Mak KK (2014) Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression. Oncogene 33(40):4857–4866

    CAS  PubMed  Google Scholar 

  105. Zhang YH, Li B, Shen L, Shen Y, Chen XD (2013) The role and clinical significance of YES-associated protein 1 in human osteosarcoma. Int J Immunopathol Pharmacol 26(1):157–167

    CAS  PubMed  Google Scholar 

  106. Tao J, Jiang MM, Jiang L, Salvo JS, Zeng HC, Dawson B, Bertin TK, Rao PH, Chen R, Donehower LA, Gannon F, Lee BH (2014) Notch activation as a driver of osteogenic sarcoma. Cancer Cell 26(3):390–401

    CAS  PubMed  Google Scholar 

  107. Engin F, Bertin T, Ma O, Jiang MM, Wang L, Sutton RE, Donehower LA, Lee B (2009) Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum Mol Genet 18(8):1464–1470

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Hughes DP (2009) How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treat Res 152:479–496

    PubMed  Google Scholar 

  109. Tanaka M, Setoguchi T, Hirotsu M, Gao H, Sasaki H, Matsunoshita Y, Komiya S (2009) Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer 100(12):1957–1965

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Kafchinski LA, Jones KB (2014) MicroRNAs in osteosarcomagenesis. Adv Exp Med Biol 804:119–127

    CAS  PubMed  Google Scholar 

  111. Nugent M (2014) MicroRNA function and dysregulation in bone tumors: the evidence to date. Cancer Manag Res 6:15–25

    PubMed Central  PubMed  Google Scholar 

  112. Sarver AL, Thayanithy V, Scott MC, Cleton-Jansen AM, Hogendoorn PC, Modiano JF, Subramanian S (2013) MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma. Orphanet J Rare Dis 8:7

    PubMed Central  PubMed  Google Scholar 

  113. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75(5):843–854

    CAS  PubMed  Google Scholar 

  114. Gougelet A, Pissaloux D, Besse A, Perez J, Duc A, Dutour A, Blay JY, Alberti L (2011) Micro-RNA profiles in osteosarcoma as a predictive tool for ifosfamide response. Int J Cancer 129(3):680–690

    CAS  PubMed  Google Scholar 

  115. Arabi L, Gsponer JR, Smida J, Nathrath M, Perrina V, Jundt G, Ruiz C, Quagliata L, Baumhoer D (2014) Upregulation of the miR-17-92 cluster and its two paraloga in osteosarcoma—reasons and consequences. Genes Cancer 5(1–2):56–63

    PubMed Central  PubMed  Google Scholar 

  116. Zhao H, Guo M, Zhao G, Ma Q, Ma B, Qiu X, Fan Q (2012) miR-183 inhibits the metastasis of osteosarcoma via downregulation of the expression of Ezrin in F5M2 cells. Int J Mol Med 30(5):1013–1020

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Zhou X, Wei M, Wang W (2013) MicroRNA-340 suppresses osteosarcoma tumor growth and metastasis by directly targeting ROCK1. Biochem Biophys Res Commun 437(4):653–658

    CAS  PubMed  Google Scholar 

  118. Poos K, Smida J, Nathrath M, Maugg D, Baumhoer D, Korsching E (2013) How microRNA and transcription factor co-regulatory networks affect osteosarcoma cell proliferation. PLoS Comput Biol 9(8):e1003210

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Thayanithy V, Dickson EL, Steer C, Subramanian S, Lou E (2014) Tumor-stromal cross talk: direct cell-to-cell transfer of oncogenic microRNAs via tunneling nanotubes. Transl Res 164(5):359–365

    CAS  PubMed  Google Scholar 

  120. Kansara M, Leong HS, Lin DM, Popkiss S, Pang P, Garsed DW, Walkley CR, Cullinane C, Ellul J, Haynes NM, Hicks R, Kuijjer ML, Cleton-Jansen AM, Hinds PW, Smyth MJ, Thomas DM (2013) Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. J Clin Invest 123(12):5351–5360

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Wang L, Zhang Q, Chen W, Shan B, Ding Y, Zhang G, Cao N, Liu L, Zhang Y (2013) B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS One 8(8):e70689

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Wang M, Wang L, Ren T, Xu L, Wen Z (2013) IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells. Cancer Biol Ther 14(2):155–163

    PubMed Central  PubMed  Google Scholar 

  123. Moore C, Eslin D, Levy A, Roberson J, Giusti V, Sutphin R (2010) Prognostic significance of early lymphocyte recovery in pediatric osteosarcoma. Pediatr Blood Cancer 55(6):1096–1102

    PubMed  Google Scholar 

  124. Jeys LM, Grimer RJ, Carter SR, Tillman RM, Abudu A (2007) Post operative infection and increased survival in osteosarcoma patients: are they associated? Ann Surg Oncol 14(10):2887–2895

    CAS  PubMed  Google Scholar 

  125. Kawano M, Itonaga I, Iwasaki T, Tsuchiya H, Tsumura H (2012) Anti-TGF-beta antibody combined with dendritic cells produce antitumor effects in osteosarcoma. Clin Orthop Relat Res 470(8):2288–2294

    PubMed Central  PubMed  Google Scholar 

  126. DeRenzo C, Gottschalk S (2014) Genetically modified T-cell therapy for osteosarcoma. Adv Exp Med Biol 804:323–340

    CAS  PubMed  Google Scholar 

  127. Rainusso N, Brawley VS, Ghazi A, Hicks MJ, Gottschalk S, Rosen JM, Ahmed N (2012) Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma. Cancer Gene Ther 19(3):212–217

    CAS  PubMed  Google Scholar 

  128. Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein ML, Conrad E, Ferguson W, Gebhardt M, Goorin AM, Harris MB, Healey J, Huvos A, Link M, Montebello J, Nadel H, Nieder M, Sato J, Siegal G, Weiner M, Wells R, Wold L, Womer R, Grier H (2005) Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23(9):2004–2011

    CAS  PubMed  Google Scholar 

  129. von Luettichau I, Segerer S, Wechselberger A, Notohamiprodjo M, Nathrath M, Kremer M, Henger A, Djafarzadeh R, Burdach S, Huss R, Nelson PJ (2008) A complex pattern of chemokine receptor expression is seen in osteosarcoma. BMC Cancer 8:23

    Google Scholar 

  130. Wang SW, Wu HH, Liu SC, Wang PC, Ou WC, Chou WY, Shen YS, Tang CH (2012) CCL5 and CCR5 interaction promotes cell motility in human osteosarcoma. PLoS One 7(4):e35101

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Wang SW, Liu SC, Sun HL, Huang TY, Chan CH, Yang CY, Yeh HI, Huang YL, Chou WY, Lin YM, Tang CH (2015) CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment. Carcinogenesis 36(1):104–114

    PubMed  Google Scholar 

  132. Chen PC, Cheng HC, Yang SF, Lin CW, Tang CH (2014) The CCN family proteins: modulators of bone development and novel targets in bone-associated tumors. Biomed Res Int 2014:437096

    PubMed Central  PubMed  Google Scholar 

  133. Manara MC, Perbal B, Benini S, Strammiello R, Cerisano V, Perdichizzi S, Serra M, Astolfi A, Bertoni F, Alami J, Yeger H, Picci P, Scotlandi K (2002) The expression of ccn3(nov) gene in musculoskeletal tumors. Am J Pathol 160(3):849–859

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Sabile AA, Arlt MJ, Muff R, Bode B, Langsam B, Bertz J, Jentzsch T, Puskas GJ, Born W, Fuchs B (2012) Cyr61 expression in osteosarcoma indicates poor prognosis and promotes intratibial growth and lung metastasis in mice. J Bone Miner Res 27(1):58–67

    CAS  PubMed  Google Scholar 

  135. Chen PC, Cheng HC, Tang CH (2013) CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway. Carcinogenesis 34(7):1669–1679

    CAS  PubMed  Google Scholar 

  136. Zhu L, McManus MM, Hughes DP (2013) Understanding the biology of bone sarcoma from early initiating events through late events in metastasis and disease progression. Front Oncol 3:230

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Ren L, Khanna C (2014) Role of ezrin in osteosarcoma metastasis. Adv Exp Med Biol 804:181–201

    CAS  PubMed  Google Scholar 

  138. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman LJ (2004) The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med 10(2):182–186

    CAS  PubMed  Google Scholar 

  139. Ren L, Hong SH, Cassavaugh J, Osborne T, Chou AJ, Kim SY, Gorlick R, Hewitt SM, Khanna C (2009) The actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC. Oncogene 28(6):792–802

    CAS  PubMed  Google Scholar 

  140. Koshkina NV, Khanna C, Mendoza A, Guan H, DeLauter L, Kleinerman ES (2007) Fas-negative osteosarcoma tumor cells are selected during metastasis to the lungs: the role of the Fas pathway in the metastatic process of osteosarcoma. Mol Cancer Res 5(10):991–999

    CAS  PubMed  Google Scholar 

  141. Gordon N, Arndt CA, Hawkins DS, Doherty DK, Inwards CY, Munsell MF, Stewart J, Koshkina NV, Kleinerman ES (2005) Fas expression in lung metastasis from osteosarcoma patients. J Pediatr Hematol Oncol 27(11):611–615

    PubMed  Google Scholar 

  142. Huang G, Nishimoto K, Yang Y, Kleinerman ES (2014) Participation of the Fas/FasL signaling pathway and the lung microenvironment in the development of osteosarcoma lung metastases. Adv Exp Med Biol 804:203–217

    CAS  PubMed  Google Scholar 

  143. Rao-Bindal K, Zhou Z, Kleinerman ES (2012) MS-275 sensitizes osteosarcoma cells to Fas ligand-induced cell death by increasing the localization of Fas in membrane lipid rafts. Cell Death Dis 3:e369

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Hou CH, Lin FL, Tong KB, Hou SM, Liu JF (2014) Transforming growth factor alpha promotes osteosarcoma metastasis by ICAM-1 and PI3K/Akt signaling pathway. Biochem Pharmacol 89(4):453–463

    CAS  PubMed  Google Scholar 

  145. El Naggar A, Clarkson P, Zhang F, Mathers J, Tognon C, Sorensen PH (2012) Expression and stability of hypoxia inducible factor 1alpha in osteosarcoma. Pediatr Blood Cancer 59(7):1215–1222

    PubMed  Google Scholar 

  146. Guo M, Cai C, Zhao G, Qiu X, Zhao H, Ma Q, Tian L, Li X, Hu Y, Liao B, Ma B, Fan Q (2014) Hypoxia promotes migration and induces CXCR4 expression via HIF-1alpha activation in human osteosarcoma. PLoS One 9(3):e90518

    PubMed Central  PubMed  Google Scholar 

  147. Scholten DJ 2nd, Timmer CM, Peacock JD, Pelle DW, Williams BO, Steensma MR (2014) Down regulation of wnt signaling mitigates hypoxia-induced chemoresistance in human osteosarcoma cells. PLoS One 9(10):e111431

    PubMed Central  PubMed  Google Scholar 

  148. Adamski J, Price A, Dive C, Makin G (2013) Hypoxia-induced cytotoxic drug resistance in osteosarcoma is independent of HIF-1Alpha. PLoS One 8(6):e65304

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Roncuzzi L, Pancotti F, Baldini N (2014) Involvement of HIF-1alpha activation in the doxorubicin resistance of human osteosarcoma cells. Oncol Rep 32(1):389–394

    CAS  PubMed  Google Scholar 

  150. Harada R, Kawamoto T, Ueha T, Minoda M, Toda M, Onishi Y, Fukase N, Hara H, Sakai Y, Miwa M, Kuroda R, Kurosaka M, Akisue T (2013) Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells. Exp Cell Res 319(13):1988–1997

    CAS  PubMed  Google Scholar 

  151. Matsubara T, Diresta GR, Kakunaga S, Li D, Healey JH (2013) additive influence of extracellular ph, oxygen tension, and pressure on invasiveness and survival of human osteosarcoma cells. Front Oncol 3:199

    PubMed Central  PubMed  Google Scholar 

  152. Rochet N, Loubat A, Laugier JP, Hofman P, Bouler JM, Daculsi G, Carle GF, Rossi B (2003) Modification of gene expression induced in human osteogenic and osteosarcoma cells by culture on a biphasic calcium phosphate bone substitute. Bone 32(6):602–610

    CAS  PubMed  Google Scholar 

  153. Adhikari AS, Agarwal N, Wood BM, Porretta C, Ruiz B, Pochampally RR, Iwakuma T (2010) CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance. Cancer Res 70(11):4602–4612

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Basu-Roy U, Basilico C, Mansukhani A (2013) Perspectives on cancer stem cells in osteosarcoma. Cancer Lett 338(1):158–167

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Siclari VA, Qin L (2010) Targeting the osteosarcoma cancer stem cell. J Orthop Surg Res 5:78

    PubMed Central  PubMed  Google Scholar 

  156. Zhang H, Wu H, Zheng J, Yu P, Xu L, Jiang P, Gao J, Wang H, Zhang Y (2013) Transforming growth factor beta1 signal is crucial for dedifferentiation of cancer cells to cancer stem cells in osteosarcoma. Stem Cells 31(3):433–446

    PubMed  Google Scholar 

  157. Wang L, Park P, Zhang H, La Marca F, Lin CY (2011) Prospective identification of tumorigenic osteosarcoma cancer stem cells in OS99-1 cells based on high aldehyde dehydrogenase activity. Int J Cancer 128(2):294–303

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Dr. Ashley Hamilton (from The Francis Crick Institute, London, UK) for her comprehensive revision of the manuscript. This work was supported by the Plan Nacional de I+D+i 2008–2011 [ISCIII/FEDER (PI11/00377, Miguel Servet Program CP11/00024 & CP11/00206) and RTICC (RD12/0036/0015, RD12/0036/0027 & RD12/0036/0017)], the Plan Nacional de I+D+i 2013–2016 [MINECO/FEDER (SAF-2013-42946-R & SAF2013-43065)], Grupo Español de Investigación en Sarcomas (GEIS), Generalitat de Catalunya (Grupo SGR330), Health Canada and Obra Social La Caixa/Fundaciò Josep Carreras.

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    1. Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

      Arantzazu Alfranca, Ander Abarrategi & Javier Garcia-Castro

    2. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, 33006, Oviedo, Spain

      Lucia Martinez-Cruzado, Juan Tornin & Rene Rodriguez

    3. Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK

      Ander Abarrategi

    4. Molecular Pathology Program, Institute of Biomedical Research of Salamanca-Centro de Investigación del Cáncer, Centro de Investigación del Cáncer (IBSAL-CIC), Salamanca, Spain

      Teresa Amaral & Enrique de Alava

    5. Department of Pathology and Biobank, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), CSIC-Universidad de Sevilla, Seville, Spain

      Teresa Amaral & Enrique de Alava

    6. Cell Therapy Program, School of Medicine, Josep Carreras Leukemia Research Institute, University of Barcelona, Barcelona, Spain

      Pablo Menendez

    7. Instituciò Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain

      Pablo Menendez

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    A. Alfranca, L. Martinez-Cruzado and J. Tornin contributed equally to this article.

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    Alfranca, A., Martinez-Cruzado, L., Tornin, J. et al. Bone microenvironment signals in osteosarcoma development. Cell. Mol. Life Sci. 72, 3097–3113 (2015). https://doi.org/10.1007/s00018-015-1918-y

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