Table of Contents Author Guidelines Submit a Manuscript
Sarcoma
Volume 2011, Article ID 959248, 12 pages
http://dx.doi.org/10.1155/2011/959248
Review Article

The Molecular Pathogenesis of Osteosarcoma: A Review

1Department of Orthopaedics, Department of Surgery, University of Melbourne, St. Vincent's Hospital, SVHM, L3, Daly Wing, 35 Victoria Parade, Fitzroy VIC 3065, Australia
2School of Biomedical and Health Sciences, Victoria University, St. Albans, VIC 3021, Australia
3Sarcoma Service, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia

Received 15 September 2010; Accepted 21 February 2011

Academic Editor: H. Kovar

Copyright © 2011 Matthew L. Broadhead 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. S. S. Bielack, B. Kempf-Bielack, G. Delling et al., “Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols,” Journal of Clinical Oncology, vol. 20, no. 3, pp. 776–790, 2002. View at Publisher · View at Google Scholar · View at Scopus
  2. V. J. Vigorita, Orthopaedic Pathology, Lippincott, Williams & Wilkins, Philadelphia, Pa, USA, 2008.
  3. S. T. Canale and J. H. Beaty, Campbell's Operative Orthopaedics, Mosby Elsvier, 2008.
  4. S. J. Cotterill, C. M. Wright, M. S. Pearce, and A. W. Craft, “Stature of young people with malignant bone tumors,” Pediatric Blood and Cancer, vol. 42, no. 1, pp. 59–63, 2004. View at Google Scholar · View at Scopus
  5. K. H. Gelberg, E. F. Fitzgerald, S. A. Hwang, and R. Dubrow, “Growth and development and other risk factors for osteosarcoma in children and young adults,” International Journal of Epidemiology, vol. 26, no. 2, pp. 272–278, 1997. View at Google Scholar · View at Scopus
  6. N. Marina, M. Gebhardt, L. Teot, and R. Gorlick, “Biology and therapeutic advances for pediatric osteosarcoma,” Oncologist, vol. 9, no. 4, pp. 422–441, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Longhi, A. Pasini, A. Cicognani et al., “Height as a risk factor for osteosarcoma,” Journal of Pediatric Hematology/Oncology, vol. 27, no. 6, pp. 314–318, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. A. P. Polednak, “Bone cancer among female radium dial workers. Latency periods and incidence rates by time after exposure: brief communication,” Journal of the National Cancer Institute, vol. 60, no. 1, pp. 77–82, 1978. View at Google Scholar
  9. P. Picci, “Osteosarcoma (osteogenic sarcoma),” Orphanet Journal of Rare Diseases, vol. 2, no. 1, article 6, 2007. View at Publisher · View at Google Scholar · View at Scopus
  10. A. Longhi, E. Barbieri, N. Fabbri et al., “Radiation-induced osteosarcoma arising 20 years after the treatment of Ewing's sarcoma,” Tumori, vol. 89, no. 5, pp. 569–572, 2003. View at Google Scholar · View at Scopus
  11. A. C. Paulino and B. Z. Fowler, “Secondary neoplasms after radiotherapy for a childhood solid tumor,” Pediatric Hematology and Oncology, vol. 22, no. 2, pp. 89–101, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. A. S. Rani and S. Kumar, “Transformation of non-tumorigenic osteoblast-like human osteosarcoma cells by hexavalent chromates: alteration of morphology, induction of anchorage-independence and proteolytic function,” Carcinogenesis, vol. 13, no. 11, pp. 2021–2027, 1992. View at Google Scholar · View at Scopus
  13. F. R. Dutra and E. J. Largent, “Osteosarcoma induced by beryllium oxide,” American Journal of Pathology, vol. 26, no. 2, pp. 197–209, 1950. View at Google Scholar · View at Scopus
  14. A. Mazabraud, “Experimental production of bone sarcomas in the rabbit by a single local injection of beryllium,” Bulletin du Cancer, vol. 62, no. 1, pp. 49–58, 1975. View at Google Scholar · View at Scopus
  15. M. L. Tan, P. F. M. Choong, and C. R. Dass, “Osteosarcoma: conventional treatment vs. gene therapy,” Cancer Biology and Therapy, vol. 8, no. 2, pp. 106–117, 2009. View at Google Scholar · View at Scopus
  16. S. M. Mendoza, T. Konishi, and C. W. Miller, “Integration of SV40 in human osteosarcoma DNA,” Oncogene, vol. 17, no. 19, pp. 2457–2462, 1998. View at Google Scholar · View at Scopus
  17. E. A. Engels, “Cancer risk associated with receipt of vaccines contaminated with simian virus 40: epidemiologic research,” Expert Review of Vaccines, vol. 4, no. 2, pp. 197–206, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. F. López-Ríos, P. B. Illei, V. Rusch, and M. Ladanyi, “Evidence against a role for SV40 infection in human mesotheliomas and high risk of false-positive PCR results owing to presence of SV40 sequences in common laboratory plasmids,” The Lancet, vol. 364, no. 9440, pp. 1157–1166, 2004. View at Publisher · View at Google Scholar · View at Scopus
  19. J. J. Manfredi, J. Dong, W. J. Liu et al., “Evidence against a role for SV40 in human mesothelioma,” Cancer Research, vol. 65, no. 7, pp. 2602–2609, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Greenspan, G. Jundt, and W. Remagen, Differential Diagnosis in Orthopaedic Oncology, Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 2007.
  21. J. German, L. P. Crippa, and D. Bloom, “Bloom's syndrome. III. Analysis of the chromosome aberration characteristic of this disorder,” Chromosoma, vol. 48, no. 4, pp. 361–366, 1974. View at Google Scholar · View at Scopus
  22. K. Fukuchi, G. M. Martin, and R. J. Monnat Jr., “Mutator phenotype of Werner syndrome is characterized by extensive deletions,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 15, pp. 5893–5897, 1989. View at Google Scholar · View at Scopus
  23. 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 Google Scholar
  24. H. T. Ta, C. R. Dass, P. F. M. Choong, and D. E. Dunstan, “Osteosarcoma treatment: state of the art,” Cancer and Metastasis Reviews, vol. 28, no. 1-2, pp. 247–263, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. B. Alberts, A. Johnson, J. Lewis et al., “Molecular biology of the cell,” Garland Science, 2008.
  26. J. G. Teodoro, S. K. Evans, and M. R. Green, “Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome,” Journal of Molecular Medicine, vol. 85, no. 11, pp. 1175–1186, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. E. I. Hauben, J. Arends, J. P. Vandenbroucke, C. J. van Asperen, E. van Marck, and P. C. W. Hogendoorn, “Multiple primary malignancies in osteosarcoma patients. Incidence and predictive value of osteosarcoma subtype for cancer syndromes related with osteosarcoma,” European Journal of Human Genetics, vol. 11, no. 8, pp. 611–618, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. J. F. McIntyre, B. Smith-Sorensen, S. H. Friend et al., “Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma,” Journal of Clinical Oncology, vol. 12, no. 5, pp. 925–930, 1994. View at Google Scholar · View at Scopus
  29. N. Chandar, B. Billig, J. McMaster, and J. Novak, “Inactivation of p53 gene in human and murine osteosarcoma cells,” British Journal of Cancer, vol. 65, no. 2, pp. 208–214, 1992. View at Google Scholar · View at Scopus
  30. C. W. Miller, A. Aslo, A. Won, M. Tan, B. Lampkin, and H. P. Koeffler, “Alterations of the p53, Rb and MDM2 genes in osteosarcoma,” Journal of Cancer Research and Clinical Oncology, vol. 122, no. 9, pp. 559–565, 1996. View at Google Scholar · View at Scopus
  31. H. Ganjavi, M. Gee, A. Narendran et al., “Adenovirus-mediated p53 gene therapy in osteosarcoma cell lines: sensitization to cisplatin and doxorubicin,” Cancer Gene Therapy, vol. 13, no. 4, pp. 415–419, 2006. View at Publisher · View at Google Scholar · View at Scopus
  32. X. Hu, A. X. Yu, B. W. Qi et al., “The expression and significance of IDH1 and p53 in osteosarcom,” Journal of Experimental & Clinical Cancer Research, vol. 29, p. 43, 2010. View at Google Scholar
  33. H. R. Park, W. Won Jung, F. Bertoni et al., “Molecular analysis of p53, MDM2 and H-ras genes in low-grade central osteosarcoma,” Pathology Research and Practice, vol. 200, no. 6, pp. 439–445, 2004. View at Publisher · View at Google Scholar · View at Scopus
  34. 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
  35. Y. B. Park, H. S. Kim, J. H. Oh, and S. H. Lee, “The co-expression of p53 protein and P-glycoprotein is correlated to a poor prognosis in osteosarcoma,” International Orthopaedics, vol. 24, no. 6, pp. 307–310, 2001. View at Publisher · View at Google Scholar · View at Scopus
  36. A. Longhi, “Osteosarcoma in blood relatives,” Oncology Reports, vol. 8, no. 1, pp. 131–136, 2001. View at Google Scholar · View at Scopus
  37. M. Serena 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 Google Scholar · View at Scopus
  38. S. Heinsohn, U. Evermann, U. Zur Stadt, S. Bielack, and H. Kabisch, “Determination of the prognostic value of loss of heterozygosity at the retinoblastoma gene in osteosarcoma,” International Journal of Oncology, vol. 30, no. 5, pp. 1205–1214, 2007. View at Google Scholar · View at Scopus
  39. 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
  40. O. Feugeas, N. Guriec, A. Babin-Boilletot et al., “Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma,” Journal of Clinical Oncology, vol. 14, no. 2, pp. 467–472, 1996. View at Google Scholar · View at Scopus
  41. K. Iida, T. Nobori, A. Matsumine et al., “Effect of retinoblastoma tumor suppressor gene expression on chemosensitivity of human osteosarcoma cell lines,” Oncology Reports, vol. 10, no. 6, pp. 1961–1965, 2003. View at Google Scholar · View at Scopus
  42. 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
  43. A. Franchi, A. Calzolari, and G. Zampi, “Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton,” Virchows Archiv, vol. 432, no. 6, pp. 515–519, 1998. View at Publisher · View at Google Scholar · View at Scopus
  44. 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
  45. 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
  46. V. D. Leaner, J. F. Chick, H. Donninger et al., “Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma,” American Journal of Pathology, vol. 174, no. 1, pp. 265–275, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. M. L. Tan, P. F. M. Choong, and C. R. Dass, “Direct anti-metastatic efficacy by the DNA enzyme Dz13 and downregulated MMP-2, MMP-9 and MT1-MMP in tumours,” Cancer Cell International, vol. 10, article 9, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. 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 Google Scholar
  49. C. M. Hattinger, G. Stoico, F. Michelacci et al., “Mechanisms of gene amplification and evidence of coamplification in drug-resistant human osteosarcoma cell lines,” Genes Chromosomes and Cancer, vol. 48, no. 4, pp. 289–309, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. 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
  51. X. K. Xie, D. S. Yang, Z. M. Ye, and H. M. Tao, “Enhancement effect of adenovirus-mediated antisense c-myc and caffeine on the cytotoxicity of cisplatin in osteosarcoma cell lines,” Chemotherapy, vol. 55, no. 6, pp. 433–440, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. C. Arvanitis, P. K. Bendapudi, J. R. Tseng, S. S. Gambhir, and D. W. Felsher, “18F and 18FDG PET imaging of osteosarcoma to non-invasively monitor in situ changes in cellular proliferation and bone differentiation upon MYC inactivation,” Cancer Biology and Therapy, vol. 7, no. 12, pp. 1947–1951, 2008. View at Google Scholar · View at Scopus
  53. A. Franchi, L. Arganini, G. Baroni et al., “Expression of transforming growth factor β isoforms in osteosarcoma variants: association of TGFβ1 with high-grade osteosarcomas,” Journal of Pathology, vol. 185, no. 3, pp. 284–289, 1998. View at Publisher · View at Google Scholar · View at Scopus
  54. F. Navid, J. J. Letterio, C. L. Yeung, M. Pegtel, and L. J. Helman, “Autocrine transforming growth factor-β growth pathway in murine osteosarcoma cell lines associated with inability to affect phosphorylation of retinoblastoma protein,” Sarcoma, vol. 4, no. 3, pp. 93–102, 2000. View at Google Scholar · View at Scopus
  55. Y. S. Hu, Y. Pan, W. H. Li, Y. Zhang, J. Li, and B. A. Ma, “Int7G24A variant of transforming growth factor-beta receptor 1 is associated with osteosarcoma susceptibility in a Chinese population,” Medical Oncology. In Press. View at Publisher · View at Google Scholar · View at Scopus
  56. Y. S. Hu, Y. Pan, W. H. Li, Y. Zhang, J. Li, and B. A. Ma, “Association between TGFBR1*6A and osteosarcoma: a Chinese case-control study,” BMC Cancer, vol. 10, article 169, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. B. Rikhof, S. De Jong, A. J. H. Suurmeijer, C. Meijer, and W. T. A. van der Graaf, “The insulin-like growth factor system and sarcomas,” Journal of Pathology, vol. 217, no. 4, pp. 469–482, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. Y. H. Wang, J. Xiong, S. F. Wang et al., “Lentivirus-mediated shRNA targeting insulin-like growth factor-1 receptor (IGF-1R) enhances chemosensitivity of osteosarcoma cells in vitro and in vivo,” Molecular and Cellular Biochemistry, vol. 341, no. 1-2, pp. 225–233, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. J. Dong, S. J. Demarest, A. Sereno et al., “Combination of two insulin-like growth factor-I receptor inhibitory antibodies targeting distinct epitopes leads to an enhanced antitumor response,” Molecular Cancer Therapeutics, vol. 9, no. 9, pp. 2593–2604, 2010. View at Google Scholar
  60. E. A. Kolb, D. Kamara, W. Zhang et al., “R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts,” Pediatric Blood and Cancer, vol. 55, no. 1, pp. 67–75, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. L. F. Lau and S. C. T. Lam, “The CCN family of angiogenic regulators: the integrin connection,” Experimental Cell Research, vol. 248, no. 1, pp. 44–57, 1999. View at Publisher · View at Google Scholar · View at Scopus
  62. T. Nishida, T. Nakanishi, M. Asano, T. Shimo, and M. Takigawa, “Effects of CTGF/Hcs 24, a hypertrophic chondrocyte-specific gene product, on the proliferation and differentiation of osteoblastic cells in vitro,” Journal of Cellular Physiology, vol. 184, no. 2, pp. 197–206, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. B. Perbal, M. Zuntini, D. Zambelli et al., “Prognostic value of CCN3 in osteosarcoma,” Clinical Cancer Research, vol. 14, no. 3, pp. 701–709, 2008. View at Publisher · View at Google Scholar · View at Scopus
  64. C. P. Rodda, M. Kubota, J. A. Heath et al., “Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy,” Journal of Endocrinology, vol. 117, no. 2, pp. 261–271, 1988. View at Google Scholar · View at Scopus
  65. R. Yang, B. H. Hoang, T. Kubo et al., “Over-expression of parathyroid hormone type 1 receptor confers an aggressive phenotype in osteosarcoma,” International Journal of Cancer, vol. 121, no. 5, pp. 943–954, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. S. Gagiannis, M. Müller, S. Uhlemann et al., “Parathyroid hormone-related protein confers chemoresistance by blocking apoptosis signaling via death receptors and mitochondria,” International Journal of Cancer, vol. 125, no. 7, pp. 1551–1557, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. A. Berdiaki, G. A. Datsis, D. Nikitovic et al., “Parathyroid hormone (PTH) peptides through the regulation of hyaluronan metabolism affect osteosarcoma cell migration,” IUBMB Life, vol. 62, no. 5, pp. 377–386, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. G. M. F. Pasquini, R. A. M. Davey, P. W. M. Ho et al., “Local secretion of parathyroid hormone-related protein by an osteoblastic osteosarcoma (UMR 106-01) cell line results in growth inhibition,” Bone, vol. 31, no. 5, pp. 598–605, 2002. View at Publisher · View at Google Scholar · View at Scopus
  69. M. L. Broadhead, C. R. Dass, and P. F. M. Choong, “Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy,” Trends in Molecular Medicine, vol. 15, no. 10, pp. 461–467, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. Y. Jan, M. Matter, J. T. Pai et al., “A mitochondrial protein, Bit1, mediates apoptosis regulated by integrins and Groucho/TLE corepressors,” Cell, vol. 116, no. 5, pp. 751–762, 2004. View at Publisher · View at Google Scholar · View at Scopus
  71. S. M. Janes and F. M. Watt, “Switch from αvβ5 to αvβ6 integrin expression protects squamous cell carcinomas from anoikis,” Journal of Cell Biology, vol. 166, no. 3, pp. 419–431, 2004. View at Publisher · View at Google Scholar · View at Scopus
  72. K. M. Nicholson and N. G. Anderson, “The protein kinase B/Akt signalling pathway in human malignancy,” Cellular Signalling, vol. 14, no. 5, pp. 381–395, 2002. View at Publisher · View at Google Scholar · View at Scopus
  73. S. J. Coniglio, T. S. Jou, and M. Symons, “Rac1 protects epithelial cells against anoikis,” Journal of Biological Chemistry, vol. 276, no. 30, pp. 28113–28120, 2001. View at Publisher · View at Google Scholar · View at Scopus
  74. R. Ley, K. E. Ewings, K. Hadfield, E. Howes, K. Balmanno, and S. J. Cook, “Extracellular signal-regulated kinases 1/2 are serum-stimulated “Bim kinases” that bind to the BH3-only protein bim causing its phosphorylation and turnover,” Journal of Biological Chemistry, vol. 279, no. 10, pp. 8837–8847, 2004. View at Publisher · View at Google Scholar · View at Scopus
  75. D. J. Hicklin and L. M. Ellis, “Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis,” Journal of Clinical Oncology, vol. 23, no. 5, pp. 1011–1027, 2005. View at Publisher · View at Google Scholar · View at Scopus
  76. H. F. Dvorak, “Angiogenesis: update 2005,” Journal of Thrombosis and Haemostasis, vol. 3, no. 8, pp. 1835–1842, 2005. View at Publisher · View at Google Scholar · View at Scopus
  77. M. Shibuya and L. Claesson-Welsh, “Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis,” Experimental Cell Research, vol. 312, no. 5, pp. 549–560, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. J. A. Nagy, A. M. Dvorak, and H. F. Dvorak, “VEGF-A and the induction of pathological angiogenesis,” Annual Review of Pathology, vol. 2, pp. 251–275, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. T. Matsumoto and H. Mugishima, “Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis,” Journal of Atherosclerosis and Thrombosis, vol. 13, no. 3, pp. 130–135, 2006. View at Google Scholar · View at Scopus
  80. D. Liao and R. S. Johnson, “Hypoxia: a key regulator of angiogenesis in cancer,” Cancer and Metastasis Reviews, vol. 26, no. 2, pp. 281–290, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. P. Carmeliet, “VEGF as a key mediator of angiogenesis in cancer,” Oncology, vol. 69, no. 3, pp. 4–10, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. J. Tran, J. Rak, C. Sheehan et al., “Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells,” Biochemical and Biophysical Research Communications, vol. 264, no. 3, pp. 781–788, 1999. View at Publisher · View at Google Scholar · View at Scopus
  83. G. D. Yancopoulos, S. Davis, N. W. Gale, J. S. Rudge, S. J. Wiegand, and J. Holash, “Vascular-specific growth factors and blood vessel formation,” Nature, vol. 407, no. 6801, pp. 242–248, 2000. View at Publisher · View at Google Scholar · View at Scopus
  84. I. B. Lobov, R. A. Renard, N. Papadopoulos et al., “Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 9, pp. 3219–3224, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. M. Kaya, T. Wada, T. Akatsuka et al., “Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis,” Clinical Cancer Research, vol. 6, no. 2, pp. 572–577, 2000. View at Google Scholar · View at Scopus
  86. H. Hara, T. Akisue, T. Fujimoto et al., “Expression of VEGF and its receptors and angiogenesis in bone and soft tissue tumors,” Anticancer Research, vol. 26, no. 6B, pp. 4307–4311, 2006. View at Google Scholar · View at Scopus
  87. E. Mantadakis, G. Kim, J. Reisch et al., “Lack of prognostic significance of intratumoral angiogenesis in nonmetastatic osteosarcoma,” Journal of Pediatric Hematology/Oncology, vol. 23, no. 5, pp. 286–289, 2001. View at Publisher · View at Google Scholar · View at Scopus
  88. M. Kreuter, R. Bieker, S. S. Bielaek et al., “Prognostic relevance of increased angiogenesis in osteosarcoma,” Clinical Cancer Research, vol. 10, no. 24, pp. 8531–8537, 2004. View at Publisher · View at Google Scholar · View at Scopus
  89. B. Ren, K. O. Yee, J. Lawler, and R. Khosravi-Far, “Regulation of tumor angiogenesis by thrombospondin-1,” Biochimica et Biophysica Acta, vol. 1765, no. 2, pp. 178–188, 2006. View at Publisher · View at Google Scholar · View at Scopus
  90. J. Cai, C. Parr, G. Watkins, W. G. Jiang, and M. Boulton, “Decreased pigment epithelium-derived factor expression in human breast cancer progression,” Clinical Cancer Research, vol. 12, no. 11, part 1, pp. 3510–3517, 2006. View at Publisher · View at Google Scholar · View at Scopus
  91. J. C. M. Clark, D. M. Thomas, P. F. M. Choong, and C. R. Dass, “RECK—a newly discovered inhibitor of metastasis with prognostic significance in multiple forms of cancer,” Cancer and Metastasis Reviews, vol. 26, no. 3-4, pp. 675–683, 2007. View at Publisher · View at Google Scholar · View at Scopus
  92. G. M. Y. Quan, J. Ojaimi, Y. Li, V. Kartsogiannis, H. Zhou, and P. F. M. Choong, “Localization of pigment epithelium-derived factor in growing mouse bone,” Calcified Tissue International, vol. 76, no. 2, pp. 146–153, 2005. View at Publisher · View at Google Scholar · View at Scopus
  93. M. A. Moses, D. Wiederschain, I. Wu et al., “Troponin I is present in human cartilage and inhibits angiogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 6, pp. 2645–2650, 1999. View at Publisher · View at Google Scholar · View at Scopus
  94. E. T. H. Ek, C. R. Dass, K. G. Contreras, and P. F. M. Choong, “Pigment epithelium-derived factor overexpression inhibits orthotopic osteosarcoma growth, angiogenesis and metastasis,” Cancer Gene Therapy, vol. 14, no. 7, pp. 616–626, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. E. T. H. Ek, C. R. Dass, K. G. Contreras, and P. F. M. Choong, “Inhibition of orthotopic osteosarcoma growth and metastasis by multitargeted antitumor activities of pigment epithelium-derived factor,” Clinical and Experimental Metastasis, vol. 24, no. 2, pp. 93–106, 2007. View at Publisher · View at Google Scholar · View at Scopus
  96. B. H. Luo, C. V. Carman, and T. A. Springer, “Structural basis of integrin regulation and signaling,” Annual Review of Immunology, vol. 25, pp. 619–647, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. A. L. Berrier and K. M. Yamada, “Cell-matrix adhesion,” Journal of Cellular Physiology, vol. 213, no. 3, pp. 565–573, 2007. View at Publisher · View at Google Scholar · View at Scopus
  98. A. S. Nimnual, L. J. Taylor, and D. Bar-Sagi, “Redox-dependent downregulation of Rho by Rac,” Nature Cell Biology, vol. 5, no. 3, pp. 236–241, 2003. View at Publisher · View at Google Scholar · View at Scopus
  99. O. Fromigué, Z. Hamidouche, and P. J. Marie, “Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion,” Journal of Biological Chemistry, vol. 283, no. 45, pp. 30549–30556, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. C. M. Lo, H. B. Wang, M. Dembo, and Y. L. Wang, “Cell movement is guided by the rigidity of the substrate,” Biophysical Journal, vol. 79, no. 1, pp. 144–152, 2000. View at Google Scholar · View at Scopus
  101. M. J. Paszek, N. Zahir, K. R. Johnson et al., “Tensional homeostasis and the malignant phenotype,” Cancer Cell, vol. 8, no. 3, pp. 241–254, 2005. View at Publisher · View at Google Scholar · View at Scopus
  102. K. W. Hunter, “Ezrin, a key component in tumor metastasis,” Trends in Molecular Medicine, vol. 10, no. 5, pp. 201–204, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. C. Khanna, X. Wan, S. Bose et al., “The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis,” Nature Medicine, vol. 10, no. 2, pp. 182–186, 2004. View at Publisher · View at Google Scholar · View at Scopus
  104. H. Birkedal-Hansen, W. G. I. Moore, M. K. Bodden et al., “Matrix metalloproteinases: a review,” Critical Reviews in Oral Biology and Medicine, vol. 4, no. 2, pp. 197–250, 1993. View at Google Scholar · View at Scopus
  105. S. Chakraborti, M. Mandal, S. Das, A. Mandal, and T. Chakraborti, “Regulation of matrix metalloproteinases. An overview,” Molecular and Cellular Biochemistry, vol. 253, no. 1-2, pp. 269–285, 2003. View at Publisher · View at Google Scholar · View at Scopus
  106. J. Oh, R. Takahashi, S. Kondo et al., “The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis,” Cell, vol. 107, no. 6, pp. 789–800, 2001. View at Publisher · View at Google Scholar · View at Scopus
  107. G. Bergers, R. Brekken, G. McMahon et al., “Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis,” Nature Cell Biology, vol. 2, no. 10, pp. 737–744, 2000. View at Publisher · View at Google Scholar · View at Scopus
  108. M. F. Burbridge, F. Cogé, J. P. Galizzi, J. A. Boutin, D. C. West, and G. C. Tucker, “The role of the matrix metalloproteinases during in vitro vessel formation,” Angiogenesis, vol. 5, no. 3, pp. 215–226, 2002. View at Publisher · View at Google Scholar · View at Scopus
  109. V. Masson, L. Rodriguez de la Ballina, C. Munaut et al., “Contribution of host MMP-2 and MMP-9 to promote tumor vascularization and invasion of malignant keratinocytes,” FASEB Journal, vol. 19, no. 2, pp. 234–236, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. P. F. Choong and A. P. Nadesapillai, “Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis,” Clinical Orthopaedics and Related Research, vol. 415, supplement, pp. S46–S58, 2003. View at Google Scholar
  111. V. Pillay, C. R. Dass, and P. F. M. Choong, “The urokinase plasminogen activator receptor as a gene therapy target for cancer,” Trends in Biotechnology, vol. 25, no. 1, pp. 33–39, 2007. View at Publisher · View at Google Scholar · View at Scopus
  112. P. F. M. Choong, M. Fernö, M. Åkermans et al., “Urokinase-plasminogen-activator levels and prognosis in 69 soft-tissue sarcomas,” International Journal of Cancer, vol. 69, no. 4, pp. 268–272, 1996. View at Publisher · View at Google Scholar · View at Scopus
  113. C. R. Dass, A. P. W. Nadesapillai, D. Robin et al., “Downregulation of uPAR confirms link in growth and metastasis of osteosarcoma,” Clinical and Experimental Metastasis, vol. 22, no. 8, pp. 643–652, 2005. View at Publisher · View at Google Scholar · View at Scopus
  114. T. A. Guise and J. M. Chirgwin, “Transforming growth factor-beta in osteolytic breast cancer bone metastases,” Clinical Orthopaedics and Related Research, vol. 415, supplement, pp. S32–S38, 2003. View at Google Scholar
  115. J. M. W. Quinn, K. Itoh, N. Udagawa et al., “Transforming growth factor β affects osteoclast differentiation via direct and indirect actions,” Journal of Bone and Mineral Research, vol. 16, no. 10, pp. 1787–1794, 2001. View at Google Scholar · View at Scopus
  116. L. A. Kingsley, P. G. J. Fournier, J. M. Chirgwin, and T. A. Guise, “Molecular biology of bone metastasis,” Molecular Cancer Therapeutics, vol. 6, no. 10, pp. 2609–2617, 2007. View at Publisher · View at Google Scholar · View at Scopus
  117. J. M. Chirgwin and T. A. Guise, “Skeletal metastases: decreasing tumor burden by targeting the bone microenvironment,” Journal of Cellular Biochemistry, vol. 102, no. 6, pp. 1333–1342, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. K. Kinpara, “Osteoclast differentiation factor in human osteosarcoma cell line,” Journal of Immunoassay, vol. 21, no. 4, pp. 327–340, 2000. View at Google Scholar · View at Scopus
  119. L. C. Hofbauer and A. E. Heufelder, “Osteoprotegerin and its cognate ligand: a new paradigm of osteoclastogenesis,” European Journal of Endocrinology, vol. 139, no. 2, pp. 152–154, 1998. View at Google Scholar · View at Scopus
  120. H. Takayanagi, “The role of NFAT in osteoclast formation,” Annals of the New York Academy of Sciences, vol. 1116, pp. 227–237, 2007. View at Publisher · View at Google Scholar · View at Scopus
  121. S. A. Stoch and J. A. Wagner, “Cathepsin K inhibitors: a novel target for osteoporosis therapy,” Clinical Pharmacology and Therapeutics, vol. 83, no. 1, pp. 172–176, 2008. View at Publisher · View at Google Scholar · View at Scopus
  122. C. Le Gall, A. Bellahcène, E. Bonnelye et al., “A cathepsin K inhibitor reduces breast cancer-induced osteolysis and skeletal tumor burden,” Cancer Research, vol. 67, no. 20, pp. 9894–9902, 2007. View at Publisher · View at Google Scholar · View at Scopus
  123. K. Husmann, R. Muff, M. E. Bolander, G. Sarkar, W. Born, and B. Fuchs, “Cathepsins and osteosarcoma: expression analysis identifies cathepsin K as an indicator of metastasis,” Molecular Carcinogenesis, vol. 47, no. 1, pp. 66–73, 2008. View at Publisher · View at Google Scholar · View at Scopus
  124. S. Tanaka, M. Amling, L. Neff et al., “c-Cbl is downstream of c-Src in a signalling pathway necessary for bone resorption,” Nature, vol. 383, no. 6600, pp. 528–531, 1996. View at Publisher · View at Google Scholar · View at Scopus
  125. J. Schlessinger, “New roles for Src kinases in control of cell survival and angiogenesis,” Cell, vol. 100, no. 3, pp. 293–296, 2000. View at Google Scholar · View at Scopus
  126. H. Glantschnig, J. E. Fisher, G. Wesolowski et al., “M-CSF, TNFalpha and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase,” Cell Death Differ, vol. 10, no. 10, pp. 1165–1177, 2003. View at Google Scholar
  127. N. Rucci, M. Šuša, and A. Teti, “Inhibition of protein kinase c-Src as a therapeutic approach for cancer and bone metastases,” Anti-Cancer Agents in Medicinal Chemistry, vol. 8, no. 3, pp. 342–349, 2008. View at Publisher · View at Google Scholar · View at Scopus
  128. T. Akiyama, C. R. Dass, and P. F. M. Choong, “Novel therapeutic strategy for osteosarcoma targeting osteoclast differentiation, bone-resorbing activity, and apoptosis pathway,” Molecular Cancer Therapeutics, vol. 7, no. 11, pp. 3461–3469, 2008. View at Publisher · View at Google Scholar · View at Scopus
  129. S. Tanaka, K. Nakamura, N. Takahasi, and T. Suda, “Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system,” Immunological Reviews, vol. 208, pp. 30–49, 2005. View at Google Scholar · View at Scopus
  130. 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 Google Scholar
  131. G. Ottaviani and N. Jaffe, “The epidemiology of osteosarcoma,” Cancer Treatment and Research, vol. 152, pp. 3–13, 2009. View at Publisher · View at Google Scholar · View at Scopus
  132. T. A. Guise, R. O'Keefe, R. L. Randall, and R. M. Terek, “Molecular biology and therapeutics in musculoskeletal oncology,” Journal of Bone and Joint Surgery. American, vol. 91, no. 3, pp. 724–732, 2009. View at Publisher · View at Google Scholar · View at Scopus
  133. M. L. Broadhead, T. Akiyama, P. F. M. Choong, and C. R. Dass, “The pathophysiological role of PEDF in bone diseases,” Current Molecular Medicine, vol. 10, no. 3, pp. 296–301, 2010. View at Publisher · View at Google Scholar · View at Scopus
  134. E. T. H. Ek, C. R. Dass, K. G. Contreras, and P. F. M. Choong, “Inhibition of orthotopic osteosarcoma growth and metastasis by multitargeted antitumor activities of pigment epithelium-derived factor,” Clinical and Experimental Metastasis, vol. 24, no. 2, pp. 93–106, 2007. View at Publisher · View at Google Scholar · View at Scopus
  135. E. T. H. Ek, C. R. Dass, K. G. Contreras, and P. F. M. Choong, “PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma,” Journal of Orthopaedic Research, vol. 25, no. 12, pp. 1671–1680, 2007. View at Publisher · View at Google Scholar · View at Scopus
  136. H. G. Kang, H. S. Kim, K. J. Kim et al., “RECK expression in osteosarcoma: correlation with matrix metalloproteinases activation and tumor invasiveness,” Journal of Orthopaedic Research, vol. 25, no. 5, pp. 696–702, 2007. View at Publisher · View at Google Scholar · View at Scopus