Skip to main content
SpringerLink
Log in

From genomics to metabolomics: emerging metastatic biomarkers in osteosarcoma

Cancer and Metastasis Reviews Aims and scope Submit manuscript

Cite this article

Abstract

Although the investigation into biomarkers specific for pulmonary metastasis within osteosarcoma (OS) has recently expanded, their usage within the clinic remains sparse. The current screening protocol after any OS diagnosis includes a chest CT scan; however, metastatic lung nodules frequently go undetected and remain the primary cause of death in OS. Recently, screening technologies such as liquid biopsy and next-generation sequencing have revealed a promising array of biomarkers with predictive and diagnostic value for the pulmonary metastasis associated with OS. These biomarkers draw from genomics, transcriptomics, epigenetics, and metabolomics. When assessed in concert, their utility is most promising as OS is a highly heterogeneous cancer. Accordingly, there has been an expansion of clinical trials not only aimed at further demonstrating the significance of these individual biomarkers but to also reveal which therapies resolve the pulmonary metastasis once detected. This review will focus on the recently discovered and novel metastatic biomarkers within OS, their molecular and cellular mechanisms, the expansion of humanized OS mouse models amenable to their testing, and the associated clinical trials aimed at managing the metastatic phase of OS.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Kansara, M., Teng, M. W., Smyth, M. J., & Thomas, D. M. (2014). Translational biology of osteosarcoma. Nature Reviews. Cancer, 14(11), 722–735. https://doi.org/10.1038/nrc3838.

    Article  CAS  PubMed  Google Scholar 

  2. Lu, J., Song, G., Tang, Q., Zou, C., Han, F., Zhao, Z., Yong, B., Yin, J., Xu, H., Xie, X., Kang, T., Lam, Y. L., Yang, H., Shen, J., & Wang, J. (2015). IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-kappaB signaling. The Journal of Clinical Investigation, 125(5), 1839–1856. https://doi.org/10.1172/JCI78437.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Yu, W., Tang, L., Lin, F., Li, D., Wang, J., Yang, Y., et al. (2014). Stereotactic radiosurgery, a potential alternative treatment for pulmonary metastases from osteosarcoma. International Journal of Oncology, 44(4), 1091–1098. https://doi.org/10.3892/ijo.2014.2295.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bacci, G., Briccoli, A., Rocca, M., Ferrari, S., Donati, D., Longhi, A., Bertoni, F., Bacchini, P., Giacomini, S., Forni, C., Manfrini, M., & Galletti, S. (2003). Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: Recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology, 14(7), 1126–1134.

    Article  CAS  PubMed  Google Scholar 

  5. Geller, D. S., & Gorlick, R. (2010). Osteosarcoma: A review of diagnosis, management, and treatment strategies. Clinical Advances in Hematology & Oncology, 8(10), 705–718.

    Google Scholar 

  6. Isakoff, M. S., Bielack, S. S., Meltzer, P., & Gorlick, R. (2015). Osteosarcoma: Current treatment and a collaborative pathway to success. Journal of Clinical Oncology, 33(27), 3029–3035. https://doi.org/10.1200/JCO.2014.59.4895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Briccoli, A., Rocca, M., Salone, M., Bacci, G., Ferrari, S., Balladelli, A., & Mercuri, M. (2005). Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer, 104(8), 1721–1725. https://doi.org/10.1002/cncr.21369.

    Article  PubMed  Google Scholar 

  8. Min, L., Choy, E., Tu, C., Hornicek, F., & Duan, Z. (2017). Application of metabolomics in sarcoma: From biomarkers to therapeutic targets. Critical Reviews in Oncology/Hematology, 116, 1–10. https://doi.org/10.1016/j.critrevonc.2017.05.003.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Perry, J. A., Kiezun, A., Tonzi, P., Van Allen, E. M., Carter, S. L., Baca, S. C., et al. (2014). Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proceedings of the National Academy of Sciences of the United States of America, 111(51), E5564–E5573. https://doi.org/10.1073/pnas.1419260111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Allegretti, M., Casini, B., Mandoj, C., Benini, S., Alberti, L., Novello, M., Melucci, E., Conti, L., Covello, R., Pescarmona, E., Milano, G. M., Annovazzi, A., Anelli, V., Ferraresi, V., Biagini, R., & Giacomini, P. (2018). Precision diagnostics of Ewing’s sarcoma by liquid biopsy: Circulating EWS-FLI1 fusion transcripts. Ther Adv Med Oncol, 10, 1758835918774337. https://doi.org/10.1177/1758835918774337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bersani, F., Lingua, M. F., Morena, D., Foglizzo, V., Miretti, S., Lanzetti, L., Carra, G., Morotti, A., Ala, U., Provero, P., Chiarle, R., Singer, S., Ladanyi, M., Tuschl, T., Ponzetto, C., & Taulli, R. (2016). Deep sequencing reveals a novel miR-22 regulatory network with therapeutic potential in rhabdomyosarcoma. Cancer Research, 76(20), 6095–6106. https://doi.org/10.1158/0008-5472.CAN-16-0709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen, K., Fallen, S., Abaan, H. O., Hayran, M., Gonzalez, C., Wodajo, F., MacDonald, T., Toretsky, J. A., & Üren, A. (2008). Wnt10b induces chemotaxis of osteosarcoma and correlates with reduced survival. Pediatric Blood & Cancer, 51(3), 349–355. https://doi.org/10.1002/pbc.21595.

    Article  CAS  Google Scholar 

  13. 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. https://doi.org/10.1371/journal.pone.0090518.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cao, J., Wang, Y., Dong, R., Lin, G., Zhang, N., Wang, J., Lin, N., Gu, Y., Ding, L., Ying, M., He, Q., & Yang, B. (2015). Hypoxia-induced WSB1 promotes the metastatic potential of osteosarcoma cells. Cancer Research, 75(22), 4839–4851. https://doi.org/10.1158/0008-5472.CAN-15-0711.

    Article  CAS  PubMed  Google Scholar 

  15. Jones, K. B., Salah, Z., Del Mare, S., Galasso, M., Gaudio, E., Nuovo, G. J., et al. (2012). miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Research, 72(7), 1865–1877. https://doi.org/10.1158/0008-5472.CAN-11-2663.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Salah, Z., Arafeh, R., Maximov, V., Galasso, M., Khawaled, S., Abou-Sharieha, S., et al. (2015). miR-27a and miR-27a* contribute to metastatic properties of osteosarcoma cells. Oncotarget, 6(7), 4920–4935. https://doi.org/10.18632/oncotarget.3025.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Pan, W., Wang, H., Jianwei, R., & Ye, Z. (2014). MicroRNA-27a promotes proliferation, migration and invasion by targeting MAP2K4 in human osteosarcoma cells. Cellular Physiology and Biochemistry, 33(2), 402–412. https://doi.org/10.1159/000356679.

    Article  CAS  PubMed  Google Scholar 

  18. Huang, G., Nishimoto, K., Zhou, Z., Hughes, D., & Kleinerman, E. S. (2012). miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression. Cancer Research, 72(4), 908–916. https://doi.org/10.1158/0008-5472.CAN-11-1460.

    Article  CAS  PubMed  Google Scholar 

  19. Hua, Y., Qiu, Y., Zhao, A., Wang, X., Chen, T., Zhang, Z., Chi, Y., Li, Q., Sun, W., Li, G., Cai, Z., Zhou, Z., & Jia, W. (2011). Dynamic metabolic transformation in tumor invasion and metastasis in mice with LM-8 osteosarcoma cell transplantation. Journal of Proteome Research, 10(8), 3513–3521. https://doi.org/10.1021/pr200147g.

    Article  CAS  PubMed  Google Scholar 

  20. Ren, L., Hong, E. S., Mendoza, A., Issaq, S., Tran Hoang, C., Lizardo, M., et al. (2017). Metabolomics uncovers a link between inositol metabolism and osteosarcoma metastasis. Oncotarget, 8(24), 38541–38553. https://doi.org/10.18632/oncotarget.15872.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sottnik, J. L., Lori, J. C., Rose, B. J., & Thamm, D. H. (2011). Glycolysis inhibition by 2-deoxy-D-glucose reverts the metastatic phenotype in vitro and in vivo. Clinical & Experimental Metastasis, 28(8), 865–875. https://doi.org/10.1007/s10585-011-9417-5.

    Article  CAS  Google Scholar 

  22. Singh, N., Das, P., Gupta, S., Sachdev, V., Srivasatava, S., Datta Gupta, S., Pandey, R. M., Sahni, P., Chauhan, S. S., & Saraya, A. (2014). Plasma cathepsin L: A prognostic marker for pancreatic cancer. World Journal of Gastroenterology, 20(46), 17532–17540. https://doi.org/10.3748/wjg.v20.i46.17532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Macklin, R., Wang, H., Loo, D., Martin, S., Cumming, A., Cai, N., et al. (2016). Extracellular vesicles secreted by highly metastatic clonal variants of osteosarcoma preferentially localize to the lungs and induce metastatic behaviour in poorly metastatic clones. Oncotarget, 7(28), 43570–43587. https://doi.org/10.18632/oncotarget.9781.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Wang, B., Su, Y., Yang, Q., Lv, D., Zhang, W., Tang, K., et al. (2015). Overexpression of long non-coding RNA HOTAIR promotes tumor growth and metastasis in human osteosarcoma. Mol Cells, 38(5), 432–440. https://doi.org/10.14348/molcells.2015.2327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ruan, W., Wang, P., Feng, S., Xue, Y., & Li, Y. (2016). Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes cell proliferation and migration by upregulating angiomotin gene expression in human osteosarcoma cells. Tumour Biology, 37(3), 4065–4073. https://doi.org/10.1007/s13277-015-4256-7.

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, S., Yu, L., Xiong, M., & Dai, G. (2018). LncRNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging miR-195-5p. Biochemical and Biophysical Research Communications, 495(2), 1822–1832. https://doi.org/10.1016/j.bbrc.2017.12.047.

    Article  CAS  PubMed  Google Scholar 

  27. Sun, J., Wang, X., Fu, C., Wang, X., Zou, J., Hua, H., & Bi, Z. (2016). Long noncoding RNA FGFR3-AS1 promotes osteosarcoma growth through regulating its natural antisense transcript FGFR3. Molecular Biology Reports, 43(5), 427–436. https://doi.org/10.1007/s11033-016-3975-1.

    Article  CAS  PubMed  Google Scholar 

  28. Dong, Y., Liang, G., Yuan, B., Yang, C., Gao, R., & Zhou, X. (2015). MALAT1 promotes the proliferation and metastasis of osteosarcoma cells by activating the PI3K/Akt pathway. Tumour Biology, 36(3), 1477–1486. https://doi.org/10.1007/s13277-014-2631-4.

    Article  CAS  PubMed  Google Scholar 

  29. Jin, H., Jin, X., Zhang, H., & Wang, W. (2017). Circular RNA hsa-circ-0016347 promotes proliferation, invasion and metastasis of osteosarcoma cells. Oncotarget, 8(15), 25571–25581. https://doi.org/10.18632/oncotarget.16104.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Liu, X., Zhong, Y., Li, J., & Shan, A. (2017). Circular RNA circ-NT5C2 acts as an oncogene in osteosarcoma proliferation and metastasis through targeting miR-448. Oncotarget, 8(70), 114829–114838. https://doi.org/10.18632/oncotarget.22162.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Huang, L., Chen, M., Pan, J., & Yu, W. (2018). Circular RNA circNASP modulates the malignant behaviors in osteosarcoma via miR-1253/FOXF1 pathway. Biochemical and Biophysical Research Communications, 500(2), 511–517. https://doi.org/10.1016/j.bbrc.2018.04.131.

    Article  CAS  PubMed  Google Scholar 

  32. Xiao-Long, M., Kun-Peng, Z., & Chun-Lin, Z. (2018). Circular RNA circ_HIPK3 is down-regulated and suppresses cell proliferation, migration and invasion in osteosarcoma. Journal of Cancer, 9(10), 1856–1862. https://doi.org/10.7150/jca.24619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bao, Q., Gong, L., Wang, J., Wen, J., Shen, Y., & Zhang, W. (2018). Extracellular vesicle RNA sequencing reveals dramatic transcriptomic alterations between metastatic and primary osteosarcoma in a liquid biopsy approach. Annals of Surgical Oncology, 25, 2642–2651. https://doi.org/10.1245/s10434-018-6642-z.

    Article  PubMed  Google Scholar 

  34. Clevers, H., & Nusse, R. (2012). Wnt/beta-catenin signaling and disease. Cell, 149(6), 1192–1205. https://doi.org/10.1016/j.cell.2012.05.012.

    Article  CAS  PubMed  Google Scholar 

  35. Nusse, R., & Clevers, H. (2017). Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell, 169(6), 985–999. https://doi.org/10.1016/j.cell.2017.05.016.

    Article  CAS  PubMed  Google Scholar 

  36. Zhao, S., Kurenbekova, L., Gao, Y., Roos, A., Creighton, C. J., Rao, P., Hicks, J., Man, T. K., Lau, C., Brown, A. M. C., Jones, S. N., Lazar, A. J., Ingram, D., Lev, D., Donehower, L. A., & Yustein, J. T. (2015). NKD2, a negative regulator of Wnt signaling, suppresses tumor growth and metastasis in osteosarcoma. Oncogene, 34(39), 5069–5079. https://doi.org/10.1038/onc.2014.429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhao, S. J., Jiang, Y. Q., Xu, N. W., Li, Q., Zhang, Q., Wang, S. Y., Li, J., Wang, Y. H., Zhang, Y. L., Jiang, S. H., Wang, Y. J., Huang, Y. J., Zhang, X. X., Tian, G. A., Zhang, C. C., Lv, Y. Y., Dai, M., Liu, F., Zhang, R., Zhou, D., & Zhang, Z. G. (2018). SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/beta-catenin signaling through stabilization of the WNT-receptor complex. Oncogene, 37(8), 1049–1061. https://doi.org/10.1038/onc.2017.403.

    Article  CAS  PubMed  Google Scholar 

  38. Semenza, G. L. (2011). Oxygen sensing, homeostasis, and disease. The New England Journal of Medicine, 365(6), 537–547. https://doi.org/10.1056/NEJMra1011165.

    Article  CAS  PubMed  Google Scholar 

  39. Dewhirst, M. W., Ong, E. T., Rosner, G. L., Rehmus, S. W., Shan, S., Braun, R. D., Brizel, D. M., & Secomb, T. W. (1996). Arteriolar oxygenation in tumour and subcutaneous arterioles: Effects of inspired air oxygen content. The British Journal of Cancer. Supplement, 27, S241–S246.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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. Experimental Cell Research, 319(13), 1988–1997. https://doi.org/10.1016/j.yexcr.2013.05.019.

    Article  CAS  PubMed  Google Scholar 

  41. Liapis, V., Labrinidis, A., Zinonos, I., Hay, S., Ponomarev, V., Panagopoulos, V., DeNichilo, M., Ingman, W., Atkins, G. J., Findlay, D. M., Zannettino, A. C. W., & Evdokiou, A. (2015). Hypoxia-activated pro-drug TH-302 exhibits potent tumor suppressive activity and cooperates with chemotherapy against osteosarcoma. Cancer Letters, 357(1), 160–169. https://doi.org/10.1016/j.canlet.2014.11.020.

    Article  CAS  PubMed  Google Scholar 

  42. Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences of the United States of America, 92(12), 5510–5514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Abdeen, A., Chou, A. J., Healey, J. H., Khanna, C., Osborne, T. S., Hewitt, S. M., Kim, M., Wang, D., Moody, K., & Gorlick, R. (2009). Correlation between clinical outcome and growth factor pathway expression in osteogenic sarcoma. Cancer, 115(22), 5243–5250. https://doi.org/10.1002/cncr.24562.

    Article  PubMed  Google Scholar 

  44. Hartmann, T. N., Burger, J. A., Glodek, A., Fujii, N., & Burger, M. (2005). CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells. Oncogene, 24(27), 4462–4471. https://doi.org/10.1038/sj.onc.1208621.

    Article  CAS  PubMed  Google Scholar 

  45. Archange, C., Nowak, J., Garcia, S., Moutardier, V., Calvo, E. L., Dagorn, J. C., & Iovanna, J. L. (2008). The WSB1 gene is involved in pancreatic cancer progression. PLoS One, 3(6), e2475. https://doi.org/10.1371/journal.pone.0002475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tong, Y., Li, Q. G., Xing, T. Y., Zhang, M., Zhang, J. J., & Xia, Q. (2013). HIF1 regulates WSB-1 expression to promote hypoxia-induced chemoresistance in hepatocellular carcinoma cells. FEBS Letters, 587(16), 2530–2535. https://doi.org/10.1016/j.febslet.2013.06.017.

    Article  CAS  PubMed  Google Scholar 

  47. Scott, M. C., Temiz, N. A., Sarver, A. E., LaRue, R. S., Rathe, S. K., Varshney, J., Wolf, N. K., Moriarity, B. S., O'Brien, T. D., Spector, L. G., Largaespada, D. A., Modiano, J. F., Subramanian, S., & Sarver, A. L. (2018). Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression, and survival in osteosarcoma. Cancer Research, 78(2), 326–337. https://doi.org/10.1158/0008-5472.CAN-17-0576.

    Article  CAS  PubMed  Google Scholar 

  48. Nicoloso, M. S., Spizzo, R., Shimizu, M., Rossi, S., & Calin, G. A. (2009). MicroRNAs—the micro steering wheel of tumour metastases. Nature Reviews. Cancer, 9(4), 293–302. https://doi.org/10.1038/nrc2619.

    Article  CAS  PubMed  Google Scholar 

  49. Rodriguez Calleja, L., Jacques, C., Lamoureux, F., Baud'huin, M., Tellez Gabriel, M., Quillard, T., Sahay, D., Perrot, P., Amiaud, J., Charrier, C., Brion, R., Lecanda, F., Verrecchia, F., Heymann, D., Ellisen, L. W., & Ory, B. (2016). DeltaNp63alpha silences a miRNA program to aberrantly initiate a wound-healing program that promotes TGFbeta-induced metastasis. Cancer Research, 76(11), 3236–3251. https://doi.org/10.1158/0008-5472.CAN-15-2317.

    Article  CAS  PubMed  Google Scholar 

  50. Frampton, A. E., Castellano, L., Colombo, T., Giovannetti, E., Krell, J., Jacob, J., et al. (2015). Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression. Lancet, 385(Suppl 1), S37. https://doi.org/10.1016/S0140-6736(15)60352-X.

    Article  PubMed  Google Scholar 

  51. Liu, T., Tang, H., Lang, Y., Liu, M., & Li, X. (2009). MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Letters, 273(2), 233–242. https://doi.org/10.1016/j.canlet.2008.08.003.

    Article  CAS  PubMed  Google Scholar 

  52. Mertens-Talcott, S. U., Chintharlapalli, S., Li, X., & Safe, S. (2007). The oncogenic microRNA-27a targets genes that regulate specificity protein transcription factors and the G2-M checkpoint in MDA-MB-231 breast cancer cells. Cancer Research, 67(22), 11001–11011. https://doi.org/10.1158/0008-5472.CAN-07-2416.

    Article  CAS  PubMed  Google Scholar 

  53. Koshkina, N. V., Khanna, C., Mendoza, A., Guan, H., DeLauter, L., & Kleinerman, E. S. (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. Molecular Cancer Research, 5(10), 991–999. https://doi.org/10.1158/1541-7786.MCR-07-0007.

    Article  CAS  PubMed  Google Scholar 

  54. Gordon, N., Koshkina, N. V., Jia, S. F., Khanna, C., Mendoza, A., Worth, L. L., & Kleinerman, E. S. (2007). Corruption of the Fas pathway delays the pulmonary clearance of murine osteosarcoma cells, enhances their metastatic potential, and reduces the effect of aerosol gemcitabine. Clinical Cancer Research, 13(15 Pt 1), 4503–4510. https://doi.org/10.1158/1078-0432.CCR-07-0313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huang, G., Nishimoto, K., Yang, Y., & Kleinerman, E. S. (2014). Participation of the Fas/FasL signaling pathway and the lung microenvironment in the development of osteosarcoma lung metastases. Advances in Experimental Medicine and Biology, 804, 203–217. https://doi.org/10.1007/978-3-319-04843-7_11.

    Article  CAS  PubMed  Google Scholar 

  56. Yang, Z., Li, X., Yang, Y., He, Z., Qu, X., & Zhang, Y. (2016). Long noncoding RNAs in the progression, metastasis, and prognosis of osteosarcoma. Cell Death & Disease, 7(9), e2389. https://doi.org/10.1038/cddis.2016.272.

    Article  CAS  Google Scholar 

  57. Tan, S. K., Pastori, C., Penas, C., Komotar, R. J., Ivan, M. E., Wahlestedt, C., & Ayad, N. G. (2018). Serum long noncoding RNA HOTAIR as a novel diagnostic and prognostic biomarker in glioblastoma multiforme. Molecular Cancer, 17(1), 74. https://doi.org/10.1186/s12943-018-0822-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Jeck, W. R., Sorrentino, J. A., Wang, K., Slevin, M. K., Burd, C. E., Liu, J., Marzluff, W. F., & Sharpless, N. E. (2013). Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA, 19(2), 141–157. https://doi.org/10.1261/rna.035667.112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hansen, T. B., Jensen, T. I., Clausen, B. H., Bramsen, J. B., Finsen, B., Damgaard, C. K., & Kjems, J. (2013). Natural RNA circles function as efficient microRNA sponges. Nature, 495(7441), 384–388. https://doi.org/10.1038/nature11993.

    Article  CAS  PubMed  Google Scholar 

  60. Zhou, X., Gao, Q., Wang, J., Zhang, X., Liu, K., & Duan, Z. (2014). Linc-RNA-RoR acts as a "sponge" against mediation of the differentiation of endometrial cancer stem cells by microRNA-145. Gynecologic Oncology, 133(2), 333–339. https://doi.org/10.1016/j.ygyno.2014.02.033.

    Article  CAS  PubMed  Google Scholar 

  61. Wu, X., Yan, L., Liu, Y., Xian, W., Wang, L., & Ding, X. (2017). MicroRNA-448 suppresses osteosarcoma cell proliferation and invasion through targeting EPHA7. PLoS One, 12(6), e0175553. https://doi.org/10.1371/journal.pone.0175553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li, Y., Zheng, F., Xiao, X., Xie, F., Tao, D., Huang, C., et al. (2017). CircHIPK3 sponges miR-558 to suppress heparanase expression in bladder cancer cells. EMBO Rep, 18(9), 1646–1659. https://doi.org/10.15252/embr.201643581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zheng, Q., Bao, C., Guo, W., Li, S., Chen, J., Chen, B., Luo, Y., Lyu, D., Li, Y., Shi, G., Liang, L., Gu, J., He, X., & Huang, S. (2016). Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nature Communications, 7, 11215. https://doi.org/10.1038/ncomms11215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wojakowska, A., Chekan, M., Widlak, P., & Pietrowska, M. (2015). Application of metabolomics in thyroid cancer research. International Journal of Endocrinology, 2015, 258763–258713. https://doi.org/10.1155/2015/258763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Holmes, E., Wilson, I. D., & Nicholson, J. K. (2008). Metabolic phenotyping in health and disease. Cell, 134(5), 714–717. https://doi.org/10.1016/j.cell.2008.08.026.

    Article  CAS  PubMed  Google Scholar 

  66. DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G., & Thompson, C. B. (2008). The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metabolism, 7(1), 11–20. https://doi.org/10.1016/j.cmet.2007.10.002.

    Article  CAS  PubMed  Google Scholar 

  67. Kort, W. J., Hulsmann, W. C., & Stehman, T. E. (1989). Modulation of metastatic ability by inhibition of cholesterol synthesis. Clinical & Experimental Metastasis, 7(5), 517–523.

    Article  CAS  Google Scholar 

  68. Chen, E. I., Hewel, J., Krueger, J. S., Tiraby, C., Weber, M. R., Kralli, A., Becker, K., Yates, J. R., & Felding-Habermann, B. (2007). Adaptation of energy metabolism in breast cancer brain metastases. Cancer Research, 67(4), 1472–1486. https://doi.org/10.1158/0008-5472.CAN-06-3137.

    Article  CAS  PubMed  Google Scholar 

  69. White, N. M., Newsted, D. W., Masui, O., Romaschin, A. D., Siu, K. W., & Yousef, G. M. (2014). Identification and validation of dysregulated metabolic pathways in metastatic renal cell carcinoma. Tumour Biology, 35(3), 1833–1846. https://doi.org/10.1007/s13277-013-1245-6.

    Article  CAS  PubMed  Google Scholar 

  70. Piskounova, E., Agathocleous, M., Murphy, M. M., Hu, Z., Huddlestun, S. E., Zhao, Z., Leitch, A. M., Johnson, T. M., DeBerardinis, R. J., & Morrison, S. J. (2015). Oxidative stress inhibits distant metastasis by human melanoma cells. Nature, 527(7577), 186–191. https://doi.org/10.1038/nature15726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Vucenik, I., Tantivejkul, K., Zhang, Z. S., Cole, K. E., Saied, I., & Shamsuddin, A. M. (1998). IP6 in treatment of liver cancer. I. IP6 inhibits growth and reverses transformed phenotype in HepG2 human liver cancer cell line. Anticancer Research, 18(6A), 4083–4090.

    CAS  PubMed  Google Scholar 

  72. Castillo, M., Smith, J. K., & Kwock, L. (2000). Correlation of myo-inositol levels and grading of cerebral astrocytomas. AJNR. American Journal of Neuroradiology, 21(9), 1645–1649.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Garber, K. (2004). Energy boost: the Warburg effect returns in a new theory of cancer. Journal of the National Cancer Institute, 96(24), 1805–1806. https://doi.org/10.1093/jnci/96.24.1805.

    Article  PubMed  Google Scholar 

  74. Ptitsyn, A. A., Weil, M. M., & Thamm, D. H. (2008). Systems biology approach to identification of biomarkers for metastatic progression in cancer. BMC Bioinformatics, 9(Suppl 9), S8. https://doi.org/10.1186/1471-2105-9-S9-S8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Yan, J. A., Xiao, H., Ji, H. X., Shen, W. H., Zhou, Z. S., Song, B., Chen, Z. W., & Li, W. B. (2010). Cathepsin L is associated with proliferation and clinical outcome of urothelial carcinoma of the bladder. The Journal of International Medical Research, 38(6), 1913–1922. https://doi.org/10.1177/147323001003800604.

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, D., Fei, Q., Li, J., Zhang, C., Sun, Y., Zhu, C., Wang, F., & Sun, Y. (2016). 2-Deoxyglucose reverses the promoting effect of insulin on colorectal cancer cells in vitro. PLoS One, 11(3), e0151115. https://doi.org/10.1371/journal.pone.0151115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Feinberg, A. P., & Tycko, B. (2004). The history of cancer epigenetics. Nature Reviews. Cancer, 4(2), 143–153. https://doi.org/10.1038/nrc1279.

    Article  CAS  PubMed  Google Scholar 

  78. Ruivo, C. F., Adem, B., Silva, M., & Melo, S. A. (2017). The biology of Cancer exosomes: Insights and new perspectives. Cancer Research, 77(23), 6480–6488. https://doi.org/10.1158/0008-5472.CAN-17-0994.

    Article  CAS  PubMed  Google Scholar 

  79. Hoshino, A., Costa-Silva, B., Shen, T. L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., Molina, H., Kohsaka, S., di Giannatale, A., Ceder, S., Singh, S., Williams, C., Soplop, N., Uryu, K., Pharmer, L., King, T., Bojmar, L., Davies, A. E., Ararso, Y., Zhang, T., Zhang, H., Hernandez, J., Weiss, J. M., Dumont-Cole, V. D., Kramer, K., Wexler, L. H., Narendran, A., Schwartz, G. K., Healey, J. H., Sandstrom, P., Jørgen Labori, K., Kure, E. H., Grandgenett, P. M., Hollingsworth, M. A., de Sousa, M., Kaur, S., Jain, M., Mallya, K., Batra, S. K., Jarnagin, W. R., Brady, M. S., Fodstad, O., Muller, V., Pantel, K., Minn, A. J., Bissell, M. J., Garcia, B. A., Kang, Y., Rajasekhar, V. K., Ghajar, C. M., Matei, I., Peinado, H., Bromberg, J., & Lyden, D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329–335. https://doi.org/10.1038/nature15756.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Perrin, S. (2014). Preclinical research: Make mouse studies work. Nature, 507(7493), 423–425. https://doi.org/10.1038/507423a.

    Article  PubMed  Google Scholar 

  81. Jacques, C., Renema, N., Lezot, F., Ory, B., Walkley, C. R., Grigoriadis, A. E., & Heymann, D. (2018). Small animal models for the study of bone sarcoma pathogenesis: Characteristics, therapeutic interests and limitations. Journal of Bone Oncology, 12, 7–13. https://doi.org/10.1016/j.jbo.2018.02.004.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Wagner, F., Holzapfel, B. M., Thibaudeau, L., Straub, M., Ling, M. T., Grifka, J., Loessner, D., Lévesque, J. P., & Hutmacher, D. W. (2016). A validated preclinical animal model for primary bone tumor research. The Journal of Bone and Joint Surgery. American Volume, 98(11), 916–925. https://doi.org/10.2106/JBJS.15.00920.

    Article  PubMed  Google Scholar 

  83. Guiho, R., Biteau, K., Grisendi, G., Chatelais, M., Brion, R., Taurelle, J., et al. (2018). In vitro and in vivo discrepancy in inducing apoptosis by mesenchymal stromal cells delivering membrane-bound tumor necrosis factor-related apoptosis inducing ligand in osteosarcoma pre-clinical models. Cytotherapy. https://doi.org/10.1016/j.jcyt.2018.06.013.

  84. Wagner, F., Holzapfel, B. M., McGovern, J. A., Shafiee, A., Baldwin, J. G., Martine, L. C., Lahr, C. A., Wunner, F. M., Friis, T., Bas, O., Boxberg, M., Prodinger, P. M., Shokoohmand, A., Moi, D., Mazzieri, R., Loessner, D., & Hutmacher, D. W. (2018). Humanization of bone and bone marrow in an orthotopic site reveals new potential therapeutic targets in osteosarcoma. Biomaterials, 171, 230–246. https://doi.org/10.1016/j.biomaterials.2018.04.030.

    Article  CAS  PubMed  Google Scholar 

  85. Jeys, L. M., Grimer, R. J., Carter, S. R., Tillman, R. M., & Abudu, A. (2007). Post operative infection and increased survival in osteosarcoma patients: Are they associated? Annals of Surgical Oncology, 14(10), 2887–2895. https://doi.org/10.1245/s10434-007-9483-8.

    Article  CAS  PubMed  Google Scholar 

  86. Tuohy, J. L., Lascelles, B. D., Griffith, E. H., & Fogle, J. E. (2016). Association of canine osteosarcoma and monocyte phenotype and chemotactic function. Journal of Veterinary Internal Medicine, 30(4), 1167–1178. https://doi.org/10.1111/jvim.13983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Goldsby, R. E., Fan, T. M., Villaluna, D., Wagner, L. M., Isakoff, M. S., Meyer, J., Lor Randall, R., Lee, S., Kim, G., Bernstein, M., Gorlick, R., Krailo, M., & Marina, N. (2013). Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group. European Journal of Cancer, 49(10), 2384–2391. https://doi.org/10.1016/j.ejca.2013.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ory, B., Heymann, M. F., Kamijo, A., Gouin, F., Heymann, D., & Redini, F. (2005). Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice. Cancer, 104(11), 2522–2529. https://doi.org/10.1002/cncr.21530.

    Article  CAS  PubMed  Google Scholar 

  89. Whelan, J. S., & Davis, L. E. (2018). Osteosarcoma, chondrosarcoma, and chordoma. Journal of Clinical Oncology, 36(2), 188–193. https://doi.org/10.1200/JCO.2017.75.1743.

    Article  CAS  PubMed  Google Scholar 

  90. Siegel, R. L., Miller, K. D., & Jemal, A. (2017). Cancer statistics, 2017. CA: a Cancer Journal for Clinicians, 67(1), 7–30. https://doi.org/10.3322/caac.21387.

    Article  Google Scholar 

Download references

Funding

This work was supported, in part, by the Department of Orthopaedic Surgery at UCLA. Dr. Duan is supported, in part, through a Grant from Sarcoma Foundation of America (SFA), a Grant from National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA151452-01.

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Sarcoma Biology Laboratory, David Geffen School of Medicine at UCLA, 615 Charles E. Young Dr. S, Los Angeles, CA, 90095, USA

    Dylan C. Dean, Shen Shen, Francis J. Hornicek & Zhenfeng Duan

  2. Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Shen Shen

Authors
  1. Dylan C. Dean
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shen Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Francis J. Hornicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenfeng Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhenfeng Duan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dean, D.C., Shen, S., Hornicek, F.J. et al. From genomics to metabolomics: emerging metastatic biomarkers in osteosarcoma. Cancer Metastasis Rev 37, 719–731 (2018). https://doi.org/10.1007/s10555-018-9763-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-018-9763-8

Keywords

search

Navigation