An overview of resistance to chemotherapy in osteosarcoma and future perspectives

Abstract

Osteosarcoma (OS) is the most common type of bone sarcoma. Despite the availability of multimodal treatment with surgery and chemotherapy, the clinical results remain unsatisfactory. The main reason for the poor outcomes in patients with OS is the development of resistance to methotrexate, cisplatin, doxorubicin, and ifosfamide. Molecular and cellular mechanisms associated with resistance to chemotherapy include DNA repair and cell-cycle alterations, enhanced drug efflux, increased detoxification, resistance to apoptosis, autophagy, tumor extracellular matrix, and angiogenesis. This versatility of cells to generate chemoresistance has motivated the use of anti-angiogenic therapy based on tyrosine kinase inhibitors. This approach has shown that other therapies, along with standard chemotherapy, can improve responses to therapy in patients with OS. Moreover, microRNAs may act as predictors of drug resistance in OS. This review provides insight into the molecular and cellular mechanisms involved in the development of resistance during the treatment of OS and discusses promising novel therapies (e.g., afatinib and palbociclib) for overcoming resistance to chemotherapy in OS.

Keywords

Osteosarcoma / therapy resistance / tyrosine kinase inhibitor / tumoral extracellular microenvironment / cell cycle

References

[1] Klein MJ.Osteosarcoma: anatomic and histologic variants.Am J Clin Pathol2006;125:555-81

[2] Ottaviani G.The etiology of osteosarcoma. In: Jaffe N, Bruland OS, Bielack S, editors. Pediatric and adolescent osteosarcoma. Boston: Springer US; 2010. pp. 15-32.

[3] Ferrari S,Mercuri M.Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute.Ann Oncol2001;12:1145-50

[4] Bielack SS,Delling G.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.J Clin Oncol2002;20:776-90

[5] Weiss A,Hoffer FA.Telangiectatic osteosarcoma: the St. Jude Children’s Research Hospital’s experience.Cancer2007;109:1627-37

[6] Bacci G,Cesari M,Bertoni F.Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients.Cancer2006;106:2701-6

[7] Meazza C.Metastatic osteosarcoma: a challenging multidisciplinary treatment.Expert Rev Anticancer Ther2016;16:543-56

[8] Casali PG,Abecassis N.ESMO Guidelines Committee, PaedCan and ERN EURACAN. Bone sarcomas: ESMO-PaedCan-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up.Ann Oncol2018;29:iv79-95

[9] Biermann JS,Reed DR.NCCN guidelines insights: bone cancer, version 2.2017.J Natl Compr Canc Netw2017;15:155-67

[10] Rosen G,Huvos AG,Marcove RC.Chemotherapy,en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma.Cancer1976;37:1-11

[11] Gill J.Advancing therapy for osteosarcoma.Nat Rev Clin Oncol2021;18:609-24

[12] Thebault E,Tran D.Successive osteosarcoma relapses after the first line O2006/Sarcome-09 trial: what can we learn for further phase-II trials?.Cancers (Basel)2021;13:1683 PMCID:PMC8038261

[13] Smeland S,Whelan J.Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.Eur J Cancer2019;109:36-50 PMCID:PMC6506906

[14] Bielack SS,Whelan JS.EURAMOS-1 investigatorsMethotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon Alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial.J Clin Oncol2015;33:2279-87

[15] Tsagozis P,Georgoudaki A.Sarcoma tumor microenvironment. In: Birbrair A, editor. Tumor microenvironments in organs. Cham: Springer International Publishing; 2020. pp. 319-48.

[16] Yan GN,Guo QN.Advances in osteosarcoma stem cell research and opportunities for novel therapeutic targets.Cancer Lett2016;370:268-74

[17] Botter SM,Fuchs B.Recent advances in osteosarcoma.Curr Opin Pharmacol2014;16:15-23

[18] Marchandet L,Charrier C,Ory B.Mechanisms of resistance to conventional therapies for osteosarcoma.Cancers (Basel)2021;13:683 PMCID:PMC7915189

[19] Flintoff WF,Gorlick R,Williams FM.Functional analysis of altered reduced folate carrier sequence changes identified in osteosarcomas.Biochim Biophys Acta2004;1690:110-7

[20] Ifergan I,Issakov J.Reduced folate carrier protein expression in osteosarcoma: implications for the prediction of tumor chemosensitivity.Cancer2003;98:1958-66

[21] Trippett T,Gorlick R,Wollner N.High dose trimetrexate with leucovorin protection in recurrent childhood malignancies: a phase II trial.Proc Am Soc Clin Oncol1999;18:231a

[22] Delepine N,Bacci G,Desbois J.Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma. Analysis of the literature.Cancer1996;78:2127-35

[23] Gorlick R,Andrulis I.Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary.Clin Cancer Res2003;9:5442-53

[24] Methotrexate, Trimetrexate Glucuronate, and Leucovorin in Treating Patients With Refractory or Recurrent Osteosarcoma. Available from: https://www.clinicaltrials.gov/ct2/show/NCT00119301 [Last accessed on 23 Jun 2022].

[25] Prudowsky ZD.Recent insights into therapy resistance in osteosarcoma.Cancers (Basel)2020;13:83 PMCID:PMC7795058

[26] Gomes CM,Romeo S.Multidrug resistance mediated by ABC transporters in osteosarcoma cell lines: mRNA analysis and functional radiotracer studies.Nucl Med Biol2006;33:831-40

[27] D’Incalci M,Galmarini CM.Trabectedin, a drug acting on both cancer cells and the tumour microenvironment.Br J Cancer2014;111:646-50 PMCID:PMC4134488

[28] Chou AJ.Chemotherapy resistance in osteosarcoma: current challenges and future directions.Expert Rev Anticancer Ther2006;6:1075-85

[29] Lee YH,Yang LC.DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells.Oncol Lett2017;14:171-9 PMCID:PMC5494897

[30] Nitiss JL.Targeting DNA topoisomerase II in cancer chemotherapy.Nat Rev Cancer2009;9:338-50 PMCID:PMC2748742

[31] Rajkumar T.Multiple pathways are involved in drug resistance to doxorubicin in an osteosarcoma cell line.Anticancer Drugs2008;19:257-65

[32] Nguyen A,Guerin E.Role of topoisomerases in pediatric high grade osteosarcomas: TOP2A gene is one of the unique molecular biomarkers of chemoresponse.Cancers (Basel)2013;5:662-75 PMCID:PMC3730327

[33] Kovac M,Ribi S.Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency.Nat Commun2015;6:8940

[34] Siddik ZH.Cisplatin: mode of cytotoxic action and molecular basis of resistance.Oncogene2003;22:7265-79

[35] Fanelli M,Patrizio MP.Cisplatin resistance in osteosarcoma: in vitro validation of candidate DNA repair-related therapeutic targets and drugs for tailored treatments.Front Oncol2020;10:331 PMCID:PMC7077033

[36] Zhang H,Hong H,Sun Z.Genetic polymorphisms in ERCC1 and ERCC2 genes are associated with response to chemotherapy in osteosarcoma patients among Chinese population: a meta-analysis.World J Surg Oncol2017;15:75 PMCID:PMC5383995

[37] Hattinger CM,Fantoni L,Riganti C.Drug resistance in osteosarcoma: emerging biomarkers, therapeutic targets and treatment strategies.Cancers (Basel)2021;13:2878 PMCID:PMC8228414

[38] Park HJ,Kim KM.The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma.J Exp Clin Cancer Res2018;37:107 PMCID:PMC5963190

[39] Olaparib in treating patients with relapsed or refractory advanced solid tumors, non-hodgkin lymphoma, or histiocytic disorders with defects in DNA damage repair genes (A pediatric MATCH treatment trial). Available from: https://clinicaltrials.gov/ct2/show/NCT03233204 [Last accessed on 23 Jun 2022].

[40] Grignani G,Pignochino Y.Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group.Lancet Oncol2018;19:1360-71

[41] Olaparib With Ceralasertib in Recurrent Osteosarcoma. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04417062 [Last accessed on 23 Jun 2022].

[42] Zoumpoulidou G,Mancusi C.Therapeutic vulnerability to PARP1,2 inhibition in RB1-mutant osteosarcoma.Nat Commun2021;12:7064 PMCID:PMC8642453

[43] National cancer institute: NCI-MATCH trial (molecular analysis for therapy choice). Available from: https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match#types-of-cancers-studied [Last accessed on 23 Jun 2022]

[44] Fellenberg J,Ewerbeck V.Identification of drug-regulated genes in osteosarcoma cells.Int J Cancer2003;105:636-43

[45] Sato N,Maehara N.Enhancement of drug-induced apoptosis by antisense oligodeoxynucleotides targeted against Mdm2 and p21WAF1/CIP1.Anticancer Res2000;20:837-42

[46] Suehara Y,Bowman A.Clinical genomic sequencing of pediatric and adult osteosarcoma reveals distinct molecular subsets with potentially targetable alterations.Clin Cancer Res2019;25:6346-56 PMCID:PMC6825534

[47] Iwata S,Yonemoto T.CDK4 overexpression is a predictive biomarker for resistance to conventional chemotherapy in patients with osteosarcoma.Oncol Rep2021;46:135

[48] Zhou Y,Yu Z,Kan Q.Expression and therapeutic implications of cyclin-dependent kinase 4 (CDK4) in osteosarcoma.Biochim Biophys Acta Mol Basis Dis2018;1864:1573-82

[49] Higuchi T,Miyake K.Sorafenib and palbociclib combination regresses a cisplatinum-resistant osteosarcoma in a PDOX mouse model.Anticancer Res2019;39:4079-84

[50] Meric-bernstam F,Dubois S.A phase IIa clinical trial combining ALRN-6924 and palbociclib for the treatment of patients with tumours harboring wild-type p53 and MDM2 amplification or MDM2/CDK4 co-amplification.Annals of Oncology2019;30:v179-80

[51] Palbociclib in treating patients with relapsed or refractory Rb positive advanced solid tumors, non-hodgkin lymphoma, or histiocytic disorders with activating alterations in cell cycle genes (a pediatric MATCH treatment trial). Available from: https://clinicaltrials.gov/ct2/show/NCT03526250 [Last accessed on 23 Jun 2022]

[52] Wang D.Abemaciclib is synergistic with doxorubicin in osteosarcoma pre-clinical models via inhibition of CDK4/6-Cyclin D-Rb pathway.Cancer Chemother Pharmacol2022;89:31-40

[53] ClinicalTrials.gov. Abemaciclib for bone and soft tissue sarcoma with cyclin-dependent kinase (CDK) pathway alteration - full text view - clinicaltrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT04040205 [Last accessed on 23 Jun 2022]

[54] Liu AS,Yang YL.A Chemotherapy-driven increase in mcl-1 mediates the effect of miR-375 on cisplatin resistance in osteosarcoma cells.Onco Targets Ther2019;12:11667-77 PMCID:PMC6942534

[55] Xu W,Zhu X,Xu Y.miR-29 family inhibits resistance to methotrexate and promotes cell apoptosis by targeting COL3A1 and MCL1 in osteosarcoma.Med Sci Monit2018;24:8812-21 PMCID:PMC6292150

[56] De Summa S,Pilato B.A promising role of TGF-β pathway in response to regorafenib in metastatic colorectal cancer: a case report.Medicina (Kaunas)2021;57:1241 PMCID:PMC8619854

[57] Watson EC,Adams RH,Coultas L.Endothelial cell survival during angiogenesis requires the pro-survival protein MCL1.Cell Death Differ2016;23:1371-9 PMCID:PMC4947668

[58] Song X,Tong J.Mcl-1 inhibition overcomes intrinsic and acquired regorafenib resistance in colorectal cancer.Theranostics2020;10:8098-110 PMCID:PMC7381732

[59] A study of PRT1419 in patients with advanced solid tumors. Available from:https://clinicaltrials.gov/ct2/show/NCT04837677 [Last accessed on 23 Jun 2022]

[60] Gill J,Roth M.HER2-targeted therapy in osteosarcoma. In: Kleinerman ES, Gorlick R, editors. Current advances in osteosarcoma. Cham: Springer International Publishing; 2020.pp.55-66.

[61] Ebb D,Grier H.Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the children’s oncology group.J Clin Oncol2012;30:2545-51 PMCID:PMC3397787

[62] Galluzzi L,Vitale I.Molecular mechanisms of cisplatin resistance.Oncogene2012;31:1869-83

[63] Modi S,Yamashita T.DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer.N Engl J Med2020;382:610-21 PMCID:PMC7458671

[64] Wen YH,Garcia R.Epidermal growth factor receptor in osteosarcoma: expression and mutational analysis.Hum Pathol2007;38:1184-91

[65] Lee JA,Kim DH.Epidermal growth factor receptor: is it a feasible target for the treatment of osteosarcoma?.Cancer Res Treat2012;44:202-9 PMCID:PMC3467424

[66] Sevelda F,Kubista B.EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance.J Exp Clin Cancer Res2015;34:134 PMCID:PMC4630894

[67] Gvozdenovic A,Born W,Fuchs B.A bispecific antibody targeting IGF-IR and EGFR has tumor and metastasis suppressive activity in an orthotopic xenograft osteosarcoma mouse model.Am J Cancer Res2017;7:1435-1449 PMCID:PMC5523026

[68] Hughes DP,Giordano TJ,Baker LH.Essential erbB family phosphorylation in osteosarcoma as a target for CI-1033 inhibition.Pediatr Blood Cancer2006;46:614-23

[69] Liu J,Zhou L.ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib.Oncotarget2015;6:21341-52 PMCID:PMC4673269

[70] Wang H,Sun M.HER4 promotes cell survival and chemoresistance in osteosarcoma via interaction with NDRG1.Biochim Biophys Acta Mol Basis Dis2018;1864:1839-49

[71] Solca F,Zoephel A.Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker.J Pharmacol Exp Ther2012;343:342-50

[72] Cruz-Ramos M,Medina-Luna D.Afatinib is active in osteosarcoma in osteosarcoma cell lines.J Cancer Res Clin Oncol2020;146:1693-700

[73] Collier C,Gandhi D,Greenfield E. Opportunities for drug repurposing in osteosarcoma: a screen of FDA-approved oncology drugs in a micrometastatic model of disease .p. No.0384. Available from: http://www.ors.org/Transactions/62/0384.pdf [Last accessed on 23 Jun 2022]

[74] Andrade RC,Amazonas MK.New drug candidates for osteosarcoma: drug repurposing based on gene expression signature.Comput Biol Med2021;134:104470

[75] Trial of afatinib in pediatric tumours. Available from: https://clinicaltrials.gov/ct2/show/NCT02372006 [Last accessed on 23 Jun 2021]

[76] Martini M,Braccini L,Hirsch E.PI3K/AKT signaling pathway and cancer: an updated review.Ann Med2014;46:372-83

[77] Wei X,Jeddo SF,Li X.MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells.Am J Transl Res2020;12:1807-1823 PMCID:PMC7270034

[78] Xu L,Wei X.The inhibition of MARK2 suppresses cisplatin resistance of osteosarcoma stem cells by regulating DNA damage and repair.J Bone Oncol2020;23:100290 PMCID:PMC7184251

[79] Castel P,Zumsteg ZS.Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment.Mol Cell Oncol2014;1:e963447 PMCID:PMC4904898

[80] Chandhanayingyong C,Staples JR,Lee FY.MAPK/ERK signaling in osteosarcomas, ewing sarcomas and chondrosarcomas: therapeutic implications and future directions.Sarcoma2012;2012:404810 PMCID:PMC3345255

[81] Grignani G,Ferraresi V.Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.Lancet Oncol2015;16:98-107

[82] Heymann MF,Heymann D.The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma.Cell Immunol2019;343:103711

[83] Chalopin A,Brown HK.Isolation of circulating tumor cells in a preclinical model of osteosarcoma: effect of chemotherapy.J Bone Oncol2018;12:83-90 PMCID:PMC6092555

[84] Yang C,Zhao F.Bone microenvironment and osteosarcoma metastasis.Int J Mol Sci2020;21:6985 PMCID:PMC7582690

[85] Crenn V,Amiaud J.Bone microenvironment has an influence on the histological response of osteosarcoma to chemotherapy: retrospective analysis and preclinical modeling.Am J Cancer Res2017;7:2333-2349 PMCID:PMC5714759

[86] Combined chemotherapy with or without zoledronic acid for patients with osteosarcoma - full text view - clinicaltrials.gov. Available from: https://clinicaltrials.gov/ct2/show/NCT00470223 [Last accessed on 23 Jun 2022]

[87] Piperno-neumann S,Rédini F.Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial.Lancet Oncol2016;17:1070-80

[88] Toulmonde M,Blay J-Y,Penel N. PEMBROSARC combination of MK3475 and metronomic cyclophosphamide (mCP) in patients (pts) with advanced sarcomas a multicentre phase II trial with 3 new combination strategies. Available from: https://ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.TPS11587 [Last accessed on 23 Jun 2022]

[89] Zhu MMT,Nielsen TO.Sarcomas: immune biomarker expression and checkpoint inhibitor trials.Cancer Treat Rev2020;91:102115

[90] Toulmonde M,Adam J.Use of PD-1 targeting, macrophage infiltration, and IDO pathway activation in sarcomas: a phase 2 clinical trial.JAMA Oncol2018;4:93-7 PMCID:PMC5833654

[91] Chen C,Ren T,Xu J.Immunotherapy for osteosarcoma: fundamental mechanism, rationale, and recent breakthroughs.Cancer Lett2021;500:1-10

[92] Isla Larrain MT,Lacunza E.IDO is highly expressed in breast cancer and breast cancer-derived circulating microvesicles and associated to aggressive types of tumors by in silico analysis.Tumour Biol2014;35:6511-9

[93] Wang J,Sun X.Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients.J Nanobiotechnology2020;18:151 PMCID:PMC7579953

[94] Lamora A,Mullard M,Redini F.TGF-β signaling in bone remodeling and osteosarcoma progression.J Clin Med2016;5:96 PMCID:PMC5126793

[95] Kawano M,Iwasaki T,Tsumura H.Anti-TGF-β antibody combined with dendritic cells produce antitumor effects in osteosarcoma.Clin Orthop Relat Res2012;470:2288-94 PMCID:PMC3392369

[96] Liang X,Ren T.Macrophages reduce the sensitivity of osteosarcoma to neoadjuvant chemotherapy drugs by secreting Interleukin-1 beta.Cancer Lett2020;480:4-14

[97] Luo Z-W,Wang Z-X,Xie H.Macrophages in osteosarcoma immune microenvironment: implications for immunotherapy.Front Oncol2020;10:2729 PMCID:PMC7758531

[98] Stockmann C,Weidemann A.Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis.Nature2008;456:814-8 PMCID:PMC3103772

[99] Zheng B,Huang Y.Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3.Biochem Biophys Res Commun2018;495:1695-701

[100] Frantz C,Weaver VM.The extracellular matrix at a glance.J Cell Sci2010;123:4195-200 PMCID:PMC2995612

[101] Cui J,Hornicek FJ,Duan Z.The role of extracelluar matrix in osteosarcoma progression and metastasis.J Exp Clin Cancer Res2020;39:178 PMCID:PMC7650219

[102] Hamano Y.Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth.Biochem Biophys Res Commun2005;333:292-8

[103] Eikesdal HP,Birrane G.Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity.Proc Natl Acad Sci USA2008;105:15040-5 PMCID:PMC2567489

[104] Wei C,Wei XX.Bifidobacteria expressing tumstatin protein for antitumor therapy in tumor-bearing mice.Technol Cancer Res Treat2016;15:498-508

[105] Walia A,Huang YH,Chang JH.Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications.Biochim Biophys Acta2015;1850:2422-38 PMCID:PMC4624607

[106] Sudhakar A,Yang C,Zeisberg M.Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins.Proc Natl Acad Sci USA2003;100:4766-71 PMCID:PMC153630

[107] Xu H,Zhang Q.Synergistic antitumor efficacy by combining adriamycin with recombinant human endostatin in an osteosarcoma model.Oncol Lett2011;2:773-8 PMCID:PMC3408098

[108] Xu M,Bi WZ.Effects of endostar combined multidrug chemotherapy in osteosarcoma.Bone2013;57:111-5

[109] Xu H,Li Y,Hao L.Perioperative rh-endostatin with chemotherapy improves the survival of conventional osteosarcoma patients: a prospective non-randomized controlled study.Cancer Biol Med2019;16:166-72 PMCID:PMC6528451

[110] Li K,Qin S.Current status and study progress of recombinant human endostatin in cancer treatment.Oncol Ther2018;6:21-43 PMCID:PMC7360016

[111] Xing P,Yan Z.Recombined humanized endostatin (Endostar) combined with chemotherapy for advanced bone and soft tissue sarcomas in stage IV.Oncotarget2017;8:36716-27 PMCID:PMC5482691

[112] Xie L,Guo W.Anti-angiogenesis target therapy for advanced osteosarcoma (Review).Oncol Rep2017;38:625-36 PMCID:PMC5562076

[113] Li YS,Tian J,Luo W.Angiogenesis process in osteosarcoma: an updated perspective of pathophysiology and therapeutics.Am J Med Sci2019;357:280-8

[114] Liao YY,Chou PY.CCL3 promotes angiogenesis by dysregulation of miR-374b/ VEGF-A axis in human osteosarcoma cells.Oncotarget2016;7:4310-25 PMCID:PMC4826207

[115] Wang SW,Sun HL.CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment.Carcinogenesis2015;36:104-14

[116] Thanapprapasr K,Thanapprapasr D,Ahmad A.pFAK-Y397 overexpression as both a prognostic and a predictive biomarker for patients with metastatic osteosarcoma.PLoS ONE2017;12:e0182989

[117] Ma J,Yang W,Xi Y.Role of relaxin-2 in human primary osteosarcoma.Cancer Cell Int2013;13:59 PMCID:PMC3698148

[118] Kampmann E,Gibis S.VEGFR2 predicts decreased patients survival in soft tissue sarcomas.Pathol Res Pract2015;211:726-30

[119] Chen D,Zhu KW.A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma.Tumour Biol2013;34:1895-9

[120] Xie L,Sun X.Apatinib for advanced osteosarcoma after failure of standard multimodal therapy: an open label phase II clinical trial.Oncologist2019;24:e542-50 PMCID:PMC6656465

[121] Italiano A,Mathoulin-Pelissier S.Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial - the lancet oncology.Lancet Oncol2020;21:446-455 PMCID:PMC8763616

[122] Gaspar N,Sirvent FJB.Single-agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of LEN + etoposide (ETP) + ifosfamide (IFM) in patients (pts) aged 2 to ≤ 25 years with relapsed/refractory osteosarcoma (OS).JCO2018;36:11527

[123] Davis LE,Ryan CW.Randomized double-blind phase II study of regorafenib in patients with metastatic osteosarcoma.J Clin Oncol2019;37:1424-31 PMCID:PMC7799443

[124] Duffaud F,Boudou-rouquette P.Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study.Lancet Oncol2019;20:120-33

[125] Grignani G,Dileo P.A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study.Ann Oncol2012;23:508-16

[126] Aggerholm-Pedersen N,Rose H.Pazopanib in the treatment of bone sarcomas: clinical experience.Transl Oncol2020;13:295-9 PMCID:PMC6931211

[127] Just MA,Wagner LM.Receptor tyrosine kinase inhibitors for the treatment of osteosarcoma and Ewing sarcoma.Pediatr Blood Cancer2021;68:e29084 PMCID:PMC8238849

[128] Giancotti FG.Integrin signaling.Science1999;285:1028-32

[129] Chen Q,Shan L,Hua Y.The importance of Src signaling in sarcoma.Oncol Lett2015;10:17-22 PMCID:PMC4486874

[130] van Oosterwijk JG,Briaire-de Bruijn IH.Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells.Br J Cancer2013;109:1214-22 PMCID:PMC3778302

[131] Baird K,Steinberg SM.Results of a randomized, double-blinded, placebo-controlled, phase 2.5 study of saracatinib (AZD0530), in patients with recurrent osteosarcoma localized to the lung.Sarcoma2020;2020:7935475

[132] Beck O,Russo A.Safety and activity of the combination of ceritinib and dasatinib in osteosarcoma.Cancers (Basel)2020;12:793 PMCID:PMC7225940

[133] Sulzmaier FJ,Schlaepfer DD.FAK in cancer: mechanistic findings and clinical applications.Nat Rev Cancer2014;14:598-610 PMCID:PMC4365862

[134] Yang M,Liao E-Y,Wang B-B.The role of integrin-β/FAK in cyclic mechanical stimulation in MG-63 cells.Int J Clin Exp Pathol2014;7:7451-9 PMCID:PMC4270589

[135] Gu HJ.Focal adhesion kinase promotes progression and predicts poor clinical outcomes in patients with osteosarcoma.Oncol Lett2018;15:6225-32 PMCID:PMC5962868

[136] Hu C,Wen J.Antitumor effect of focal adhesion kinase inhibitor PF562271 against human osteosarcoma in vitro and in vivo.Cancer Sci2017;108:1347-56 PMCID:PMC5497929

[137] Diaz Osterman CJ,Kleinschmidt EG.FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy.Elife2019;8:e47327 PMCID:PMC6721800

[138] Stereotactic body radiotherapy and focal adhesion kinase inhibitor in advanced pancreas adenocarcinoma. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04331041 [Last accessed on 23 Jun 2022]

[139] Vismodegib, FAK inhibitor GSK2256098, capivasertib, and abemaciclib in treating patients with progressive meningiomas. Available from: https://clinicaltrials.gov/ct2/show/NCT02523014 [Last accessed on 23 Jun 2022].

[140] Phase II study of VS-6063 in patients with KRAS mutant non-small cell lung cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT01951690 [Last accessed on 23 Jun 2022].

[141] Window of opportunity study of VS-6063 (defactinib) in surgical resectable malignant pleural mesothelioma participants. Available from: https://clinicaltrials.gov/ct2/show/NCT02004028 [Last accessed on 23 Jun 2022]

[142] Study of pembrolizumab with or without defactinib following chemotherapy as a neoadjuvant and adjuvant treatment for resectable pancreatic ductal adenocarcinoma. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03727880 [Last accessed on 23 Jun 2022]

[143] A study of VS-6766 v. VS-6766 + defactinib in recurrent low-grade serous ovarian cancer with and without a KRAS mutation. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04625270 [Last accessed on 23 Jun 2022]

[144] A study of VS-6766 v. VS-6766 + defactinib in recurrent G12V or other KRAS-mutant non-small cell lung cancer. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04620330 [Last accessed on 23 Jun 2022]

[145] Study of FAK (defactinib) and PD-1 (pembrolizumab) inhibition in advanced solid malignancies (FAK-PD1). Available from: https://clinicaltrials.gov/ct2/show/NCT02758587 [Last accessed on 23 Jun 2022].

[146] Vaupel P.Accomplices of the hypoxic tumor microenvironment compromising antitumor immunity: adenosine, lactate, acidosis, vascular endothelial growth factor, potassium ions, and phosphatidylserine.Front Immunol2017;8:1887 PMCID:PMC5742577

[147] Vaupel P.Hypoxia-/HIF-1α-driven factors of the tumor microenvironment impeding antitumor immune responses and promoting malignant progression. In: Thews O, Lamanna JC, Harrison DK, editors. Oxygen Transport to Tissue XL. Cham: Springer International Publishing; 2018. pp. 171-5.

[148] Pötzl J,Bankel L.Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-γ and induces NK cell-dependent lymphoma control without other immunotherapies.Int J Cancer2017;140:2125-33

[149] Calcinotto A,Grioni M.Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes.Cancer Res2012;72:2746-56

[150] Lilienthal I.Targeting molecular mechanisms underlying treatment efficacy and resistance in osteosarcoma: a review of current and future strategies.Int J Mol Sci2020;21:6885 PMCID:PMC7555161

[151] Avnet S,Cortini M.Altered pH gradient at the plasma membrane of osteosarcoma cells is a key mechanism of drug resistance.Oncotarget2016;7:63408-23 PMCID:PMC5325373

[152] Vigano S,Irving M.Targeting adenosine in cancer immunotherapy to enhance T-cell function.Front Immunol2019;10:925 PMCID:PMC6562565

[153] Vultaggio-Poma V,Di Virgilio F.Extracellular ATP: A feasible target for cancer therapy.Cells2020;9:2496 PMCID:PMC7698494

[154] Kordaß T,Eichmüller SB.Controlling the immune suppressor: transcription factors and micrornas regulating CD73/NT5E.Front Immunol2018;9:813 PMCID:PMC5915482

[155] Loi S,Haibe-Kains B.CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer.Proc Natl Acad Sci USA2013;110:11091-6 PMCID:PMC3704029

[156] Jones KB,Del Mare S.miRNA signatures associate with pathogenesis and progression of osteosarcoma.Cancer Res2012;72:1865-77 PMCID:PMC3328547

[157] Petruk N,Åkerfelt M.CD73 facilitates EMT progression and promotes lung metastases in triple-negative breast cancer.Sci Rep2021;11:6035 PMCID:PMC7966763

[158] Borea PA,Merighi S,Varani K.Pharmacology of adenosine receptors: the state of the art.Physiol Rev2018;98:1591-625

[159] Fishman P,Synowitz M.Adenosine receptors and cancer. In: Wilson CN, Mustafa SJ, editors. Adenosine Receptors in Health and Disease. Berlin: Springer Berlin Heidelberg; 2009. pp. 399-441.

[160] Carroll SH,Kulkarni N,Gerstenfeld LC.A2B adenosine receptor promotes mesenchymal stem cell differentiation to osteoblasts and bone formation in vivo.J Biol Chem2012;287:15718-27 PMCID:PMC3346096

[161] Zhang YW,Ikeda M,Murota S.Connexin43 suppresses proliferation of osteosarcoma U2OS cells through post-transcriptional regulation of p27.Oncogene2001;20:4138-49

[162] Zhang D,Yang Z.Silencing Ubc9 expression suppresses osteosarcoma tumorigenesis and enhances chemosensitivity to HSV-TK/GCV by regulating connexin 43 SUMOylation.Int J Oncol2018;53:1323-31

[163] Jiang J,An Z.New antibody therapeutics targeting connexin hemichannels in treatment of osteosarcoma and breast cancer bone metastasis.Eur J Cancer2020;138:S54

[164] Munerati M,Ferrari D,Nastruzzi C.Macrophages loaded with doxorubicin by ATP-mediated permeabilization: potential carriers for antitumor therapy.Biochim Biophys Acta Mol Cell Res1994;1224:269-76

[165] Giuliani AL,Ricco T.Trophic activity of human P2X7 receptor isoforms A and B in osteosarcoma.PLoS One2014;9:e107224 PMCID:PMC4165768

[166] Qi B,Wang C.Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate.J Exp Clin Cancer Res2016;35:161 PMCID:PMC5048460

[167] Wang Y.Quantum dots, lighting up the research and development of nanomedicine.Nanomedicine2011;7:385-402

[168] Desai SA,Khulbe P.Drug delivery nanocarriers and recent advances ventured to improve therapeutic efficacy against osteosarcoma: an overview.J Egypt Natl Canc Inst2021;33:4

[169] Villegas MR,Noureddine A.Multifunctional protocells for enhanced penetration in 3D extracellular tumoral matrices.Chem Mater2018;30:112-20

[170] Díaz-Saldívar P.ATP-loaded biomimetic nanoparticles as controlled release system for extracellular drugs in cancer applications.Int J Nanomedicine2019;14:2433-47 PMCID:PMC6454990

[171] Feiz MS.Targeted delivery of adenosine 5’-triphosphate using chitosan-coated mesoporous hydroxyapatite: a theranostic pH-sensitive nanoplatform with enhanced anti-cancer effect.Int J Biol Macromol2019;129:1090-102

[172] Maire G,Yoshimoto M,Zielenska M.Analysis of miRNA-gene expression-genomic profiles reveals complex mechanisms of microRNA deregulation in osteosarcoma.Cancer Genet2011;204:138-46

[173] Chen SM,Hu LY.The effect of microRNA-124 overexpression on anti-tumor drug sensitivity.PLoS One2015;10:e0128472 PMCID:PMC4482746

[174] FdAd, Hande MP, Tong W-M, Lansdorp PM, Wang Z-Q, Jackson SP. Functions of poly(ADP-ribose) polymerase in controlling telomere length and chromosomal stability.Nat Genet1999;23:76-80

[175] Kobayashi E,Duan Z. MicroRNA involvement in osteosarcoma. Sarcoma. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329862/ [Last accessed on 23 Jun 2022]

[176] He C,Xu X.Functional elucidation of MiR-34 in osteosarcoma cells and primary tumor samples.Biochem Biophys Res Commun2009;388:35-40

[177] Creighton CJ,Yu Z.Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers.Cancer Res2010;70:1906-15 PMCID:PMC2831102

[178] Dai N,Cun Y.miR-513a-5p regulates radiosensitivity of osteosarcoma by targeting human apurinic/apyrimidinic endonuclease.Oncotarget2018;9:25414-26 PMCID:PMC5986632

[179] Liang W,Li M,Zhong Z.MicroRNA-765 sensitizes osteosarcoma cells to cisplatin via downregulating APE1 expression.Onco Targets Ther2019;12:7203-14 PMCID:PMC6731985

[180] Zhu Z,Wang J,Zhou L.MiR-138 acts as a tumor suppressor by targeting EZH2 and enhances cisplatin-induced apoptosis in osteosarcoma cells.PLoS One2016;11:e0150026 PMCID:PMC4809565

[181] Wang GC,Tong DK.MiR-367 negatively regulates apoptosis induced by adriamycin in osteosarcoma cells by targeting KLF4.J Bone Oncol2016;5:51-6 PMCID:PMC4908187

[182] Wei R,Deng Z,Cai L.miR-140-5p attenuates chemotherapeutic drug-induced cell death by regulating autophagy through inositol 1,4,5-trisphosphate kinase 2 (IP3k2) in human osteosarcoma cells.Biosci Rep2016;36:e00392 PMCID:PMC5064456

[183] Lin BC,Yu CQ.MicroRNA-184 modulates doxorubicin resistance in osteosarcoma cells by targeting BCL2L1.Med Sci Monit2016;22:1761-5 PMCID:PMC4917317

[184] Duan Z,Shen J.miR-15b modulates multidrug resistance in human osteosarcoma in vitro and in vivo.Mol Oncol2017;11:151-66 PMCID:PMC5300234

[185] Chang Z,Li K,Hu Z.Blocked autophagy by miR-101 enhances osteosarcoma cell chemosensitivity in vitro.ScientificWorldJournal2014;2014:794756 PMCID:PMC4072053

[186] Guo S,Liu W.miR-22 inhibits osteosarcoma cell proliferation and migration by targeting HMGB1 and inhibiting HMGB1-mediated autophagy.Tumour Biol2014;35:7025-34

[187] Li X,Chen Y,Yang X.miR-22 targets the 3’ UTR of HMGB1 and inhibits the HMGB1-associated autophagy in osteosarcoma cells during chemotherapy.Tumour Biol2014;35:6021-8

[188] Xu R,Chen H.MicroRNA-30a downregulation contributes to chemoresistance of osteosarcoma cells through activating Beclin-1-mediated autophagy.Oncol Rep2016;35:1757-63

[189] Li Y,Hu Y.MicroRNA-199a-5p inhibits cisplatin-induced drug resistance via inhibition of autophagy in osteosarcoma cells.Oncol Lett2016;12:4203-8 PMCID:PMC5104258

[190] Chen L,Jiang H.miR-155 mediates drug resistance in osteosarcoma cells via inducing autophagy.Exp Ther Med2014;8:527-32 PMCID:PMC4079430

[191] Zhou J,Chen Y.microRNA-143 is associated with the survival of ALDH1+CD133+ osteosarcoma cells and the chemoresistance of osteosarcoma.Exp Biol Med (Maywood)2015;240:867-75 PMCID:PMC4935406

[192] Di Fiore R,Pentimalli F.Let-7d miRNA shows both antioncogenic and oncogenic functions in osteosarcoma-derived 3AB-OS cancer stem cells.J Cell Physiol2016;231:1832-41

[193] Di Fiore R,Pentimalli F.MicroRNA-29b-1 impairs in vitro cell proliferation, selfrenewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells.Int J Oncol2014;45:2013-23 PMCID:PMC4432724

[194] Xu M,Xu CX,Wang Y.MiR-34c inhibits osteosarcoma metastasis and chemoresistance.Med Oncol2014;31:972

[195] Zhou Y,Tseng KF.Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression.Acta Pharmacol Sin2016;37:519-29 PMCID:PMC4820798

[196] Shao XJ,Xue J,Ji XQ.The down-regulation of MicroRNA-497 contributes to cell growth and cisplatin resistance through PI3K/Akt pathway in osteosarcoma.Cell Physiol Biochem2015;36:2051-62

[197] Zhao G,Yang T.MicroRNA-221 induces cell survival and cisplatin resistance through PI3K/Akt pathway in human osteosarcoma.PLoS One2013;8:e53906 PMCID:PMC3553141

[198] Xu E,Ma J.miR-146b-5p promotes invasion and metastasis contributing to chemoresistance in osteosarcoma by targeting zinc and ring finger 3.Oncol Rep2016;35:275-83

[199] Zhou C,Lv H,Sun J.Hypoxia-inducible microRNA-488 regulates apoptosis by targeting Bim in osteosarcoma.Cell Oncol (Dordr)2016;39:463-71

[200] Vanas V,Stockhammer V.MicroRNA-21 increases proliferation and cisplatin sensitivity of osteosarcoma-derived cells.PLoS One2016;11:e0161023 PMCID:PMC4981312

[201] Lv C,Tu G.MicroRNA-21 promotes proliferation, invasion and suppresses apoptosis in human osteosarcoma line MG63 through PTEN/Akt pathway.Tumour Biol2016;37:9333-42

[202] Liu J,Wang X.Circles reshaping the RNA world: from waste to treasure.Mol Cancer2017;16:58 PMCID:PMC5345220

[203] Jeck WR,Wang K.Circular RNAs are abundant, conserved, and associated with ALU repeats.RNA2013;19:141-57 PMCID:PMC3543092

[204] Kristensen LS,Stagsted LVW,Hansen TB.The biogenesis, biology and characterization of circular RNAs.Nat Rev Genet2019;20:675-91

[205] Li Z,Bao C.Exon-intron circular RNAs regulate transcription in the nucleus.Nat Struct Mol Biol2015;22:256-64

[206] Barrett SP.Circular RNAs: analysis, expression and potential functions.Development2016;143:1838-47 PMCID:PMC4920157

[207] Salzman J.Circular RNA expression: its potential regulation and function.Trends Genet2016;32:309-16 PMCID:PMC4948998

[208] Chen I,Chuang TJ.Biogenesis, identification, and function of exonic circular RNAs.Wiley Interdiscip Rev RNA2015;6:563-79 PMCID:PMC5042038

[209] Zhang H,Lang X.Expression of circ_001569 is upregulated in osteosarcoma and promotes cell proliferation and cisplatin resistance by activating the Wnt/β-catenin signaling pathway.Oncol Lett2018;16:5856-62 PMCID:PMC6176349

[210] Kun-Peng Z,Chun-Lin Z.Overexpressed circPVT1, a potential new circular RNA biomarker, contributes to doxorubicin and cisplatin resistance of osteosarcoma cells by regulating ABCB1.Int J Biol Sci2018;14:321-30 PMCID:PMC5859477

[211] Chen J,Zheng Q.Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer.Cancer Lett2017;388:208-19

[212] Zhang C,Liu Z.Upregulated expression of LncRNA nicotinamide nucleotide transhydrogenase antisense RNA 1 is correlated with unfavorable clinical outcomes in cancers.BMC Cancer2020;20:1-13 PMCID:PMC7489002

[213] Chen S.Long noncoding RNAs: functions and mechanisms in colon cancer.Mol Cancer2020;19:1-13 PMCID:PMC7697375

[214] Yao RW,Chen LL.Cellular functions of long noncoding RNAs.Nat Cell Biol2019;21:542-51

[215] Guh C-Y,Chu H-P.Functions and properties of nuclear lncRNAs-from systematically mapping the interactomes of lncRNAs.J Biomed Sci2020;27:1-14 PMCID:PMC7079490

[216] Yang G,Yi X.Crosstalk between long non-coding RNAs and Wnt/β-catenin signalling in cancer.J Cell Mol Med2018;22:2062-70 PMCID:PMC5867104

[217] Aillaud M.Emerging roles of long noncoding RNAs in the cytoplasmic milieu.Noncoding RNA2020;6:44 PMCID:PMC7711603

[218] Ong CT.Enhancer function: new insights into the regulation of tissue-specific gene expression.Nat Rev Genet2011;12:283-93 PMCID:PMC3175006

[219] Xie H,Xu C.Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease.Biochem Biophys Res Commun2015;463:569-74

[220] Quagliata L,Piscuoglio S.Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients.Hepatology2014;59:911-23 PMCID:PMC3943759

[221] Zhang H,Wang YX,Liu SL.Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma.Tumour Biol2015;36:8805-9

[222] Li Z,Wang Q.Overexpression of long non-coding RNA HOTTIP increases chemoresistance of osteosarcoma cell by activating the Wnt/β-catenin pathway.Am J Transl Res2016;8:2385-93 PMCID:PMC4891451

[223] Li D,Wang G.Circular RNA circPVT1 contributes to doxorubicin (DXR) resistance of osteosarcoma cells by regulating TRIAP1 via miR-137.Biomed Res Int2021;2021:7463867 PMCID:PMC8088374

[224] Kun-Peng Z,Lei Z,Jian-Ping H.Screening circular RNA related to chemotherapeutic resistance in osteosarcoma by RNA sequencing.Epigenomics2018;10:1327-46

[225] Ma XL,Hu JP,Zhu KP.Doxorubicin-induced novel circRNA_0004674 facilitates osteosarcoma progression and chemoresistance by upregulating MCL1 through miR-142-5p.Cell Death Discov2021;7:309 PMCID:PMC8542045

[226] Bai Y,Bai J.Hsa_circ_0004674 promotes osteosarcoma doxorubicin resistance by regulating the miR-342-3p/FBN1 axis.J Orthop Surg Res2021;16:510 PMCID:PMC8371803

[227] Wei W,Duan W.Circular RNA circ_0081001 knockdown enhances methotrexate sensitivity in osteosarcoma cells by regulating miR-494-3p/TGM2 axis.J Orthop Surg Res2021;16:50 PMCID:PMC7805151

[228] Li X,Zhang X.Circular RNA hsa_circ_0000073 contributes to osteosarcoma cell proliferation, migration, invasion and methotrexate resistance by sponging miR-145-5p and miR-151-3p and upregulating NRAS.Aging (Albany NY)2020;12:14157-73 PMCID:PMC7425447

[229] Yuan J,Zhang Q,Li G.CircPRDM2 contributes to doxorubicin resistance of osteosarcoma by elevating EZH2 via sponging miR-760.Cancer Manag Res2021;13:4433-45 PMCID:PMC8180268

[230] Zhang Z,Luo F.Circular RNA circ-CHI3L1.2 modulates cisplatin resistance of osteosarcoma cells via the miR-340-5p/LPAATβ axis.Hum Cell2021;34:1558-68

[231] Zhu K,Shen G.Long noncoding RNA expression profiles of the doxorubicin-resistant human osteosarcoma cell line MG63/DXR and its parental cell line MG63 as ascertained by microarray analysis.Int J Clin Exp Pathol2015;8:8754-73 PMCID:PMC4583851

[232] Zhang CL,Ma XL.Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2.Cancer Lett2017;396:66-75

[233] Han Z.Long non-coding RNA LUCAT1 modulates methotrexate resistance in osteosarcoma via miR-200c/ABCB1 axis.Biochem Biophys Res Commun2018;495:947-53

[234] Kun-Peng Z,Chun-Lin Z.LncRNA FENDRR sensitizes doxorubicin-resistance of osteosarcoma cells through down-regulating ABCB1 and ABCC1.Oncotarget2017;8:71881-93 PMCID:PMC5641097

[235] Wang Y,Zheng X.Long non-coding RNA LINC00161 sensitises osteosarcoma cells to cisplatin-induced apoptosis by regulating the miR-645-IFIT2 axis.Cancer Lett2016;382:137-46

[236] Maiuri MC,Kimchi A.Self-eating and self-killing: crosstalk between autophagy and apoptosis.Nat Rev Mol Cell Biol2007;8:741-52

[237] Lei W,Ya J,Yujun B.MiR-199a-3p affects the multi-chemoresistance of osteosarcoma through targeting AK4.BMC Cancer2018;18:631 PMCID:PMC5987492

[238] Shen C,Tao L,Yang Z.Chloroquine blocks the autophagic process in cisplatin-resistant osteosarcoma cells by regulating the expression of p62/SQSTM1.Int J Mol Med2013;32:448-56

[239] Liu WD,Hua YQ,Cai ZD.Effect of rapamycin and chloroquine on osteosarcoma.Zhonghua Yi Xue Za Zhi2017;97:1510-4

[240] Cufí S,Oliveras-Ferraros C,Vellon L.Autophagy positively regulates the CD44(+) CD24(-/low) breast cancer stem-like phenotype.Cell Cycle2011;10:3871-85

[241] Zhang D,Sun H.Defective autophagy leads to the suppression of stem-like features of CD271⁺ osteosarcoma cells.J Biomed Sci2016;23:82 PMCID:PMC5116184

[242] Batlle E.Cancer stem cells revisited.Nat Med2017;23:1124-34

[243] Najafi M,Majidpoor J.Cancer stem cell (CSC) resistance drivers.Life Sci2019;234:116781

[244] Honoki K,Kubo A.Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance.Oncol Rep2010;24:501-5

[245] Schiavone K,Heymann M.The heterogeneity of osteosarcoma: the role played by cancer stem cells. In: Birbrair A, editor. Stem cells heterogeneity in cancer. Cham: Springer International Publishing; 2019. pp. 187-200.

[246] Yokoi E,Shimura K.Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer.Invest New Drugs2019;37:818-27

[247] Funes JM,Henderson S.Transformation of human mesenchymal stem cells increases their dependency on oxidative phosphorylation for energy production.Proc Natl Acad Sci USA2007;104:6223-8 PMCID:PMC1851087

[248] Chen KS,Kim J.A novel TP53-KPNA3 translocation defines a de novo treatment-resistant clone in osteosarcoma.Cold Spring Harb Mol Case Stud2016;2:a000992 PMCID:PMC5002927

[249] Rubio R,Garcia-Castro J.Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells.Stem Cells2014;32:1136-48

[250] Mohseny AB,Romeo S.Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2.J Pathol2009;219:294-305

[251] Tu B,Liu S.Mesenchymal stem cells promote osteosarcoma cell survival and drug resistance through activation of STAT3.Oncotarget2016;7:48296-308 PMCID:PMC5217018