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Stem Cells International
Volume 2016 (2016), Article ID 3631764, 13 pages
http://dx.doi.org/10.1155/2016/3631764
Review Article

Osteosarcoma: Cells-of-Origin, Cancer Stem Cells, and Targeted Therapies

1Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London WC2A 3LY, UK
2Central University Hospital of Asturias (HUCA) and Institute of Oncology of Asturias (IUOPA), 33011 Oviedo, Spain
3Complutense University of Madrid, 28040 Madrid, Spain
4Orthopaedic Pathophysiology and Regenerative Medicine Unit, Rizzoli Orthopaedic Institute, 40136 Bologna, Italy
5Department of Biomedical and Neuromotor Sciences, University of Bologna, 40123 Bologna, Italy
6Cellular Biotechnology Laboratory, Institute of Health Carlos III (ISCIII), Majadahonda, 28220 Madrid, Spain

Received 7 January 2016; Accepted 10 May 2016

Academic Editor: Andrzej Lange

Copyright © 2016 Ander Abarrategi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. E. Rosenberg, A. M. Cleton-Jansen, G. de Pinieux et al., “Conventional osteosarcoma,” in WHO Classification of Tumours of Soft Tissue and Bone, C. D. M. Fletcher, J. A. Bridge, P. C. W. Hogendoorn, and F. Mertens, Eds., pp. 282–288, International Agency for Research on Cancer, Lyon, France, 4th edition, 2013. View at Google Scholar
  2. A. Alfranca, L. Martinez-Cruzado, J. Tornin et al., “Bone microenvironment signals in osteosarcoma development,” Cellular and Molecular Life Sciences, vol. 72, no. 16, pp. 3097–3113, 2015. View at Publisher · View at Google Scholar · View at Scopus
  3. S. M. Botter, D. Neri, and B. Fuchs, “Recent advances in osteosarcoma,” Current Opinion in Pharmacology, vol. 16, no. 1, pp. 15–23, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. D. C. Allison, S. C. Carney, E. R. Ahlmann et al., “A meta-analysis of osteosarcoma outcomes in the modern medical era,” Sarcoma, vol. 2012, Article ID 704872, 10 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  5. A. J. Ng, A. J. Mutsaers, E. K. Baker, and C. R. Walkley, “Genetically engineered mouse models and human osteosarcoma,” Clinical Sarcoma Research, vol. 2, no. 1, article 19, 2012. View at Publisher · View at Google Scholar
  6. N. Tang, W.-X. Song, J. Luo, R. C. Haydon, and T.-C. He, “Osteosarcoma development and stem cell differentiation,” Clinical Orthopaedics and Related Research, vol. 466, no. 9, pp. 2114–2130, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. K. B. Jones, “Osteosarcomagenesis: modeling cancer initiation in the mouse,” Sarcoma, vol. 2011, Article ID 694136, 10 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. D. Malkin, K. W. Jolly, N. Barbier et al., “Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms,” The New England Journal of Medicine, vol. 326, no. 20, pp. 1309–1315, 1992. View at Publisher · View at Google Scholar · View at Scopus
  9. F. L. Wong, J. D. Boice Jr., D. H. Abramson et al., “Cancer incidence after retinoblastoma: radiation dose and sarcoma risk,” Journal of the American Medical Association, vol. 278, no. 15, pp. 1262–1267, 1997. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Overholtzer, P. H. Rao, R. Favis et al., “The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 20, pp. 11547–11552, 2003. View at Google Scholar
  11. B.-I. Wadayama, J. Toguchida, T. Shimizu et al., “Mutation spectrum of the retinoblastoma gene in osteosarcomas,” Cancer Research, vol. 54, no. 11, pp. 3042–3048, 1994. View at Google Scholar · View at Scopus
  12. R. Rodriguez, R. Rubio, and P. Menendez, “Modeling sarcomagenesis using multipotent mesenchymal stem cells,” Cell Research, vol. 22, no. 1, pp. 62–77, 2012. View at Publisher · View at Google Scholar · View at Scopus
  13. S. D. Berman, E. Calo, A. S. Landman et al., “Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 11851–11856, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. P. P. Lin, M. K. Pandey, F. Jin, A. K. Raymond, H. Akiyama, and G. Lozano, “Targeted mutation of p53 and Rb in mesenchymal cells of the limb bud produces sarcomas in mice,” Carcinogenesis, vol. 30, no. 10, pp. 1789–1795, 2009. View at Publisher · View at Google Scholar · View at Scopus
  15. C. R. Walkley, R. Qudsi, V. G. Sankaran et al., “Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease,” Genes and Development, vol. 22, no. 12, pp. 1662–1676, 2008. View at Publisher · View at Google Scholar · View at Scopus
  16. E. Calo, J. A. Quintero-Estades, P. S. Danielian, S. Nedelcu, S. D. Berman, and J. A. Lees, “Rb regulates fate choice and lineage commitment in vivo,” Nature, vol. 466, no. 7310, pp. 1110–1114, 2010. View at Publisher · View at Google Scholar · View at Scopus
  17. M. S. Benassi, L. Molendini, G. Gamberi et al., “Alteration of prb/p16/cdk4 regulation in human osteosarcoma,” International Journal of Cancer, vol. 84, no. 5, pp. 489–493, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. J. A. López-Guerrero, C. López-Ginés, A. Pellín, C. Carda, and A. Llombart-Bosch, “Deregulation of the G1 to S-phase cell cycle checkpoint is involved in the pathogenesis of human osteosarcoma,” Diagnostic Molecular Pathology, vol. 13, no. 2, pp. 81–91, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. G. M. Maelandsmo, J.-M. Berner, V. A. Florenes et al., “Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas—relationship to amplification and mRNA levels of CDK4 and CCND1,” British Journal of Cancer, vol. 72, no. 2, pp. 393–398, 1995. View at Publisher · View at Google Scholar · View at Scopus
  20. Y. Zhang, Y. Xiong, and W. G. Yarbrough, “ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways,” Cell, vol. 92, no. 6, pp. 725–734, 1998. View at Publisher · View at Google Scholar · View at Scopus
  21. F. Lonardo, T. Ueda, A. G. Huvos, J. Healey, and M. Ladanyi, “p53 and MDM2 alterations in osteosarcomas: correlation with clinicopathologic features and proliferative rate,” Cancer, vol. 79, no. 8, pp. 1541–1547, 1997. View at Publisher · View at Google Scholar · View at Scopus
  22. M. Ladanyi, C. Cha, R. Lewis, S. C. Jhanwar, A. G. Huvos, and J. H. Healey, “MDM2 gene amplification in metastatic osteosarcoma,” Cancer Research, vol. 53, no. 1, pp. 16–18, 1993. View at Google Scholar · View at Scopus
  23. W. W. Lockwood, D. Stack, T. Morris et al., “Cyclin E1 is amplified and overexpressed in osteosarcoma,” Journal of Molecular Diagnostics, vol. 13, no. 3, pp. 289–296, 2011. View at Publisher · View at Google Scholar · View at Scopus
  24. G. Gamberi, M. S. Benassi, T. Bohling et al., “C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression,” Oncology, vol. 55, no. 6, pp. 556–563, 1998. View at Publisher · View at Google Scholar · View at Scopus
  25. D. J. Papachristou, A. Batistatou, G. P. Sykiotis, I. Varakis, and A. G. Papavassiliou, “Activation of the JNK-AP-1 signal transduction pathway is associated with pathogenesis and progression of human osteosarcomas,” Bone, vol. 32, no. 4, pp. 364–371, 2003. View at Publisher · View at Google Scholar · View at Scopus
  26. J.-X. Wu, P. M. Carpenter, C. Gresens et al., “The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas,” Oncogene, vol. 5, no. 7, pp. 989–1000, 1990. View at Google Scholar · View at Scopus
  27. Z.-Q. Wang, J. Liang, K. Schellander, E. F. Wagner, and A. E. Grigoriadis, “c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos,” Cancer Research, vol. 55, no. 24, pp. 6244–6251, 1995. View at Google Scholar · View at Scopus
  28. J. Smida, D. Baumhoer, M. Rosemann et al., “Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma,” Clinical Cancer Research, vol. 16, no. 16, pp. 4256–4267, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Ueda, J. H. Healey, A. G. Huvos, and M. Ladanyi, “Amplification of the MYC gene in osteosarcoma secondary to Paget's disease of bone,” Sarcoma, vol. 1, no. 3-4, pp. 131–134, 1997. View at Publisher · View at Google Scholar · View at Scopus
  30. I. Scionti, F. Michelacci, M. Pasello et al., “Clinical impact of the methotrexate resistance-associated genes C-MYC and dihydrofolate reductase (DHFR) in high-grade osteosarcoma,” Annals of Oncology, vol. 19, no. 8, pp. 1500–1508, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. F. Lamoureux, G. Picarda, J. Rousseau et al., “Therapeutic efficacy of soluble receptor activator of nuclear factor-κB-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma,” Molecular Cancer Therapeutics, vol. 7, no. 10, pp. 3389–3398, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. F. Lamoureux, P. Richard, Y. Wittrant et al., “Therapeutic relevance of osteoprotegerin gene therapy in osteosarcoma: blockade of the vicious cycle between tumor cell proliferation and bone resorption,” Cancer Research, vol. 67, no. 15, pp. 7308–7318, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. G. Moriceau, B. Ory, B. Gobin et al., “Therapeutic approach of primary bone tumours by bisphosphonates,” Current Pharmaceutical Design, vol. 16, no. 27, pp. 2981–2987, 2010. View at Publisher · View at Google Scholar · View at Scopus
  34. G. M. Y. Quan and P. F. M. Choong, “Anti-angiogenic therapy for osteosarcoma,” Cancer and Metastasis Reviews, vol. 25, no. 4, pp. 707–713, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. B. Gobin, M. B. Huin, F. Lamoureux et al., “BYL719, a new α-specific PI3K inhibitor: single administration and in combination with conventional chemotherapy for the treatment of osteosarcoma,” International Journal of Cancer, vol. 136, no. 4, pp. 784–796, 2015. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. Ma, Y. Ren, E. Q. Han et al., “Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy,” Biochemical and Biophysical Research Communications, vol. 431, no. 2, pp. 274–279, 2013. View at Publisher · View at Google Scholar · View at Scopus
  37. P. McQueen, S. Ghaffar, Y. Guo, E. M. Rubin, X. Zi, and B. H. Hoang, “The Wnt signaling pathway: implications for therapy in osteosarcoma,” Expert Review of Anticancer Therapy, vol. 11, no. 8, pp. 1223–1232, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. S. R. Martins-Neves, W. E. Corver, D. I. Paiva-Oliveira et al., “Osteosarcoma stem cells have active Wnt/β-catenin and overexpress SOX2 and KLF4,” Journal of Cellular Physiology, vol. 231, no. 4, pp. 876–886, 2016. View at Publisher · View at Google Scholar · View at Scopus
  39. X. Mu, C. Isaac, N. Greco, J. Huard, and K. Weiss, “Notch signaling is associated with ALDH activity and an aggressive metastatic phenotype in murine osteosarcoma cells,” Frontiers in Oncology, vol. 3, article 143, 2013. View at Publisher · View at Google Scholar · View at Scopus
  40. Y. Cai, T. Cai, and Y. Chen, “Wnt pathway in osteosarcoma, from oncogenic to therapeutic,” Journal of Cellular Biochemistry, vol. 115, no. 4, pp. 625–631, 2014. View at Publisher · View at Google Scholar · View at Scopus
  41. Y. Li, J. Zhang, D. Ma et al., “Curcumin inhibits proliferation and invasion of osteosarcoma cells through inactivation of Notch-1 signaling,” The FEBS Journal, vol. 279, no. 12, pp. 2247–2259, 2012. View at Publisher · View at Google Scholar · View at Scopus
  42. G. Chen, C. Deng, and Y.-P. Li, “TGF-β and BMP signaling in osteoblast differentiation and bone formation,” International Journal of Biological Sciences, vol. 8, no. 2, pp. 272–288, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Lamora, M. Mullard, J. Amiaud et al., “Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases,” Oncotarget, vol. 6, no. 16, pp. 14413–14427, 2015. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Lamora, J. Talbot, G. Bougras et al., “Overexpression of Smad7 blocks primary tumor growth and lung metastasis development in osteosarcoma,” Clinical Cancer Research, vol. 20, no. 19, pp. 5097–5112, 2014. View at Publisher · View at Google Scholar · View at Scopus
  45. H. Zhang, H. Wu, J. Zheng et al., “Transforming growth factor β1 signal is crucial for dedifferentiation of cancer cells to cancer stem cells in osteosarcoma,” STEM CELLS, vol. 31, no. 3, pp. 433–446, 2013. View at Publisher · View at Google Scholar · View at Scopus
  46. E. Kobayashi, F. J. Hornicek, and Z. Duan, “MicroRNA involvement in osteosarcoma,” Sarcoma, vol. 2012, Article ID 359739, 8 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. R. Di Fiore, R. Drago-Ferrante, F. Pentimali et al., “MicroRNA-29b-1 impairs in vitro cell proliferation, self-renewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells,” International Journal of Oncology, vol. 45, no. 5, pp. 2013–2023, 2014. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Xu, H. Jin, C.-X. Xu et al., “miR-382 inhibits osteosarcoma metastasis and relapse by targeting y box-binding protein 1,” Molecular Therapy, vol. 23, no. 1, pp. 89–98, 2015. View at Publisher · View at Google Scholar · View at Scopus
  49. T. Fujiwara, T. Katsuda, K. Hagiwara et al., “Clinical relevance and therapeutic significance of microRNA-133a expression profiles and functions in malignant osteosarcoma-initiating cells,” Stem Cells, vol. 32, no. 4, pp. 959–973, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. B. Song, Y. Wang, M. A. Titmus et al., “Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells,” Molecular Cancer, vol. 9, article 96, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. B. S. Moriarity, G. M. Otto, E. P. Rahrmann et al., “A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis,” Nature Genetics, vol. 47, no. 6, pp. 615–624, 2015. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Kovac, C. Blattmann, S. Ribi et al., “Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency,” Nature Communications, vol. 6, article 8940, 2015. View at Publisher · View at Google Scholar
  53. M. L. Kuijjer, H. Rydbeck, S. H. Kresse et al., “Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data,” Genes Chromosomes and Cancer, vol. 51, no. 7, pp. 696–706, 2012. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Ou, W.-W. Cai, L. Zender et al., “MMP13, Birc2 (clAP1), and Birc3 (clAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression,” Cancer Research, vol. 69, no. 6, pp. 2559–2567, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Xiong, S. Wu, Q. Du, A. Wang, and Z. Wang, “Integrated analysis of gene expression and genomic aberration data in osteosarcoma (OS),” Cancer Gene Therapy, vol. 22, no. 11, pp. 524–529, 2015. View at Publisher · View at Google Scholar
  56. N. Entz-Werle, T. Lavaux, N. Metzger et al., “Involvement of MET/TWIST/APC combination or the potential role of ossification factors in pediatric high-grade osteosarcoma oncogenesis,” Neoplasia, vol. 9, no. 8, pp. 678–688, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. X. Chen, A. Bahrami, A. Pappo et al., “Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma,” Cell Reports, vol. 7, no. 1, pp. 104–112, 2014. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Kansara, M. W. Teng, M. J. Smyth, and D. M. Thomas, “Translational biology of osteosarcoma,” Nature Reviews Cancer, vol. 14, no. 11, pp. 722–735, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Mendoza, H. David, G. M. Gaylord, and C. W. Miller, “Allelic loss at 10q26 in osteosarcoma in the region of the BUB3 and FGFR2 genes,” Cancer Genetics and Cytogenetics, vol. 158, no. 2, pp. 142–147, 2005. View at Publisher · View at Google Scholar · View at Scopus
  60. K. Rao-Bindal and E. S. Kleinerman, “Epigenetic regulation of apoptosis and cell cycle in osteosarcoma,” Sarcoma, vol. 2011, Article ID 679457, 5 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. L. L. Wang, A. Gannavarapu, C. A. Kozinetz et al., “Association between osteosarcoma and deleterious mutations in the RECQL4 gene Rothmund-Thomson syndrome,” Journal of the National Cancer Institute, vol. 95, no. 9, pp. 669–674, 2003. View at Publisher · View at Google Scholar · View at Scopus
  62. J. E. Visvader, “Cells of origin in cancer,” Nature, vol. 469, no. 7330, pp. 314–322, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. A. J. Mutsaers and C. R. Walkley, “Cells of origin in osteosarcoma: mesenchymal stem cells or osteoblast committed cells?” Bone, vol. 62, pp. 56–63, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. W. Xiao, A. B. Mohseny, P. C. Hogendoorn, and A. M. Cleton-Jansen, “Mesenchymal stem cell transformation and sarcoma genesis,” Clinical Sarcoma Research, vol. 3, no. 1, article 10, 2013. View at Publisher · View at Google Scholar
  65. R. Rodríguez, J. García-Castro, C. Trigueros, M. García Arranz, and P. Menéndez, “Multipotent mesenchymal stromal cells: clinical applications and cancer modeling,” Advances in Experimental Medicine and Biology, vol. 741, pp. 187–205, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. R. Rodriguez, J. Tornin, C. Suarez et al., “Expression of FUS-CHOP fusion protein in immortalized/transformed human mesenchymal stem cells drives mixoid liposarcoma formation,” Stem Cells, vol. 31, no. 10, pp. 2061–2072, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. A. J. Mutsaers, A. J. M. Ng, E. K. Baker et al., “Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and lineage-restricted transgenic shRNA,” Bone, vol. 55, no. 1, pp. 166–178, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. S. D. Molyneux, M. A. Di Grappa, A. G. Beristain et al., “Prkar1a is an osteosarcoma tumor suppressor that defines a molecular subclass in mice,” The Journal of Clinical Investigation, vol. 120, no. 9, pp. 3310–3325, 2010. View at Publisher · View at Google Scholar · View at Scopus
  69. J. L. Sottnik, B. Campbell, R. Mehra, O. Behbahani-Nejad, C. L. Hall, and E. T. Keller, “Osteocytes serve as a progenitor cell of osteosarcoma,” Journal of Cellular Biochemistry, vol. 115, no. 8, pp. 1420–1429, 2014. View at Publisher · View at Google Scholar · View at Scopus
  70. J. Tao, M.-M. Jiang, L. Jiang et al., “Notch activation as a driver of osteogenic sarcoma,” Cancer Cell, vol. 26, no. 3, pp. 390–401, 2014. View at Publisher · View at Google Scholar · View at Scopus
  71. L. H. Chan, W. Wang, W. Yeung, Y. Deng, P. Yuan, and K. K. Mak, “Hedgehog signaling induces osteosarcoma development through Yap1 and H19 overexpression,” Oncogene, vol. 33, no. 40, pp. 4857–4866, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. T. Quist, H. Jin, J.-F. Zhu, K. Smith-Fry, M. R. Capecchi, and K. B. Jones, “The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse,” Oncogene, vol. 34, no. 32, pp. 4278–4284, 2015. View at Publisher · View at Google Scholar · View at Scopus
  73. R. Rubio, J. García-Castro, I. Gutiérrez-Aranda et al., “Deficiency in p53 but not retinoblastoma induces the transformation of mesenchymal stem cells in vitro and initiates leiomyosarcoma in vivo,” Cancer Research, vol. 70, no. 10, pp. 4185–4194, 2010. View at Publisher · View at Google Scholar · View at Scopus
  74. R. Rubio, I. Gutierrez-Aranda, A. I. Sáez-Castillo et al., “The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development,” Oncogene, vol. 32, no. 41, pp. 4970–4980, 2013. View at Publisher · View at Google Scholar · View at Scopus
  75. R. Rubio, A. Abarrategi, J. Garcia-Castro et al., “Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells,” Stem Cells, vol. 32, no. 5, pp. 1136–1148, 2014. View at Publisher · View at Google Scholar · View at Scopus
  76. A. B. Mohseny, K. Szuhai, S. Romeo et al., “Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2,” The Journal of Pathology, vol. 219, no. 3, pp. 294–305, 2009. View at Publisher · View at Google Scholar · View at Scopus
  77. T. Shimizu, T. Ishikawa, E. Sugihara et al., “C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis,” Oncogene, vol. 29, no. 42, pp. 5687–5699, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. A.-M. Cleton-Jansen, J. K. Anninga, I. H. Briaire-de Bruijn et al., “Profiling of high-grade central osteosarcoma and its putative progenitor cells identifies tumourigenic pathways,” British Journal of Cancer, vol. 101, no. 11, pp. 1909–1918, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. D. R. Lemos, C. Eisner, C. I. Hopkins, and F. M. V. Rossi, “Skeletal muscle-resident MSCs and bone formation,” Bone, vol. 80, pp. 19–23, 2015. View at Publisher · View at Google Scholar · View at Scopus
  80. F. S. Kaplan, S. A. Chakkalakal, and E. M. Shore, “Fibrodysplasia ossificans progressiva: mechanisms and models of skeletal metamorphosis,” Disease Models and Mechanisms, vol. 5, no. 6, pp. 756–762, 2012. View at Publisher · View at Google Scholar · View at Scopus
  81. U. Basu-Roy, C. Basilico, and A. Mansukhani, “Perspectives on cancer stem cells in osteosarcoma,” Cancer Letters, vol. 338, no. 1, pp. 158–167, 2013. View at Publisher · View at Google Scholar · View at Scopus
  82. F. S. Dela Cruz, “Cancer stem cells in pediatric sarcomas,” Frontiers in Oncology, vol. 3, article 168, 2013. View at Publisher · View at Google Scholar · View at Scopus
  83. B. Liu, W. Ma, R. K. Jha, and K. Gurung, “Cancer stem cells in osteosarcoma: recent progress and perspective,” Acta Oncologica, vol. 50, no. 8, pp. 1142–1150, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. V. A. Siclari and L. Qin, “Targeting the osteosarcoma cancer stem cell,” Journal of Orthopaedic Surgery and Research, vol. 5, no. 1, article 78, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. V. Tirino, V. Desiderio, F. Paino et al., “Cancer stem cells in solid tumors: an overview and new approaches for their isolation and characterization,” The FASEB Journal, vol. 27, no. 1, pp. 13–24, 2013. View at Publisher · View at Google Scholar · View at Scopus
  86. C. P. Gibbs, V. G. Kukekov, J. D. Reith et al., “Stem-like cells in bone sarcomas: implications for tumorigenesis,” Neoplasia, vol. 7, no. 11, pp. 967–976, 2005. View at Publisher · View at Google Scholar · View at Scopus
  87. L. Wang, P. Park, and C.-Y. Lin, “Characterization of stem cell attributes in human osteosarcoma cell lines,” Cancer Biology and Therapy, vol. 8, no. 6, pp. 543–552, 2009. View at Google Scholar · View at Scopus
  88. H. Wilson, M. Huelsmeyer, R. Chun, K. M. Young, K. Friedrichs, and D. J. Argyle, “Isolation and characterisation of cancer stem cells from canine osteosarcoma,” Veterinary Journal, vol. 175, no. 1, pp. 69–75, 2008. View at Publisher · View at Google Scholar · View at Scopus
  89. M. Salerno, S. Avnet, G. Bonuccelli et al., “Sphere-forming cell subsets with cancer stem cell properties in human musculoskeletal sarcomas,” International Journal of Oncology, vol. 43, no. 1, pp. 95–102, 2013. View at Publisher · View at Google Scholar · View at Scopus
  90. A. He, X. Yang, Y. Huang et al., “CD133+CD+ cells mediate in the lung metastasis of osteosarcoma,” Journal of Cellular Biochemistry, vol. 116, no. 8, pp. 1719–1729, 2015. View at Publisher · View at Google Scholar · View at Scopus
  91. J. Li, X.-Y. Zhong, Z.-Y. Li et al., “CD133 expression in osteosarcoma and derivation of CD133+ cells,” Molecular Medicine Reports, vol. 7, no. 2, pp. 577–584, 2013. View at Publisher · View at Google Scholar · View at Scopus
  92. V. Tirino, V. Desiderio, F. Paino et al., “Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo,” FASEB Journal, vol. 25, no. 6, pp. 2022–2030, 2011. View at Publisher · View at Google Scholar · View at Scopus
  93. A. S. Adhikari, N. Agarwal, B. M. Wood et al., “CD117 and Stro-1 identify osteosarcoma tumor-initiating cells associated with metastasis and drug resistance,” Cancer Research, vol. 70, no. 11, pp. 4602–4612, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. J. Tian, X. Li, M. Si, T. Liu, and J. Li, “CD271+ osteosarcoma cells display stem-like properties,” PLoS ONE, vol. 9, no. 6, article e98549, 2014. View at Publisher · View at Google Scholar · View at Scopus
  95. M. Murase, M. Kano, T. Tsukahara et al., “Side population cells have the characteristics of cancer stem-like cells/cancer-initiating cells in bone sarcomas,” British Journal of Cancer, vol. 101, no. 8, pp. 1425–1432, 2009. View at Publisher · View at Google Scholar · View at Scopus
  96. D.-X. Sun, G.-J. Liao, K.-G. Liu, and H. Jian, “Endosialin-expressing bone sarcoma stem-like cells are highly tumor-initiating and invasive,” Molecular Medicine Reports, vol. 12, no. 4, pp. 5665–5670, 2015. View at Publisher · View at Google Scholar · View at Scopus
  97. K. Honoki, H. Fujii, A. Kubo et al., “Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance,” Oncology Reports, vol. 24, no. 2, pp. 501–505, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. L. Wang, P. Park, H. Zhang, F. La Marca, and C.-Y. Lin, “Prospective identification of tumorigenic osteosarcoma cancer stem cells in OS99-1 cells based on high aldehyde dehydrogenase activity,” International Journal of Cancer, vol. 128, no. 2, pp. 294–303, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. P. P. Levings, S. V. McGarry, T. P. Currie et al., “Expression of an exogenous human Oct-4 promoter identifies tumor-initiating cells in osteosarcoma,” Cancer Research, vol. 69, no. 14, pp. 5648–5655, 2009. View at Publisher · View at Google Scholar · View at Scopus
  100. L. Yu, S. Liu, W. Guo et al., “hTERT promoter activity identifies osteosarcoma cells with increased EMT characteristics,” Oncology Letters, vol. 7, no. 1, pp. 239–244, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. L. Yu, S. Liu, C. Zhang et al., “Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity,” Oncotarget, vol. 4, no. 12, pp. 2326–2338, 2013. View at Publisher · View at Google Scholar · View at Scopus
  102. R. Di Fiore, A. Santulli, R. D. Ferrante et al., “Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment,” Journal of Cellular Physiology, vol. 219, no. 2, pp. 301–313, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. Q.-L. Tang, Y. Liang, X.-B. Xie et al., “Enrichment of osteosarcoma stem cells by chemotherapy,” Chinese Journal of Cancer, vol. 30, no. 6, pp. 426–432, 2011. View at Publisher · View at Google Scholar · View at Scopus
  104. N. Naka, S. Takenaka, N. Araki et al., “Synovial sarcoma is a stem cell malignancy,” Stem Cells, vol. 28, no. 7, pp. 1119–1131, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. H. Fujii, K. Honoki, T. Tsujiuchi, A. Kido, K. Yoshitani, and Y. Takakura, “Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines,” International Journal of Oncology, vol. 34, no. 5, pp. 1381–1386, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. G.-N. Yan, Y.-F. Lv, and Q.-N. Guo, “Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets,” Cancer Letters, vol. 370, no. 2, pp. 268–274, 2016. View at Publisher · View at Google Scholar
  107. U. Basu-Roy, E. Seo, L. Ramanathapuram et al., “Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas,” Oncogene, vol. 31, no. 18, pp. 2270–2282, 2012. View at Publisher · View at Google Scholar · View at Scopus
  108. M. Salerno, S. Avnet, G. Bonuccelli, S. Hosogi, D. Granchi, and N. Baldini, “Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD,” PLoS ONE, vol. 9, no. 10, Article ID e110340, 2014. View at Publisher · View at Google Scholar · View at Scopus
  109. H. He, J. Ni, and J. Huang, “Molecular mechanisms of chemoresistance in osteosarcoma (Review),” Oncology Letters, vol. 7, no. 5, pp. 1352–1362, 2014. View at Publisher · View at Google Scholar · View at Scopus
  110. S. R. Martins-Neves, Á. O. Lopes, A. do Carmo et al., “Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line,” BMC Cancer, vol. 12, article 139, 2012. View at Publisher · View at Google Scholar · View at Scopus
  111. M. Yang, M. Yan, R. Zhang, J. Li, and Z. Luo, “Side population cells isolated from human osteosarcoma are enriched with tumor-initiating cells,” Cancer Science, vol. 102, no. 10, pp. 1774–1781, 2011. View at Publisher · View at Google Scholar · View at Scopus
  112. C. Gonçalves, S. R. Martins-Neves, D. Paiva-Oliveira, V. E. B. Oliveira, C. Fontes-Ribeiro, and C. M. F. Gomes, “Sensitizing osteosarcoma stem cells to doxorubicin-induced apoptosis through retention of doxorubicin and modulation of apoptotic-related proteins,” Life Sciences, vol. 130, pp. 47–56, 2015. View at Publisher · View at Google Scholar · View at Scopus
  113. V. Plaks, N. Kong, and Z. Werb, “The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?” Cell Stem Cell, vol. 16, no. 3, pp. 225–238, 2015. View at Publisher · View at Google Scholar · View at Scopus
  114. N. Z. Kuhn and R. S. Tuan, “Regulation of stemness and stem cell niche of mesenchymal stem cells: implications in tumorigenesis and metastasis,” Journal of Cellular Physiology, vol. 222, no. 2, pp. 268–277, 2010. View at Publisher · View at Google Scholar · View at Scopus
  115. W. Zeng, R. Wan, Y. Zheng, S. R. Singh, and Y. Wei, “Hypoxia, stem cells and bone tumor,” Cancer Letters, vol. 313, no. 2, pp. 129–136, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. B. F. Boyce and L. Xing, “Functions of RANKL/RANK/OPG in bone modeling and remodeling,” Archives of Biochemistry and Biophysics, vol. 473, no. 2, pp. 139–146, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. P. F. M. Choong, M. L. Broadhead, J. C. M. Clark, D. E. Myers, and C. R. Dass, “The molecular pathogenesis of osteosarcoma: a review,” Sarcoma, vol. 2011, Article ID 959248, 12 pages, 2011. View at Publisher · View at Google Scholar · View at Scopus
  118. J. L. Harwood, J. H. Alexander, J. L. Mayerson, and T. J. Scharschmidt, “Targeted chemotherapy in bone and soft-tissue sarcoma,” Orthopedic Clinics of North America, vol. 46, no. 4, pp. 587–608, 2015. View at Publisher · View at Google Scholar · View at Scopus
  119. C. M. Hattinger, M. Fanelli, E. Tavanti et al., “Advances in emerging drugs for osteosarcoma,” Expert Opinion on Emerging Drugs, vol. 20, no. 3, pp. 495–514, 2015. View at Publisher · View at Google Scholar · View at Scopus
  120. D. Heymann and F. Rédini, “Targeted therapies for bone sarcomas,” Bonekey Reports, vol. 2, article 378, 2013. View at Publisher · View at Google Scholar
  121. R. Cathomas, C. Rothermundt, B. Bode, B. Fuchs, R. Von Moos, and M. Schwitter, “RANK ligand blockade with denosumab in combination with sorafenib in chemorefractory osteosarcoma: a possible step forward?” Oncology, vol. 88, no. 4, pp. 257–260, 2014. View at Publisher · View at Google Scholar · View at Scopus
  122. V. B. Sampson, R. Gorlick, D. Kamara, and E. Anders Kolb, “A review of targeted therapies evaluated by the pediatric preclinical testing program for osteosarcoma,” Frontiers in Oncology, vol. 3, article 132, 2013. View at Publisher · View at Google Scholar · View at Scopus
  123. C. DeRenzo and S. Gottschalk, “Genetically modified T-cell therapy for osteosarcoma,” Advances in Experimental Medicine and Biology, vol. 804, pp. 323–340, 2014. View at Publisher · View at Google Scholar · View at Scopus
  124. M. Kawano, I. Itonaga, T. Iwasaki, H. Tsuchiya, and H. Tsumura, “Anti-TGF-β antibody combined with dendritic cells produce antitumor effects in osteosarcoma,” Clinical Orthopaedics and Related Research, vol. 470, no. 8, pp. 2288–2294, 2012. View at Publisher · View at Google Scholar · View at Scopus
  125. N. Rainusso, V. S. Brawley, A. Ghazi et al., “Immunotherapy targeting HER2 with genetically modified T cells eliminates tumor-initiating cells in osteosarcoma,” Cancer Gene Therapy, vol. 19, no. 3, pp. 212–217, 2012. View at Publisher · View at Google Scholar · View at Scopus
  126. N. Tarek and D. A. Lee, “Natural killer cells for osteosarcoma,” Advances in Experimental Medicine and Biology, vol. 804, pp. 341–353, 2014. View at Publisher · View at Google Scholar · View at Scopus
  127. R. Di Fiore, D. Fanale, R. Drago-Ferrante et al., “Genetic and molecular characterization of the human osteosarcoma 3AB-OS cancer stem cell line: a possible model for studying osteosarcoma origin and stemness,” Journal of Cellular Physiology, vol. 228, no. 6, pp. 1189–1201, 2013. View at Publisher · View at Google Scholar · View at Scopus
  128. M. Gemei, C. Corbo, F. D'Alessio, R. Di Noto, R. Vento, and L. Del Vecchio, “Surface proteomic analysis of differentiated versus stem-like osteosarcoma human cells,” Proteomics, vol. 13, no. 22, pp. 3293–3297, 2013. View at Publisher · View at Google Scholar · View at Scopus
  129. D. Zuch, A.-H. Giang, Y. Shapovalov et al., “Targeting radioresistant osteosarcoma cells with parthenolide,” Journal of Cellular Biochemistry, vol. 113, no. 4, pp. 1282–1291, 2012. View at Publisher · View at Google Scholar · View at Scopus
  130. R. K. Mongre, S. S. Sodhi, M. Ghosh et al., “The novel inhibitor BRM270 downregulates tumorigenesis by suppression of NF-κB signaling cascade in MDR-induced stem like cancer-initiating cells,” International Journal of Oncology, vol. 46, no. 6, pp. 2573–2585, 2015. View at Publisher · View at Google Scholar · View at Scopus
  131. C. Gong, H. Liao, J. Wang et al., “LY294002 induces G0/G1 cell cycle arrest and apoptosis of cancer stem-like cells from human osteosarcoma via downregulation of PI3K activity,” Asian Pacific Journal of Cancer Prevention, vol. 13, no. 7, pp. 3103–3107, 2012. View at Publisher · View at Google Scholar · View at Scopus
  132. X.-J. Yi, Y.-H. Zhao, L.-X. Qiao, C.-L. Jin, J. Tian, and Q.-S. Li, “Aberrant Wnt/β-catenin signaling and elevated expression of stem cell proteins are associated with osteosarcoma side population cells of high tumorigenicity,” Molecular Medicine Reports, vol. 12, no. 4, pp. 5042–5048, 2015. View at Publisher · View at Google Scholar · View at Scopus
  133. U. Krause, D. M. Ryan, B. H. Clough, and C. A. Gregory, “An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity,” Cell Death and Disease, vol. 5, no. 2, Article ID e1093, 2014. View at Publisher · View at Google Scholar · View at Scopus
  134. B. Song, Y. Wang, Y. Xi et al., “Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells,” Oncogene, vol. 28, no. 46, pp. 4065–4074, 2009. View at Publisher · View at Google Scholar · View at Scopus
  135. Y. Wang, J. Yao, H. Meng et al., “A novel long non-coding RNA, hypoxia-inducible factor-2α promoter upstream transcript, functions as an inhibitor of osteosarcoma stem cells in vitro,” Molecular Medicine Reports, vol. 11, no. 4, pp. 2534–2540, 2015. View at Publisher · View at Google Scholar · View at Scopus
  136. X. Chen, C. Hu, W. Zhang et al., “Metformin inhibits the proliferation, metastasis, and cancer stem-like sphere formation in osteosarcoma MG63 cells in vitro,” Tumor Biology, vol. 36, no. 12, pp. 9873–9883, 2015. View at Publisher · View at Google Scholar
  137. I. Quattrini, A. Conti, L. Pazzaglia et al., “Metformin inhibits growth and sensitizes osteosarcoma cell lines to cisplatin through cell cycle modulation,” Oncology Reports, vol. 31, no. 1, pp. 370–375, 2014. View at Publisher · View at Google Scholar · View at Scopus
  138. Y. Chang, Y. Zhao, W. Gu et al., “Bufalin inhibits the differentiation and proliferation of cancer stem cells derived from primary osteosarcoma cells through Mir-148a,” Cellular Physiology and Biochemistry, vol. 36, no. 3, pp. 1186–1196, 2015. View at Publisher · View at Google Scholar · View at Scopus
  139. Y. Chang, Y. Zhao, H. Zhan, X. Wei, T. Liu, and B. Zheng, “Bufalin inhibits the differentiation and proliferation of human osteosarcoma cell line hMG63-derived cancer stem cells,” Tumor Biology, vol. 35, no. 2, pp. 1075–1082, 2014. View at Publisher · View at Google Scholar · View at Scopus
  140. Q.-L. Tang, Z.-Q. Zhao, J.-C. Li et al., “Salinomycin inhibits osteosarcoma by targeting its tumor stem cells,” Cancer Letters, vol. 311, no. 1, pp. 113–121, 2011. View at Publisher · View at Google Scholar · View at Scopus
  141. M. Ni, M. Xiong, X. Zhang et al., “Poly(lactic-co-glycolic acid) nanoparticles conjugated with CD133 aptamers for targeted salinomycin delivery to CD133+ osteosarcoma cancer stem cells,” International Journal of Nanomedicine, vol. 10, pp. 2537–2554, 2015. View at Publisher · View at Google Scholar · View at Scopus
  142. J. Li, W. Liu, K. Zhao et al., “Diallyl trisulfide reverses drug resistance and lowers the ratio of CD133+ cells in conjunction with methotrexate in a human osteosarcoma drug-resistant cell subline,” Molecular Medicine Reports, vol. 2, no. 2, pp. 245–252, 2009. View at Publisher · View at Google Scholar · View at Scopus
  143. Y. Li, J. Zhang, L. Zhang, M. Si, H. Yin, and J. Li, “Diallyl trisulfide inhibits proliferation, invasion and angiogenesis of osteosarcoma cells by switching on suppressor microRNAs and inactivating of Notch-1 signaling,” Carcinogenesis, vol. 34, no. 7, pp. 1601–1610, 2013. View at Publisher · View at Google Scholar · View at Scopus
  144. G. Di Pompo, M. Salerno, D. Rotili et al., “Novel histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in sarcoma cancer stem cells,” Journal of Medicinal Chemistry, vol. 58, no. 9, pp. 4073–4079, 2015. View at Publisher · View at Google Scholar · View at Scopus
  145. X. Mu, D. Brynien, and K. R. Weiss, “The HDAC inhibitor Vorinostat diminishes the in vitro metastatic behavior of Osteosarcoma cells,” BioMed Research International, vol. 2015, Article ID 290368, 6 pages, 2015. View at Publisher · View at Google Scholar · View at Scopus
  146. J.-F. Xu, X.-H. Pan, S.-J. Zhang et al., “CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models,” Oncotarget, vol. 6, no. 27, pp. 23662–23670, 2015. View at Publisher · View at Google Scholar · View at Scopus
  147. L. Vermeulen, F. de Sousa e Melo, D. J. Richel, and J. P. Medema, “The developing cancer stem-cell model: clinical challenges and opportunities,” The Lancet Oncology, vol. 13, no. 2, pp. e83–e89, 2012. View at Publisher · View at Google Scholar · View at Scopus
  148. J. Tornin, L. Martinez-Cruzado, L. Santos et al., “Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma,” Oncotarget, 2016. View at Publisher · View at Google Scholar