Osteosarcoma: A review with emphasis on pathogenesis and chemoresistance

Main Article Content

Steven J. Kuerbitz, MD Matthew B. Henderson, DO

Abstract

Osteosarcoma is the most common malignant primary bone tumor among children and adolescents. Patterns of presentation and clinical progression have been well-characterized, and cytogenetic and molecular analyses have demonstrated genomic complexity with a substantial degree of structural variation. Nevertheless, extensive research has facilitated only limited understanding of the molecular events that govern oncogenic transformation of a mesenchymal progenitor or that drive clinical phenotypes such as metastasis and chemoresponsiveness. Initial clinical management of patients is well-standardized, and the majority of patients whose tumors are localized at the time of presentation, are amenable to effective surgical resection, and exhibit extensive tumoricidal response to chemotherapy can enjoy long term survival. Outcomes for the significant proportion of patients differing with respect to any one of these clinical characteristics are much less favorable, however, and therapeutic strategies to address clinically advanced disease and chemoresistance to date have been disappointing. This review will discuss the current understanding of OS oncogenesis, clinical presentation, and the status of OS clinical management. The discussion will focus on genetic and epigenetic events associated with chemoresistance in OS and the insights such a mechanistic understanding may offer toward circumventing this major clinical barrier. 

Article Details

How to Cite
KUERBITZ, Steven J.; HENDERSON, Matthew B.. Osteosarcoma: A review with emphasis on pathogenesis and chemoresistance. Medical Research Archives, [S.l.], v. 8, n. 7, july 2020. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2170>. Date accessed: 24 apr. 2024. doi: https://doi.org/10.18103/mra.v8i7.2170.
Section
Review Articles

References

. Damron TA, Ward WG, Stewart A. Osteosarcoma, chondrosarcoma, and ewing’s sarcoma: National cancer data base report. Clinical Orthopaedics and Related Research. 2007;(459):40-47. doi:10.1097/BLO.0b013e318059b8c9.
2. Cripe TP, Yeager ND, eds. Malignant Pediatric Bone Tumors – Treatment & Management. 1st ed. Springer International Publishing; 2015.
3. Stiller CA, Desandes E, Danon SE, et al. Cancer incidence and survival in European adolescents (1978-1997). report from the automated childhood cancer information system project. European Journal of Cancer. 2006;42(13):2006-2018. doi:10.1016/j.ejca.2006.06.002.
4. Nie Z, Peng H. Osteosarcoma in patients below 25 years of age: An observational study of incidence, metastasis, treatment and outcomes. Oncology Letters. 2018;16(5):6502-6514. doi:10.3892/ol.2018.9453.
5. Ripperger T, Bielack SS, Borkhardt A, et al. Childhood cancer predisposition syndromes—A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology. American Journal of Medical Genetics, Part A. 2017;173(4):1017-1037. doi:10.1002/ajmg.a.38142.
6. Mirabello L, Troisi R. Osteosarcoma incidence and survival improvement. Cancer. 2009;115(7):1531-1543. doi:10.1002/cncr.24121.Osteosarcoma.
7. Durfee RA, Mohammed M, Luu HH. Review of Osteosarcoma and Current Management. Rheumatology and Therapy. 2016;3(2):221-243. doi:10.1007/s40744-016-0046-y.
8. Fletcher CDM, Bridge JA, Hogendoorn PCW MF, ed. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. World Health Organization; 2013.
9. de Azevedo JWV, de Medeiros Fernandes TAA, Fernandes JV, et al. Biology and pathogenesis of human osteosarcoma (Review). Oncology Letters. 2020;19(2):1099-1116. doi:10.3892/ol.2019.11229.
10. Almalki SG, Agrawal DK. Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation. 2016;92(1-2):41-51. doi:10.1016/j.diff.2016.02.005.
11. Caplan AI. Mesenchymal stem cells: Time to change the name! Stem Cells Translational Medicine. 2017;6(6):1445-1451. doi:10.1002/sctm.17-0051.
12. Horwitz EM, le Blanc K, Dominici M, et al. Clarification of the nomenclature for MSC: The international society for cellular therapy position statement. Cytotherapy. 2005;7(5):393-395. doi:10.1080/14653240500319234.
13. Bianco P, Robey PG. Skeletal stem cells. Development (Cambridge). 2015;142(6):1023-1027. doi:10.1242/dev.102210.
14. Berendsen AD, Olsen BR. Bone development. Bone. 2015;80:14-18. doi:10.1016/j.bone.2015.04.035.
15. Alfranca A, Martinez-Cruzado L, Tornin J, et al. Bone microenvironment signals in osteosarcoma development. Cellular and Molecular Life Sciences. 2015;72(16):3097-3113. doi:10.1007/s00018-015-1918-y.
16. Berman SD, Calo E, Landman AS, et al. Metastatic Osteosarcoma Induced by Inactivation of Rb and P53 in the Osteoblast Lineage. PNAS. 2008;105(33):11851-56.
17. Walkley CR, Qudsi R, Sankaran VG, et al. Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes and Development. 2008;22(12):1662-1676. doi:10.1101/gad.1656808.
18. Lengner CJ, Steinman HA, Gagnon J, et al. Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling. Journal of Cell Biology. 2006;172(6):909-921. doi:10.1083/jcb.200508130.
19. Rubio R, Gutierrez-Aranda I, Sáez-Castillo AI, et al. The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma development. Oncogene. 2013;32(41):4970-4980. doi:10.1038/onc.2012.507.
20. Shimizu T, Ishikawa T, Sugihara E, et al. C-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis. Oncogene. 2010;29(42):5687-5699. doi:10.1038/onc.2010.312.
21. Wang J,Wu P, Chen P, Lee C, Chen W. Generation of osteosarcomas from a combination of Rb silencing and c-Myc Overexpression in human mesenchymal stem cells. Stem Cells Translational Medicine. 2017;6:527-538.
22. Yang Y, Yang R, Roth M, et al. Genetically transforming human osteoblasts to sarcoma: Development of an osteosarcoma model. Genes and Cancer. 2017;8(1-2):484-494. doi:10.18632/genesandcancer.133.
23. Abarrategi A, Tornin J, Lucia MC, et al. Osteosarcoma: cells-of-origin, cancer stem cells, and targeted therapies. Stem Cells International. 2016;2016. doi:10.1155/2016/3631764.
24. Basu-Roy U, Basilico C, Mansukhani A. Perspectives on cancer stem cells in osteosarcoma. Cancer Letters. 2013;338(1):158-167. doi:10.1016/j.canlet.2012.05.028.
25. Gibbs CP, Kukekov VG, Reith JD, et al. Stem-like cells in bone sarcomas: Implications for tumorigenesis. Neoplasia. 2005;7(11):967-976. doi:10.1593/neo.05394.
26. Salerno M, Avnet S, Bonuccelli G, et al. Sphere-forming cell subsets with cancer stem cell properties in human musculoskeletal sarcomas. International Journal of Oncology. 2013;43(1):95-102. doi:10.3892/ijo.2013.1927.
27. Hilton MJ, Tu X, Wu X, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nature Medicine. 2008;14(3):306-314. doi:10.1038/nm1716.
28. Tu B, Du L, Fan QM, Tang Z, Tang TT. STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer Letters. 2012;325(1):80-88. doi:10.1016/j.canlet.2012.06.006.
29. Siclari VA, Qin L. Targeting the osteosarcoma cancer stem cell. Journal of Orthopaedic Surgery and Research. 2010;5(1). doi:10.1186/1749-799X-5-78.
30. Kuhn NZ, Tuan RS. Regulation of stemness and stem cell niche of mesenchymal stem cells: Implications in tumorigenesis and metastasis. Journal of Cellular Physiology. 2010;222(2):268-277. doi:10.1002/jcp.21940.
31. Zheng Y, Wang G, Chen R, Hua Y, Cai Z. Mesenchymal stem cells in the osteosarcoma microenvironment: Their biological properties, influence on tumor growth, and therapeutic implications. Stem Cell Research and Therapy. 2018;9(1). doi:10.1186/s13287-018-0780-x.
32. Kansara M, Teng M, Smyth M TD. Translational Biology of Osteosarcoma. Nature Reviews: Cancer. 2014;14(11):722-735.
33. Smida J, Xu H, Zhang Y, et al. Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma. International Journal of Cancer. 2017;141(4):816-828. doi:10.1002/ijc.30778.
34. Morrow J. Osteosarcoma genetics and epigenetics: Emerging biology and candidate therapies. Critical Review in Oncogenesis. 2015;20:173-197.
35. Martin JW, Squire JA, Zielenska M. The genetics of osteosarcoma. Sarcoma. 2012;2012. doi:10.1155/2012/627254
36. Mayhew CN, Carter SL, Fox SR, et al. RB loss abrogates cell cycle control and genome integrity to promote liver tumorigenesis. Gastroenterology. 2007;133(3):976-984. doi:10.1053/j.gastro.2007.06.025.
37. Overholtzer M, Rao PH, Favis R, et al. The Presence of P53 Mutations in Human Osteosarcomas Correlates with High Levels of Genomic Instability. PNAS. 2003; 100(20): 11547-11552. www.pnas.orgcgidoi10.1073pnas.1934852100.
38. Artigas N, Gámez B, Cubillos-Rojas M, et al. P53 inhibits SP7/Osterix activity in the transcriptional program of osteoblast differentiation. Cell Death and Differentiation. 2017;24(12):2022-2031. doi:10.1038/cdd.2017.113.
39. Henriksen J, Aagesen TH, Maelandsmo GM, Lothe RA, Myklebost O, Forus A. Amplification and overexpression of COPS3 in osteosarcomas potentially target TP53 for proteasome-mediated degradation. Oncogene. 2003;22(34):5358-5361. doi:10.1038/sj.onc.1206671.
40. Kulikov R, Letienne J, Kaur M, Grossman SR, Arts J, Blattner C. Mdm2 facilitates the association of p53 with the proteasome. PNAS. 2010; 107(22). doi:10.1073/pnas.0911716107/-/DCSupplemental.
41. Yan T, Wunder JS, Gokgoz N, et al. COPS3 amplification and clinical outcome in osteosarcoma. Cancer. 2007;109(9):1870-1876. doi:10.1002/cncr.22595.
42. Hansen MF, Koufos A, Galliet BL, et al. Osteosarcoma and retinoblastoma: A shared chromosomal mechanism revealing recessive predisposition. Proc. Natl. Acad. Sci. 1985; 82: 6216-6220.
43. Smida J, Baumhoer D, Rosemann M, et al. Genomic alterations and allelic imbalances are strong prognostic predictors in osteosarcoma. Clinical Cancer Research. 2010;16(16):4256-4267. doi:10.1158/1078-0432.CCR-10-0284.
44. Del Mare S, Kurek K, Stein G, Lian J, and Aqeilan R. Role of the WWOX tumor suppressor gene in bone homeo-stasis and the pathogenesis of osteosarcoma. American Journal of Cancer Research. 2011;1(5):585-594.
45. Aqeilan R, Trapasso F, Hussain S, et al. Targeted Deletion of Wwox Reveals a Tumor Suppressor Function. PNAS. 2007; 104: 3949-3954.
46. Squire JA, Martin JW, Zielenska M, Stein GS, van Wijnen AJ. The role of RUNX2 in osteosarcoma oncogenesis. Sarcoma. 2011;2011. doi:10.1155/2011/282745.
47. Lo JY, Chou YT, Lai FJ, Hsu LJ. Regulation of cell signaling and apoptosis by tumor suppressor WWOX. Experimental Biology and Medicine. 2015;240(3):383-391. doi:10.1177/1535370214566747.
48. Kurek KC, del Mare S, Salah Z, et al. Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. Cancer Research. 2010;70(13):5577-5586. doi:10.1158/0008-5472.CAN-09-4602.
49. Freeman SS, Allen SW, Ganti R, et al. Copy number gains in EGFR and copy number losses in PTEN are common events in osteosarcoma tumors. Cancer. 2008;113(6):1453-1461. doi:10.1002/cncr.23782.
50. Xi Y, Chen Y. Oncogenic and therapeutic targeting of PTEN loss in bone malignancies. Journal of Cellular Biochemistry. 2015;116(9):1837-1847. doi:10.1002/jcb.25159.
51. Xi Y, Chen Y. PTEN Plays Dual roles as a tumor suppressor in osteosarcoma cells. Journal of Cellular Biochemistry. 2017;118(9):2684-2692. doi:10.1002/jcb.25888.
52. Zhao GS, Gao ZR, Zhang Q, et al. TSSC3 promotes autophagy via inactivating the Src-mediated PI3K/Akt/mTOR pathway to suppress tumorigenesis and metastasis in osteosarcoma, and predicts a favorable prognosis. Journal of Experimental and Clinical Cancer Research. 2018;37(1). doi:10.1186/s13046-018-0856-6.
53. Wu X, Cai Z dong, Lou L ming, Zhu Y bo. Expressions of p53, c-MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients. Cancer Epidemiology. 2012;36(2):212-216. doi:10.1016/j.canep.2011.08.002.
54. Shi Y, He R, Zhuang Z, et al. A risk signature-based on metastasis-associated genes to predict survival of patients with osteosarcoma. Journal of Cellular Biochemistry. 2020: 1-12. doi:10.1002/jcb.29622.
55. Han G, Wang Y. C-Myc overexpression promotes osteosarcoma cell invasion via activation of MEK-ERK pathway. Oncology Research. 2012;20(4):149-156.
56. Cai Y, Cai T, Chen Y. Wnt pathway in osteosarcoma, from oncogenic to therapeutic. Journal of Cellular Biochemistry. 2014;115(4):625-631. doi:10.1002/jcb.24708.
57. Zanotti S, Canalis E. Notch signaling in skeletal health and disease. European Journal of Endocrinology. 2013;168(6). doi:10.1530/EJE-13-0115.
58. McManus M, Weiss K. Understanding the role of notch in osteosarcoma. Advances in Experimental Medicine and Biology. 2014;804:67-92.
59. Hughes D. How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize. Cancer Treatment and Research. 2009;152:479-496.
60. Feinberg A. The History of Cancer Epigenetics. Nature Reviews : Cancer. 2004;4.
61. van der Wijst M, Venkiteswaran M, Chen H, Xu GL, Plösch T, Rots MG. Local chromatin microenvironment determines DNMT activity: From DNA methyltransferase to DNA demethylase or DNA dehydroxymethylase. Epigenetics. 2015;10(8):671-676. doi:10.1080/15592294.2015.1062204.
62. Goelz S, Vogelstein B, Hamilton S FA. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985;228(4696):187-190.
63. Baylin S, Herman J, Graff J, Vertino P IJ. Alterations in DNA methylation: A fundamental aspect of neoplasia. Advances in Cancer Research. 1998;72:141-196.
64. Baylin S CW. Aberrant gene silencing in tumor progression: Implications for control of cancer. Cold Spring Harbor Symposia on quantitative biology. 2005;70:427-433.
65. Xu J, Li D, Cai Z, et al. An integrative analysis of DNA methylation in osteosarcoma. Journal of Bone Oncology. 2017;9:34-40. doi:10.1016/j.jbo.2017.05.001.
66. Chen XG, Ma L, Xu JX. Abnormal DNA methylation may contribute to the progression of osteosarcoma. Molecular Medicine Reports. 2018;17(1):193-199. doi:10.3892/mmr.2017.7869.
67. Tsuchiya T, Sekine KI, Hinohara SI, Namiki T, Nobori T, Kaneko Y. Analysis of the P16INK4 , P14ARF , P15 , TP53 , and MDM2 Genes and Their Prognostic Implications in Osteosarcoma and Ewing Sarcoma. Cancer Genetics and Cytogenetics. 2000; 120(2):91-8.
68. Wang X, Chao L, Jin G, Ma G, Zang Y SJ. Association Between CpG Island Methylation of the WWOX Gene and Its Expression in Breast Cancers. Tumour biology: the journal of the international society for oncodevelopmental biology and medicine. 2009;30(1):8-14.
69. Yan H, Sun J. Methylation status of WWOX gene promoter CpG islands in epithelial ovarian cancer and its clinical significance. Biomedical Reports. 2013;1(3):375-378. doi:10.3892/br.2013.86.
70. Wen J, Xu Z, Li J, et al. Decreased WWOX Expression Promotes Angiogenesis in Osteosarcoma. Oncotarget. 2017; 8(37):60917-60932. www.impactjournals.com/oncotarget.
71. Kansara M, Tsang M, Kodjabachian L, et al. Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice. Journal of Clinical Investigation. 2009;119(4):837-851. doi:10.1172/JCI37175.
72. Han W, Liu J. Epigenetic silencing of the Wnt antagonist APCDD1 by promoter DNA hyper-methylation contributes to osteosarcoma cell invasion and metastasis. Biochemical and Biophysical Research Communications. 2017;491(1):91-97. doi:10.1016/j.bbrc.2017.07.049.
73. Hou P, Ji M, Yang B, et al. Quantitative analysis of promoter hypermethylation in multiple genes in osteosarcoma. Cancer. 2006;106(7):1602-1609. doi:10.1002/cncr.21762.
74. Tian W, Li Y, Zhang J, Li J, Gao J. Combined analysis of DNA methylation and gene expression profiles of osteosarcoma identified several prognosis signatures. Gene. 2018;650:7-14. doi:10.1016/j.gene.2018.01.093.
75. Wenpeng Z, Han S, Sun K. Combined analysis of gene expression, miRNA expression and DNA methylation profiles of osteosarcoma. Oncology Reports. 2017;37(2):1175-1181. doi:10.3892/or.2016.5324.
76. Kresse SH, Rydbeck H, Skårn M, et al. Integrative Analysis Reveals Relationships of Genetic and Epigenetic Alterations in Osteosarcoma. PLoS ONE. 2012;7(11). doi:10.1371/journal.pone.0048262.
77. Wang TX, Tan WL, Huang JC, et al. Identification of aberrantly methylated differentially expressed genes targeted by differentially expressed miRNA in osteosarcoma. Annals of Translational Medicine. 2020;8(6):373-373. doi:10.21037/atm.2020.02.74.
78. Wang Q. CpG methylation patterns are associated with gene expression variation in osteosarcoma. Molecular Medicine Reports. 2017;16(1):901-907. doi:10.3892/mmr.2017.6635.
79. Lu J, Song G, Tang Q, et al. IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling. Journal of Clinical Investigation. 2015;125(5):1839-1856. doi:10.1172/JCI78437.
80. Dante R. Quantitative Determination of Methylated CpG in Satellite DNA I and in LlRn DNA Sequences Extracted from Rat Kidney Tissue and from Rat Kidney Cell Lines. Eur. J. Biochem. 1988; 175: 135-139.
81. Rodriguez J, Frigola J, Vendrell E, et al. Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. Cancer Research. 2006;66(17):8462-8468. doi:10.1158/0008-5472.CAN-06-0293.
82. Daskalos A, Nikolaidis G, Xinarianos G, et al. Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer. International Journal of Cancer. 2009;124(1):81-87. doi:10.1002/ijc.23849.
83. Ross J, Rand K MP. Hypomethylation of repeated DNA sequences in cancer. Epigenomics. 2010;2(2):245-269.
84. Kawano H, Saeki H, Kitao H, et al. Chromosomal instability associated with global DNA hypomethylation is associated with the initiation and progression of esophageal squamous cell carcinoma. Annals of Surgical Oncology. 2014;21(4):696-702. doi:10.1245/s10434-014-3818-z.
85. Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring Harbor Perspectives in Biology. 2016;8(4). doi:10.1101/cshperspect.a019521.
86. Piao L, Yuan X, Zhuang M, et al. Histone methyltransferase SUV39H2 serves oncogenic roles in osteosarcoma. Oncology Reports. 2019;41(1):325-332. doi:10.3892/or.2018.6843.
87. Kraushaar DC, Zhao K. The epigenomics of embryonic stem cell differentiation. International Journal of Biological Sciences. 2013;9(10):1134-1144. doi:10.7150/ijbs.7998.
88. Easwaran H, Johnstone SE, van Neste L, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Research. 2012;22(5):837-849. doi:10.1101/gr.131169.111.
89. la Noce M, Paino F, Mele L, et al. HDAC2 depletion promotes osteosarcoma’s stemness both in vitro and in vivo: A study on a putative new target for CSCs directed therapy. Journal of Experimental and Clinical Cancer Research. 2018;37(1). doi:10.1186/s13046-018-0978-x.
90. Lu B, He Y, He J, et al. Epigenetic profiling identifies LIF as a super-enhancer-controlled regulator of stem cell-like properties in osteosarcoma. Molecular Cancer Research. 2020;18(1):57-67.
91. Cech TR, Steitz JA. The noncoding RNA revolution - Trashing old rules to forge new ones. Cell. 2014;157(1):77-94. doi:10.1016/j.cell.2014.03.008.
92. Carthew RW, Sontheimer EJ. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642-655. doi:10.1016/j.cell.2009.01.035.
93. Acunzo M, Romano G, Wernicke D, Croce CM. MicroRNA and cancer - A brief overview. Advances in Biological Regulation. 2015;57:1-9. doi:10.1016/j.jbior.2014.09.013.
94. Liu Y, Dou M, Song X, et al. The emerging role of the piRNA/piwi complex in cancer. Molecular Cancer. 2019;18(1). doi:10.1186/s12943-019-1052-9.
95. Schmitz SU, Grote P, Herrmann BG. Mechanisms of long noncoding RNA function in development and disease. Cellular and Molecular Life Sciences. 2016;73(13):2491-2509. doi:10.1007/s00018-016-2174-5.
96. Kristensen LS, Hansen TB, Venø MT, Kjems J. Circular RNAs in cancer: Opportunities and challenges in the field. Oncogene. 2018;37(5):555-565. doi:10.1038/onc.2017.361.
97. Maire G, Martin JW, Yoshimoto M, Chilton-MacNeill S, Zielenska M, Squire JA. Analysis of miRNA-gene expression-genomic profiles reveals complex mechanisms of microRNA deregulation in osteosarcoma. Cancer Genetics. 2011;204(3):138-146. doi:10.1016/j.cancergen.2010.12.012.
98. Zhang CL, Zhu KP, Shen GQ, Zhu ZS. A long non-coding RNA contributes to doxorubicin resistance of osteosarcoma. Tumor Biology. 2016;37(2):2737-2748. doi:10.1007/s13277-015-4130-7.
99. Yang BF, Cai W, Chen B. LncRNA SNHG12 Regulated Proliferation of Gastric Carcinoma Cell via MicroRNA-199a/b-5p. European review for medical and pharmacological sciences. 2018; 22(5):1297-1306.
100. Han J, Shen X. Long noncoding RNAs in osteosarcoma via various signaling pathways. Journal of Clinical Laboratory Analysis. 2020. doi:10.1002/jcla.23317
101. Qu F, Li CB, Yuan BT, et al. MicroRNA-26a induces osteosarcoma cell growth and metastasis via the Wnt/β-catenin pathway. Oncology Letters. 2016;11(2):1592-1596. doi:10.3892/ol.2015.4073
102. Pan BL, Wu L, Pan L, et al. Up-regulation of microRNA-340 promotes osteosarcoma cell apoptosis while suppressing proliferation, migration, and invasion by inactivating the CTNNB1-mediated Notch signaling pathway. Bioscience Reports. 2018;38(4). doi:10.1042/BSR20171615.
103. Pan BL, Tong ZW, Wu L, et al. Effects of MicroRNA-206 on osteosarcoma cell proliferation, apoptosis, migration and invasion by targeting ANXA2 through the AKT signaling pathway. Cellular Physiology and Biochemistry. 2018;45(4):1410-1422. doi:10.1159/000487567.
104. Li Q, Li H, Zhao X, et al. DNA methylation mediated downregulation of miR-449c controls osteosarcoma cell cycle progression by directly targeting oncogene c-Myc. International Journal of Biological Sciences. 2017;13(8):1038-1050. doi:10.7150/ijbs.19476.
105. Chen Z, Zhang W, Jiang K, et al. MicroRNA-300 regulates the ubiquitination of PTEN through the CRL4BDCAF13 E3 ligase in osteosarcoma cells. Molecular Therapy - Nucleic Acids. 2018;10:254-268. doi:10.1016/j.omtn.2017.12.010.
106. Kong D, Wang Y. Knockdown of lncRNA HULC inhibits proliferation, migration, invasion, and promotes apoptosis by sponging miR-122 in osteosarcoma. Journal of Cellular Biochemistry. 2018;119(1):1050-1061. doi:10.1002/jcb.26273.
107. Li X, Lu H, Fan G, et al. A novel interplay between HOTAIR and DNA methylation in osteosarcoma cells indicates a new therapeutic strategy. Journal of Cancer Research and Clinical Oncology. 2017;143(11):2189-2200. doi:10.1007/s00432-017-2478-3.
108. Wang B, Qu XL, Liu J, Lu J, Zhou ZY. HOTAIR promotes osteosarcoma development by sponging miR-217 and targeting ZEB1. Journal of Cellular Physiology. 2019;234(5):6173-6181. doi:10.1002/jcp.27394.
109. Zhang Z, Xu H, Hu W, Hu T WX. LINC01116 promotes proliferation, invasion and migration of osteosarcoma cells by silencing p53 and EZH2. European Review for Medical and Pharmacological Sciences. 2019;23:6813-6823.
110. Wu H, He Y, Chen H, et al. LncRNA THOR increases osteosarcoma cell stemness and migration by enhancing SOX9 mRNA stability. FEBS Open Bio. 2019;9(4):781-790. doi:10.1002/2211-5463.12620.
111. Widhe B, Widhe T. Initial symptoms and clinical features in osteosarcoma and ewing sarcoma. Journal of Bone and Joint Surgery - Series A. 2000;82(5):667-674. doi:10.2106/00004623-200005000-00007.
112. Goedhart LM, Gerbers JG, Ploegmakers JJW, Jutte PC. Delay in diagnosis and its effect on clinical outcome in high-grade sarcoma of bone: A referral oncological centre study. Orthopaedic Surgery. 2016;8(2):122-128. doi:10.1111/os.12239.
113. Longhi A, Errani C, Paolis M de, Mercuri M, Bacci G. Primary bone osteosarcoma in the pediatric age : State of the art. Cancer Treatment Reviews. 2006;32:423-436. doi:10.1016/j.ctrv.2006.05.005.
114. Smeland S, Bielack SS, Whelan J, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. European Journal of Cancer. 2019;109:36-50. doi:10.1016/j.ejca.2018.11.027.
115. Stuart H. Orkin, MD, David G. Nathan, MD, David Ginsburg, MD, A. Thomas Look, MD, David E. Fisher, MD, PhD and Samuel Lux, IV M. Nathan and Oski’s Hematology of Infancy and Childhood. 8th ed. Philadelphia, PA: Saunders; 2015.
116. Geller DS, Gorlick R. Osteosarcoma: A review of diagnosis, management, and treatment strategies. Clinical Advances in Hematology and Oncology. 2010;8(10):705-718.
117. Jaffe N. Historical perspective on the introduction and use of chemotherapy for the treatment of osteosarcoma. Advances in Experimental Medicine and Biology. 2014;804. doi:10.1007/978-3-319-04843-7_1.
118. Sutow W, Sullivan M, Fernbach D, Cangir A GS. Adjuvant chemotherapy in primary treatment of osteogenic sarcoma: A southwest oncology group study. Cancer. 1975;36(5):1598-1602.
119. Winkler K, Beron G, Delling G, et al. Neoadjuvant Chemotherapy of Osteosarcoma: Results of a Randomized Cooperative Trial (COSS-82) With Salvage Chemotherapy Based on Histological Tumor Response. Journal of Clinical Oncology. 1988;6:329-337.
120. Rosen G, Caparros R, Huvos AG, et al. Preoperative Chemotherapy for Osteogenic Sarcoma: Selection of Postoperative Adjuvant Chemotherapy Based on the Response of the Primary Tumor to Preoperative Chemotherapy. Cancer. 1982;49:1221-1230.
121. Harrison DJ, Geller DS, Gill JD, et al. Current and future therapeutic approaches for osteosarcoma. Expert Review of Anticancer Therapy. 2018;18(1):39-50. doi:10.1080/14737140.2018.1413939.
122. He X, Gao Z, Xu H, Zhang Z, Fu P. A meta-analysis of randomized control trials of surgical methods with osteosarcoma outcomes. Journal of Orthopaedic Surgery and Research. 2017;12(1). doi:10.1186/s13018-016-0500-0.
123. Li X, Zhang Y, Wan S, et al. A comparative study between limb-salvage and amputation for treating osteosarcoma. Journal of Bone Oncology. 2016;5(1):15-21. doi:10.1016/j.jbo.2016.01.001.
124. Bertrand TE, Cruz A, Binitie O, Cheong D, Letson GD. Do surgical margins affect local recurrence and survival in extremity, nonmetastatic, high-grade osteosarcoma?. Clinical Orthopaedics and Related Research. 2016;474(3):677-683. doi:10.1007/s11999-015-4359-x.
125. Li X, Moretti VM, Ashana AO, Lackman RD. Impact of close surgical margin on local recurrence and survival in osteosarcoma. International Orthopaedics. 2012;36(1):131-137. doi:10.1007/s00264-011-1230-x.
126. Isakoff MS, Barkauskas DA, Ebb D, Morris C, Letson GD. Poor survival for osteosarcoma of the pelvis: A report from the children’s oncology group. Clinical Orthopaedics and Related Research. 2012;470(7):2007-2013. doi:10.1007/s11999-012-2284-9.
127. Bielack S, Bieling P, Erttmann R WK. Intraarterial chemotherapy for osteosarcoma: does the result really justify the effort? Cancer Treatment and Research. 1993;62:85-92.
128. Schwartz CL, Wexler LH, Krailo MD, et al. Intensified chemotherapy with dexrazoxane cardioprotection in newly diagnosed nonmetastatic osteosarcoma: A report from the children’s oncology group. Pediatric Blood and Cancer. 2016;63(1):54-61. doi:10.1002/pbc.25753.
129. Treon SP, Chabner BA. Concepts in Use of High-Dose Methotrexate Therapy. Clinical Chemistry. 1996; 42(8):1322-1329.
130. Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival - A report from the children’s oncology group. Journal of Clinical Oncology. 2008;26(4):633-638. doi:10.1200/JCO.2008.14.0095.
131. Marina NM, Smeland S, Bielack SS, et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. The Lancet Oncology. 2016;17(10):1396-1408. doi:10.1016/S1470-2045(16)30214-5.
132. Han XG, Mo HM, Liu XQ, et al. TIMP3 overexpression improves the sensitivity of osteosarcoma to cisplatin by reducing IL-6 production. Frontiers in Genetics. 2018;9. doi:10.3389/fgene.2018.00135.
133. Yang J, Shah R, Robling AG, et al. HMGB1 is a bone-active cytokine. Journal of Cellular Physiology. 2008;214(3):730-739. doi:10.1002/jcp.21268.
134. Huang J, Ni J, Liu K, et al. HMGB1 promotes drug resistance in osteosarcoma. Cancer Research. 2012;72(1):230-238. doi:10.1158/0008-5472.CAN-11-2001.
135. Ma Y, Ren Y, Han EQ, et al. Inhibition of the Wnt-β-catenin and Notch signaling pathways sensitizes osteosarcoma cells to chemotherapy. Biochemical and Biophysical Research Communications. 2013;431(2):274-279. doi:10.1016/j.bbrc.2012.12.118.
136. Ren HY, Zhang YH, Li HY, et al. Prognostic role of hypoxia-inducible factor-1 alpha expression in osteosarcoma: A meta-analysis. OncoTargets and Therapy. 2016;9:1477-1487. doi:10.2147/OTT.S95490.
137. Comerford KM, Wallace TJ, Karhausen J, Louis NA, Montalto MC, Colgan SP. Hypoxia-Inducible Factor-1-Dependent Regulation of the Multidrug Resistance (MDR1) Gene. Cancer Research. 2002; 62:3387-3394.
138. Roncuzzi L, Pancotti F, Baldini N. Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells. Oncology Reports. 2014;32(1):389-394. doi:10.3892/or.2014.3181.
139. Li C, Guo D, Tang B, Zhang Y, Zhang K, Nie L. Notch1 is associated with the multidrug resistance of hypoxic osteosarcoma by regulating MRP1 gene expression. Neoplasma. 2016;63(5):734-742. doi:10.4149/neo_2016_510.
140. Lu J, Pokharei D. MRP1 and its role in anticancer drug resistance. Drug Metabolism Reviews. 2015;47(4):406-419.
141. Zheng D, Wu W, Dong N, et al. Mxd1 mediates hypoxia-induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene. Molecular Carcinogenesis. 2017;56(10):2234-2244. doi:10.1002/mc.22676.
142. Ma Q, Zhang Y. Hypoxia promotes chemotherapy resistance by down-regulating SKA1 gene expression in human osteosarcoma. Cancer Biology & Therapy. 2017;18(3):177-185. doi:10.1080/15384047.2017.1294285.
143. Adamski J, Price A, Dive C, Makin G. Hypoxia-induced cytotoxic drug resistance in osteosarcoma Is independent of HIF-1Alpha. PLoS ONE. 2013;8(6). doi:10.1371/journal.pone.0065304.
144. Kolenda J, Jensen SS, Aaberg-Jessen C, et al. Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. Journal of Neuro-Oncology. 2011;103(1):43-58. doi:10.1007/s11060-010-0357-8.
145. Lock FE, McDonald PC, Lou Y, et al. Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche. Oncogene. 2013;32(44):5210-5219. doi:10.1038/onc.2012.550.
146. Crowder SW, Balikov DA, Hwang YS, Sung HJ. Cancer stem cells under hypoxia as a chemoresistance factor in the breast and brain. Current Pathobiology Reports. 2014;2(1):33-40. doi:10.1007/s40139-013-0035-6.
147. Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: Tumor heterogeneity, plasticity of stem-like states, and drug resistance. Molecular Cell. 2014;54(5):716-727. doi:10.1016/j.molcel.2014.05.015.
148. Scionti I, Michelacci F, Pasello M, et al. Clinical impact of the methotrexate resistance-associated genes C-MYC and dihydrofolate reductase (DHFR) in high-grade osteosarcoma. Annals of Oncology. 2008;19(8):1500-1508. doi:10.1093/annonc/mdn148.
149. Kuerbitz SJ, Plunkett BS, Walsh W, Kastan MB. Wild-type P53 is a cell cycle checkpoint determinant following irradiation. Proc. Natl. Acad. Sci. 1992; 89: 7491-7495.
150. Bertheau P, Espié M, Turpin E, et al. TP53 status and response to chemotherapy in breast cancer. Pathobiology. 2008;75(2):132-139. doi:10.1159/000123851.
151. Sun Y, Xia P, Zhang H, Liu B, Shi Y. P53 Is Required for Doxorubicin-Induced Apoptosis via the TGF-Beta Signaling Pathway in Osteosarcoma-Derived Cells. American Journal of Cancer Research. 2016;6(1):114-125.
152. Chen XIN, Lv C, Zhu X, et al. MicroRNA-504 modulates osteosarcoma cell chemoresistance to cisplatin by targeting p53. Oncology Letters. 2019;17(2):1664-1674. doi:10.3892/ol.2018.9749.
153. Yuan XW, Zhu XF, Huang XF, et al. p14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner. Cancer Biology and Therapy. 2007;6(7):1074-1080. doi:10.4161/cbt.6.7.4324.
154. Rosenblum JM, Ari Wijetunga NA, Fazzari MJ, et al. Predictive properties of DNA methylation patterns in primary tumor samples for osteosarcoma relapse status. Epigenetics. 2015;10(1):31-39. doi:10.4161/15592294.2014.989084.
155. Cui Q, Jiang W, Guo J, et al. Relationship between hypermethylated MGMT Gene and osteosarcoma necrosis rate after chemotherapy. Pathology and Oncology Research. 2011;17(3):587-591. doi:10.1007/s12253-010-9354-7.
156. Hau P, Stupp R, Hegi ME. MGMT Methylation Status: The Advent of Stratified Therapy in Glioblastoma?. Disease Markers. 2007;23:97-104.
157. Sonaglio V, de Carvalho AC, Toledo SRC, et al. Aberrant DNA methylation of ESR1 and P14ARF genes could be useful as prognostic indicators in osteosarcoma. OncoTargets and Therapy. 2013;6:713-723. doi:10.2147/OTT.S44918.
158. Osuna MAL, Garcia-Lopez J, Ayachi I el, et al. Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. Cancer Research. 2019;79(6):1054-1068. doi:10.1158/0008-5472.CAN-18-1255.
159. He C, Sun J, Liu C, Jiang Y, Hao Y. Elevated H3K27me3 levels sensitize osteosarcoma to cisplatin. Clinical Epigenetics. 2019;11(1). doi:10.1186/s13148-018-0605-x.
160. Zhu Z, Tang J, Wang J, Duan G, Zhou L, Zhou X. MIR-138 acts as a tumor suppressor by targeting EZH2 and enhances cisplatin-induced apoptosis in osteosarcoma cells. PLoS ONE. 2016;11(3). doi:10.1371/journal.pone.0150026.
161. Chen R, Zhao WQ, Fang C, Yang X, Ji M. Histone methyltransferase SETD2: A potential tumor suppressor in solid cancers. Journal of Cancer. 2020;11(11):3349-3356. doi:10.7150/jca.38391.
162. He C, Liu C, Wang L, Sun Y, Jiang Y, Hao Y. Histone methyltransferase NSD2 regulates apoptosis and chemosensitivity in osteosarcoma. Cell Death and Disease. 2019;10(2). doi:10.1038/s41419-019-1347-1.
163. Li Z, Zhao L, Wang Q. Overexpression of Long Non-Coding RNA HOTTIP Increases Chemoresistance of Osteosarcoma Cell by Activating the Wnt/β-Catenin Pathway. American Journal of Translational Research. 2016; 8(5):2385-2393.
164. Zhang Y, Duan G, Feng S. MicroRNA-301a modulates doxorubicin resistance in osteosarcoma cells by targeting AMP-activated protein kinase alpha 1. Biochemical and Biophysical Research Communications. 2015;459(3):367-373. doi:10.1016/j.bbrc.2015.02.101.
165. Li Z, Dou P, Liu T, He S. Application of long noncoding RNAs in osteosarcoma: Biomarkers and therapeutic targets. Cellular Physiology and Biochemistry. 2017;42(4):1407-1419. doi:10.1159/000479205.
166. Chen D, Liu D, Chen Z. Potential therapeutic implications of miRNAs in osteosarcoma chemotherapy. Tumor Biology. 2017;39(9). doi:10.1177/1010428317705762.
167. Xie B, Li Y, Zhao R, et al. Identification of key genes and miRNAs in osteosarcoma patients with chemoresistance by bioinformatics analysis. BioMed Research International. 2018;2018. doi:10.1155/2018/4761064.
168. Yang R, Qin J, Hoang BH, Healey JH, Gorlick R. Polymorphisms and methylation of the reduced folate carrier in osteosarcoma. Clinical Orthopaedics and Related Research. 2008; 466: 2046-2051. doi:10.1007/s11999-008-0323-3.
169. Patiño-García A, Zalacaín M, Marrodán L, San-Julián M, Sierrasesúmaga L. Methotrexate in pediatric osteosarcoma: Response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. Journal of Pediatrics. 2009;154(5):688-693. doi:10.1016/j.jpeds.2008.11.030.
170. Ifergan I, Meller I, Issakov J, Assaraf YG. Reduced folate carrier protein expression in osteosarcoma: Implications for the prediction of tumor chemosensitivity. Cancer. 2003;98(9):1958-1966. doi:10.1002/cncr.11741.
171. Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature Reviews Cancer. 2018;18(7):452-464. doi:10.1038/s41568-018-0005-8.
172. He C, Sun Z, Hoffman RM, et al. P-glycoprotein overexpression is associated with cisplatin resistance in human osteosarcoma. Anticancer Research. 2019;39(4):1711-1718. doi:10.21873/anticanres.13277.
173. Caronia D, Patiño-Garcia A, Peréz-Martínez A, et al. Effect of ABCB1 and ABCC3 polymorphisms on osteosarcoma survival after chemotherapy: A pharmacogenetic study. PLoS ONE. 2011;6(10). doi:10.1371/journal.pone.0026091.
174. Jiang B, Yan L WQ. ABCB1 (C1236T) Polymorphism Affects P-Glycoprotein-Mediated Transport of Methotrexate, Doxorubicin, Actinomycin D, and Etoposide. DNA and Cell Biology. 2019;38(5):485-490.
175. Sun DX, Liao GJ, Liu KG, Jian H. Endosialin-expressing bone sarcoma stem-like cells are highly tumor-initiating and invasive. Molecular Medicine Reports. 2015;12(4):5665-5670. doi:10.3892/mmr.2015.4218.
176. Li JZ, Tian ZQ, Jiang SN, Feng T. Effect of variation of ABCB1 and GSTP1 on osteosarcoma survival after chemotherapy. Genetics and Molecular Research. 2014;13(2):3186-3192. doi:10.4238/2014.April.25.3.
177. Pasello M, Michelacci F, Scionti I, et al. Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma. Cancer Research. 2008;68(16):6661-6668. doi:10.1158/0008-5472.CAN-07-5840.
178. Yang LM, Li XH, Bao CF. Glutathione S-transferase p1 and DNA polymorphisms with the response to chemotherapy and the prognosis of bone Tumor. Asian Pacific Journal of Cancer Prevention. 2012;13(11):5883-5886. doi:10.7314/APJCP.2012.13.11.5883.
179. Guo W, Healey JH, Meyers PA, et al. Mechanisms of Methotrexate Resistance in Osteosarcoma. Clinical Cancer Research. 1999; 5:621-627.
180. Torreggiani E, Roncuzzi L, Perut F, Zini N, Baldini N. Multimodal transfer of MDR by exosomes in human osteosarcoma. International Journal of Oncology. 2016;49(19):189-196. doi:10.3892/ijo.2016.3509.
181. Li J, Yang Z, Li Y, Xia J, Li D, Li H. Cell apoptosis, autophagy and necroptosis in osteosarcoma treatment. Oncotarget. 2016;7(28).
182. He H, Ni J, Huang JUN. Molecular mechanisms of chemoresistance in osteosarcoma (Review). Oncology Letters. 2014;7:1352-1362. doi:10.3892/ol.2014.1935.
183. Conrad M, Angeli JPF, Vandenabeele P, Stockwell BR. Regulated necrosis: Disease relevance and therapeutic opportunities. Nature Reviews Drug Discovery. 2016;15(5):348-366. doi:10.1038/nrd.2015.6.
184. Matt S, Hofmann TG. The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cellular and Molecular Life Sciences. 2016;73(15):2829-2850. doi:10.1007/s00018-016-2130-4.
185. Liao Y, Yu H, Lv J, et al. Targeting autophagy is a promising therapeutic strategy to overcome chemoresistance and reduce metastasis in osteosarcoma (Review). International Journal of Oncology. 2019;55:1213-1222. doi:10.3892/ijo.2019.4902.
186. Kim M, Jung JY, Choi S, et al. GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy. Autophagy. 2017;13(1):149-168. doi:10.1080/15548627.2016.1239676.
187. Wu W, Li W, Zhou Y, Zhang C. Inhibition of Beclin1 Affects the Chemotherapeutic Sensitivity of Osteosarcoma. International Journal of Clinical and Experimental Pathology. 2014; 7(10):7114-7122.
188. Zhao D, Yuan H, Yi F, Meng C, Zhu Q. Autophagy prevents doxorubicin-induced apoptosis in osteosarcoma. Molecular Medicine Reports. 2014;9(5):1975-1981. doi:10.3892/mmr.2014.2055.
189. Zhao S, Lu N, Chai Y, Yu X. Rapamycin inhibits tumor growth of human osteosarcomas. Journal of the Balkan Union of Oncology. 2015;20(2): 588-594.
190. Ding L, Congwei L, Bei Q, et al. MTOR: An attractive therapeutic target for osteosarcoma?. Oncotarget. 2016; 7(31): 50805-50813.
191. Coventon J. A review of the mechanism of action and clinical applications of sorafenib in advanced osteosarcoma. Journal of Bone Oncology. 2017;8:4-7. doi:10.1016/j.jbo.2017.07.001.
192. Wagner LM, Fouladi M, Ahmed A, et al. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: A report from the children’s oncology group. Pediatric Blood and Cancer. 2015;62(3):440-444. doi:10.1002/pbc.25334.
193. Chen Y, Cao J, Zhang N, et al. Advances in differentiation therapy for osteosarcoma. Drug Discovery Today. 2019; 00(00). doi:10.1016/j.drudis.2019.08.010.
194. Heymann MF, Schiavone K, Heymann D. Bone sarcomas in the immunotherapy era. British Journal of Pharmacology. 2020: 1-18. doi:10.1111/bph.14999.
195. Heymann MF, Lézot F, Heymann D. The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma. Cellular Immunology. 2019;343. doi:10.1016/j.cellimm.2017.10.011.
196. Majzner RG, Theruvath JL, Nellan A, et al. CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clinical Cancer Research. 2019; 25(8):2560-2574. doi:10.1158/1078-0432.CCR-18-0432.
197. Pinto NR, Applebaum MA, Volchenboum SL, et al. Advances in risk classification and treatment strategies for neuroblastoma. Journal of Clinical Oncology. 2015;33(27):3008-3017.doi:10.1200/JCO.2014.59.4648.