{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T09:06:34Z","timestamp":1788944794203,"version":"build-2803163510"},"reference-count":150,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>OS is the most common primary malignant bone tumor, predominantly affecting children, adolescents, and young adults. Despite advances in multimodal treatment, patient outcomes have remained largely unchanged over the past decades, particularly in cases of metastatic or recurrent disease. Increasing evidence highlights the pivotal role of the tumor microenvironment (TME) in OS progression, metastasis, immune evasion, and therapeutic resistance. The OS TME comprises a complex and dynamic network of tumor cells, immune cells, cancer-associated fibroblasts, mesenchymal stromal cells, endothelial cells, extracellular matrix components, and soluble factors that collectively regulate tumor behavior. This review summarizes the current understanding of the OS TME, highlighting the interactions between malignant cells and their surrounding microenvironment and their contribution to tumor growth, angiogenesis, invasion, metastatic dissemination, and treatment response. Moreover, here we discuss the strengths and limitations of the most relevant preclinical models currently used to investigate OS biology and evaluate novel therapeutic strategies. Three-dimensional (3D) culture systems, including spheroids, organoids, and biomimetic scaffold-based models, today are considered the models able to best recapitulate the structural, mechanical, and cellular complexity of the native tumor microenvironment than conventional two-dimensional cultures. In addition, patient-derived xenograft (PDX) models are reviewed for their ability to preserve the histopathological, molecular, and genetic characteristics of the original tumors, making them valuable platforms for translational research, biomarker discovery, and personalized medicine.<\/jats:p>","DOI":"10.3390\/cancers18182909","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:05:43Z","timestamp":1788941143000},"page":"2909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Osteosarcoma Tumor Microenvironment: From Cellular Interactions to Advanced Preclinical Models"],"prefix":"10.3390","volume":"18","author":[{"given":"Giuseppe","family":"Di Feo","sequence":"first","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Di Paola","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriana","family":"Di Domenico","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2530-3267","authenticated-orcid":false,"given":"Lucia","family":"Argenziano","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvira","family":"Pota","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9396-2906","authenticated-orcid":false,"given":"Daniela","family":"Di Pinto","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Di Martino","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Maddalena","family":"Marrapodi","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Woman, Child and General and Specialist Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Argenziano, M., Tortora, C., Pota, E., Di Paola, A., Di Martino, M., Di Leva, C., Di Pinto, D., and Rossi, F. (2021). Osteosarcoma in Children: Not Only Chemotherapy. Pharmaceuticals, 14.","DOI":"10.3390\/ph14090923"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2763","DOI":"10.18632\/oncotarget.27669","article-title":"Can Denosumab be used in combination with Doxorubicin in Osteosarcoma?","volume":"11","author":"Punzo","year":"2020","journal-title":"Oncotarget"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"150","DOI":"10.6065\/apem.2015.20.3.150","article-title":"Bone mineral density change during adjuvant chemotherapy in pediatric osteosarcoma","volume":"20","author":"Ahn","year":"2015","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12929-024-01049-y","article-title":"Osteosarcoma in a ceRNET perspective","volume":"31","author":"Mosca","year":"2024","journal-title":"J. Biomed. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107753","DOI":"10.1016\/j.pharmthera.2020.107753","article-title":"Tumor microenvironment as a therapeutic target in cancer","volume":"221","author":"Xiao","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Orrapin, S., Moonmuang, S., Udomruk, S., Yongpitakwattana, P., Pruksakorn, D., and Chaiyawat, P. (2024). Unlocking the tumor-immune microenvironment in osteosarcoma: Insights into the immune landscape and mechanisms. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1394284"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhu, T., Han, J., Yang, L., Cai, Z., Sun, W., Hua, Y., and Xu, J. (2022). Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.907550"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s13046-020-01685-w","article-title":"The role of extracelluar matrix in osteosarcoma progression and metastasis","volume":"39","author":"Cui","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fu, Y., Bao, Q., Liu, Z., He, G., Wen, J., Liu, Q., Xu, Y., Jin, Z., and Zhang, W. (2021). Development and Validation of a Hypoxia-Associated Prognostic Signature Related to Osteosarcoma Metastasis and Immune Infiltration. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.633607"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Schmidt, A.A., Prasad, A., Huisman, A.R., Wakefield, M.R., and Fang, Y. (2025). Exploring the Tumor Microenvironment in Osteosarcoma: Driver of Resistance and Progression. Cancers, 17.","DOI":"10.3390\/cancers17193106"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.bone.2014.02.003","article-title":"Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells?","volume":"62","author":"Mutsaers","year":"2014","journal-title":"Bone"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Otani, S., Ohnuma, M., Ito, K., and Matsushita, Y. (2023). Cellular dynamics of distinct skeletal cells and the development of osteosarcoma. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1181204"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"881","DOI":"10.2174\/1871520615666150304151228","article-title":"RUNX2 and Osteosarcoma","volume":"15","author":"Li","year":"2015","journal-title":"Anti-Cancer Agents Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"250103","DOI":"10.1098\/rsob.250103","article-title":"Bone marrow endosteum in homeostasis and metastasis","volume":"15","author":"Nakai","year":"2025","journal-title":"Open Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0009-8981(99)00230-2","article-title":"Proteinases in bone resorption: Obvious and less obvious roles","volume":"291","author":"Engsig","year":"2000","journal-title":"Clin. Chim. Acta"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"N\u00f8rregaard, K.S., J\u00fcrgensen, H.J., G\u00e5rdsvoll, H., Engelholm, L.H., Behrendt, N., and S\u00f8e, K. (2021). Osteosarcoma and Metastasis Associated Bone Degradation-A Tale of Osteoclast and Malignant Cell Cooperativity. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22136865"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1002\/cncr.11132","article-title":"Mechanisms of osteolytic bone metastases in breast carcinoma","volume":"97","author":"Mundy","year":"2003","journal-title":"Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.jconrel.2021.11.005","article-title":"Targeting bone microenvironments for treatment and early detection of cancer bone metastatic niches","volume":"341","author":"Yang","year":"2022","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1002\/1097-0142(20000615)88:12+<2892::AID-CNCR2>3.0.CO;2-Y","article-title":"Molecular mechanisms of osteolytic bone metastases","volume":"88","author":"Guise","year":"2000","journal-title":"Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1002\/jbmr.2182","article-title":"Bisphosphonates inhibit osteosarcoma-mediated osteolysis via attenuation of tumor expression of MCP-1 and RANKL","volume":"29","author":"Ohba","year":"2014","journal-title":"J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/sj.bjc.6605723","article-title":"Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone","volume":"103","author":"Cumming","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1038\/s41598-020-80504-w","article-title":"The number of osteoclasts in a biopsy specimen can predict the efficacy of neoadjuvant chemotherapy for primary osteosarcoma","volume":"11","author":"Araki","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s13402-021-00598-w","article-title":"The role of tumor-associated macrophages in osteosarcoma progression\u2014Therapeutic implications","volume":"44","author":"Huang","year":"2021","journal-title":"Cell. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1158\/2326-6066.CIR-16-0259","article-title":"All-Trans Retinoic Acid Prevents Osteosarcoma Metastasis by Inhibiting M2 Polarization of Tumor-Associated Macrophages","volume":"5","author":"Zhou","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1158\/1078-0432.CCR-10-2047","article-title":"Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: A rationale for treatment with macrophage activating agents","volume":"17","author":"Buddingh","year":"2011","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"78343","DOI":"10.18632\/oncotarget.13055","article-title":"Dysregulation of macrophage polarization is associated with the metastatic process in osteosarcoma","volume":"7","author":"Dumars","year":"2016","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e001772","DOI":"10.1136\/jitc-2020-001772","article-title":"Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes","volume":"9","author":"Ligon","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6322","DOI":"10.1038\/s41467-020-20059-6","article-title":"Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma","volume":"11","author":"Zhou","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wu, L., Saxena, S., Awaji, M., and Singh, R.K. (2019). Tumor-Associated Neutrophils in Cancer: Going Pro. Cancers, 11.","DOI":"10.3390\/cancers11040564"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1182\/blood-2010-01-259028","article-title":"In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days","volume":"116","author":"Pillay","year":"2010","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by TGF-beta: \u201cN1\u201d versus \u201cN2\u201d TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/imr.13178","article-title":"Neutrophil interactions with T cells, platelets, endothelial cells, and of course tumor cells","volume":"314","author":"Segal","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41568-020-0281-y","article-title":"Neutrophil diversity and plasticity in tumour progression and therapy","volume":"20","author":"Jaillon","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1051\/sicotj\/2017028","article-title":"Osteosarcoma: A comprehensive review","volume":"4","author":"Misaghi","year":"2018","journal-title":"Sicot-j"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7207","DOI":"10.1038\/s41467-022-34689-5","article-title":"Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment","volume":"13","author":"Jiang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e13051","DOI":"10.1097\/MD.0000000000013051","article-title":"Prognostic significance of matrix metalloproteinase 9 expression in osteosarcoma: A meta-analysis of 16 studies","volume":"97","author":"Zhou","year":"2018","journal-title":"Medicine"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bonecchi, R., Mantovani, A., and Jaillon, S. (2022). Chemokines as Regulators of Neutrophils: Focus on Tumors, Therapeutic Targeting, and Immunotherapy. Cancers, 14.","DOI":"10.3390\/cancers14030680"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41577-020-00490-y","article-title":"Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity","volume":"21","author":"Veglia","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"108114","DOI":"10.1016\/j.pharmthera.2022.108114","article-title":"Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy","volume":"235","author":"Joshi","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3356","DOI":"10.1172\/JCI80005","article-title":"Myeloid-derived suppressor cells in the tumor microenvironment: Expect the unexpected","volume":"125","author":"Marvel","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41413-022-00237-6","article-title":"Characterizing the tumor microenvironment at the single-cell level reveals a novel immune evasion mechanism in osteosarcoma","volume":"11","author":"Liu","year":"2023","journal-title":"Bone Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e1199","DOI":"10.1002\/ctm2.1199","article-title":"Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target","volume":"13","author":"Li","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00262-016-1925-3","article-title":"Increased PD-L1 and T-cell infiltration in the presence of HLA class I expression in metastatic high-grade osteosarcoma: A rationale for T-cell-based immunotherapy","volume":"66","author":"Sundara","year":"2017","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.intimp.2016.01.023","article-title":"CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma","volume":"34","author":"Han","year":"2016","journal-title":"Int. Immunopharmacol."},{"key":"ref_45","first-page":"5197","article-title":"Extraskeletal osteosarcoma with partial spontaneous regression","volume":"29","author":"Matsuo","year":"2009","journal-title":"Anticancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s13287-018-0780-x","article-title":"Mesenchymal stem cells in the osteosarcoma microenvironment: Their biological properties, influence on tumor growth, and therapeutic implications","volume":"9","author":"Zheng","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.3892\/or.2013.2619","article-title":"CXCR4-mediated osteosarcoma growth and pulmonary metastasis is promoted by mesenchymal stem cells through VEGF","volume":"30","author":"Zhang","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_48","first-page":"1231","article-title":"Increased osteoclast activity is associated with aggressiveness of osteosarcoma","volume":"33","author":"Avnet","year":"2008","journal-title":"Int. J. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1002\/mc.23188","article-title":"The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses","volume":"59","author":"Westrich","year":"2020","journal-title":"Mol. Carcinog."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.immuni.2019.03.024","article-title":"Transforming Growth Factor-\u03b2 Signaling in Immunity and Cancer","volume":"50","author":"Batlle","year":"2019","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.ccell.2017.10.005","article-title":"Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors","volume":"32","author":"Kumar","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.canlet.2012.06.006","article-title":"STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma","volume":"325","author":"Tu","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.actbio.2019.07.011","article-title":"Osteomimetic matrix components alter cell migration and drug response in a 3D tumour-engineered osteosarcoma model","volume":"96","author":"Pavlou","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Fan, J., Jin, Y., Lv, F., Wu, W., Sun, L., and Wang, C. (2025). Cancer-associated fibroblasts in osteosarcoma: Key players in immune escape and targeted therapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1668535"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-3-030-37184-5_6","article-title":"Endothelial Cells in the Tumor Microenvironment","volume":"1234","author":"Sobierajska","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1007\/s00018-019-03351-7","article-title":"Tumor angiogenesis: Causes, consequences, challenges and opportunities","volume":"77","author":"Lugano","year":"2020","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1093\/cvr\/cvt215","article-title":"Pericytes modulate endothelial sprouting","volume":"100","author":"Chang","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s12032-015-0651-6","article-title":"Pericytes in sarcomas of bone","volume":"32","author":"Chang","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"De Martino, V., Rossi, M., Battafarano, G., Pepe, J., Minisola, S., and Del Fattore, A. (2021). Extracellular Vesicles in Osteosarcoma: Antagonists or Therapeutic Agents?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212586"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7249","DOI":"10.4049\/jimmunol.180.11.7249","article-title":"Human tumor-derived exosomes down-modulate NKG2D expression","volume":"180","author":"Clayton","year":"2008","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7458","DOI":"10.1158\/0008-5472.CAN-06-3456","article-title":"Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2","volume":"67","author":"Clayton","year":"2007","journal-title":"Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2621","DOI":"10.1002\/ijc.24249","article-title":"Induction of myeloid-derived suppressor cells by tumor exosomes","volume":"124","author":"Xiang","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"8931","DOI":"10.2147\/OTT.S266835","article-title":"Information Transfer and Biological Significance of Neoplastic Exosomes in the Tumor Microenvironment of Osteosarcoma","volume":"13","author":"Pu","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Yang, L., Huang, X., Guo, H., Wang, L., Yang, W., Wu, W., Jing, D., and Shao, Z. (2021). Exosomes as Efficient Nanocarriers in Osteosarcoma: Biological Functions and Potential Clinical Applications. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.737314"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1747677","DOI":"10.1080\/2162402X.2020.1747677","article-title":"Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions","volume":"9","author":"Gordon","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.arcmed.2020.10.018","article-title":"Tumor-derived Exosomes Induced M2 Macrophage Polarization and Promoted the Metastasis of Osteosarcoma Cells Through Tim-3","volume":"52","author":"Cheng","year":"2021","journal-title":"Arch. Med. Res."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Rall\u00f3n, N., Garc\u00eda, M., Garc\u00eda-Samaniego, J., Cabello, A., \u00c1lvarez, B., Restrepo, C., Nistal, S., G\u00f3rgolas, M., and Benito, J.M. (2018). Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193829"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1186\/s12943-024-02105-9","article-title":"Advances on immunotherapy for osteosarcoma","volume":"23","author":"Yu","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Fan, Q., Wang, Y., Cheng, J., Pan, B., Zang, X., Liu, R., and Deng, Y. (2024). Single-cell RNA-seq reveals T cell exhaustion and immune response landscape in osteosarcoma. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1362970"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13045-024-01651-5","article-title":"Dual inhibition of LAG-3 and PD-1 with IBI110 and sintilimab in advanced solid tumors: The first-in-human phase Ia\/Ib study","volume":"17","author":"Mao","year":"2024","journal-title":"J. Hematol. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Han, Z., Chen, G., and Wang, D. (2025). Emerging immunotherapies in osteosarcoma: From checkpoint blockade to cellular therapies. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1579822"},{"key":"ref_73","first-page":"4","article-title":"Progranulin induces immune escape in breast cancer via up-regulating PD-L1 expression on tumor-associated macrophages (TAMs) and promoting CD8(+) T cell exclusion","volume":"40","author":"Fang","year":"2021","journal-title":"J. Exp. Clin. Cancer Res. CR"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zhra, M., Akhund, S.A., and Mohammad, K.S. (2025). Advancements in Osteosarcoma Therapy: Overcoming Chemotherapy Resistance and Exploring Novel Pharmacological Strategies. Pharmaceuticals, 18.","DOI":"10.3390\/ph18040520"},{"key":"ref_75","first-page":"910","article-title":"2D and 3D cell cultures\u2014A comparison of different types of cancer cell cultures","volume":"14","author":"Kolenda","year":"2018","journal-title":"Arch. Med. Sci. AMS"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Colella, G., Fazioli, F., Gallo, M., De Chiara, A., Apice, G., Ruosi, C., Cimmino, A., and de Nigris, F. (2018). Sarcoma Spheroids and Organoids-Promising Tools in the Era of Personalized Medicine. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020615"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.4103\/0973-1482.55147","article-title":"Short-term exposure of multicellular tumor spheroids of a human glioma cell line to the glycolytic inhibitor 2-deoxy-D-glucose is more toxic than continuous exposure","volume":"5","author":"Khaitan","year":"2009","journal-title":"J. Cancer Res. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.2174\/1381612825666191014163923","article-title":"Application of Three-dimensional (3D) Tumor Cell Culture Systems and Mechanism of Drug Resistance","volume":"25","author":"Shehzad","year":"2019","journal-title":"Curr. Pharm. Des."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1016\/j.biotechadv.2016.11.002","article-title":"3D tumor spheroids: An overview on the tools and techniques used for their analysis","volume":"34","author":"Costa","year":"2016","journal-title":"Biotechnol. Adv."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.pharmthera.2016.03.013","article-title":"Three-dimensional culture systems in cancer research: Focus on tumor spheroid model","volume":"163","author":"Nath","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_81","first-page":"e55544","article-title":"An Efficient and Flexible Cell Aggregation Method for 3D Spheroid Production","volume":"12","author":"Maritan","year":"2017","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Ohguro, H., Watanabe, M., Sato, T., Nishikiori, N., Umetsu, A., Higashide, M., Yano, T., Suzuki, H., Miyazaki, A., and Takada, K. (2024). Application of Single Cell Type-Derived Spheroids Generated by Using a Hanging Drop Culture Technique in Various In Vitro Disease Models: A Narrow Review. Cells, 13.","DOI":"10.3390\/cells13181549"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"19717","DOI":"10.1038\/s41598-019-56241-0","article-title":"A 3D Printed Hanging Drop Dripper for Tumor Spheroids Analysis Without Recovery","volume":"9","author":"Zhao","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e2300587","DOI":"10.1002\/biot.202300587","article-title":"The choice of ultra-low attachment plates impacts primary human and primary canine hepatocyte spheroid formation, phenotypes, and function","volume":"19","author":"Xing","year":"2024","journal-title":"Biotechnol. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"592","DOI":"10.5966\/sctm.2012-0003","article-title":"CD133+, CD166+CD44+, and CD24+CD44+ phenotypes fail to reliably identify cell populations with cancer stem cell functional features in established human colorectal cancer cell lines","volume":"1","author":"Muraro","year":"2012","journal-title":"Stem Cells Transl. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1002\/ijc.30540","article-title":"Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-\u03baB activation","volume":"140","author":"Avnet","year":"2017","journal-title":"Int. J. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Jubelin, C., Mu\u00f1oz-Garcia, J., Cochonneau, D., Ollivier, E., Vallette, F., Heymann, M.F., Oliver, L., and Heymann, D. (2023). Technical report: Liquid overlay technique allows the generation of homogeneous osteosarcoma, glioblastoma, lung and prostate adenocarcinoma spheroids that can be used for drug cytotoxicity measurements. Front. Bioeng. Biotechnol., 11.","DOI":"10.3389\/fbioe.2023.1260049"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Cortini, M., Macchi, F., Reggiani, F., Vitale, E., Lipreri, M.V., Perut, F., Ciarrocchi, A., Baldini, N., and Avnet, S. (2023). Endogenous Extracellular Matrix Regulates the Response of Osteosarcoma 3D Spheroids to Doxorubicin. Cancers, 15.","DOI":"10.3390\/cancers15041221"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"119660","DOI":"10.1016\/j.bbamcr.2024.119660","article-title":"Identification of MCM4 and PRKDC as new regulators of osteosarcoma cell dormancy based on 3D cell cultures","volume":"1871","author":"Jubelin","year":"2024","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1700083","DOI":"10.1002\/adbi.201700083","article-title":"Embedded Spheroids as Models of the Cancer Microenvironment","volume":"1","author":"Tevis","year":"2017","journal-title":"Adv. Biosyst."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s10238-015-0398-6","article-title":"Overexpression of miR-664 is associated with enhanced osteosarcoma cell migration and invasion ability via targeting SOX7","volume":"17","author":"Bao","year":"2017","journal-title":"Clin. Exp. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41392-020-00248-x","article-title":"Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma","volume":"5","author":"Wang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"343462","DOI":"10.1016\/j.aca.2024.343462","article-title":"Single cell combined with laser ablation ICP-MS to study cisplatinum (IV) loaded nanoparticles penetration pathways in osteosarcoma spheroids","volume":"1336","author":"Gallego","year":"2025","journal-title":"Anal. Chim. Acta"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"12540","DOI":"10.1039\/D4TB01541J","article-title":"Multimodal layer-by-layer nanoparticles: A breakthrough in gene and drug delivery for osteosarcoma","volume":"12","author":"Crisafulli","year":"2024","journal-title":"J. Mater. Chem. B"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"117284","DOI":"10.1016\/j.biopha.2024.117284","article-title":"Chalcones induce apoptosis, autophagy and reduce spreading in osteosarcoma 3D models","volume":"179","author":"Rossi","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.jconrel.2024.10.068","article-title":"Advancing osteosarcoma 3D modeling in vitro for novel tumor microenvironment-targeted therapies development","volume":"376","author":"Costa","year":"2024","journal-title":"J. Control. Release Off. J. Control. Release Soc."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1111\/iep.12329","article-title":"Extracellular matrix dynamics in cell migration, invasion and tissue morphogenesis","volume":"100","author":"Yamada","year":"2019","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"14548","DOI":"10.1021\/acsami.8b22724","article-title":"Mechanical Property of Hydrogels and the Presence of Adipose Stem Cells in Tumor Stroma Affect Spheroid Formation in the 3D Osteosarcoma Model","volume":"11","author":"Kundu","year":"2019","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1016\/j.biomaterials.2013.11.038","article-title":"Embedded multicellular spheroids as a biomimetic 3D cancer model for evaluating drug and drug-device combinations","volume":"35","author":"Charoen","year":"2014","journal-title":"Biomaterials"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Contessi Negrini, N., Ricci, C., Bongiorni, F., Trombi, L., D\u2019Alessandro, D., Danti, S., and Far\u00e8, S. (2022). An Osteosarcoma Model by 3D Printed Polyurethane Scaffold and In Vitro Generated Bone Extracellular Matrix. Cancers, 14.","DOI":"10.3390\/cancers14082003"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"22294","DOI":"10.1038\/s41598-020-79448-y","article-title":"Scaffold-based 3D cellular models mimicking the heterogeneity of osteosarcoma stem cell niche","volume":"10","author":"Bassi","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_102","first-page":"55011","article-title":"3D Tumor-Engineered Model Replicating the Osteosarcoma Stem Cell Niche and In Vivo Tumor Complexity","volume":"16","author":"Bassi","year":"2024","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1039\/C9BM02075F","article-title":"Hydrogel 3D in vitro tumor models for screening cell aggregation mediated drug response","volume":"8","author":"Monteiro","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Lu, C., Jin, A., Gao, C., Qiao, H., Liu, H., Zhang, Y., Sun, W., Yang, S.M., and Liu, Y. (2024). Synergistic Approach of High-Precision 3D Printing and Low Cell Adhesion for Enhanced Self-Assembled Spheroid Formation. Biosensors, 15.","DOI":"10.3390\/bios15010007"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41556-020-0472-5","article-title":"Fast and efficient generation of knock-in human organoids using homology-independent CRISPR-Cas9 precision genome editing","volume":"22","author":"Artegiani","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1247125","DOI":"10.1126\/science.1247125","article-title":"Organogenesis in a dish: Modeling development and disease using organoid technologies","volume":"345","author":"Lancaster","year":"2014","journal-title":"Science"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1126\/science.aaw6985","article-title":"Cancer modeling meets human organoid technology","volume":"364","author":"Tuveson","year":"2019","journal-title":"Science"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/s41388-024-02942-4","article-title":"Targeted inhibition of SCF(SKP2) confers anti-tumor activities resulting in a survival benefit in osteosarcoma","volume":"43","author":"Wang","year":"2024","journal-title":"Oncogene"},{"key":"ref_109","first-page":"e56332","article-title":"Practical Considerations in Studying Metastatic Lung Colonization in Osteosarcoma Using the Pulmonary Metastasis Assay","volume":"133","author":"Lizardo","year":"2018","journal-title":"J. Vis. Exp. JoVE"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41388-024-03205-y","article-title":"Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma","volume":"44","author":"Zhang","year":"2025","journal-title":"Oncogene"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1002\/cam4.386","article-title":"S-adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: Therapeutic and diagnostic clinical applications","volume":"4","author":"Parashar","year":"2015","journal-title":"Cancer Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1007\/s13402-024-00949-3","article-title":"Exploring the impact of PDGFD in osteosarcoma metastasis through single-cell sequencing analysis","volume":"47","author":"Huang","year":"2024","journal-title":"Cell. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e2500632","DOI":"10.1002\/advs.202500632","article-title":"A Dual Approach with Organoid and CRISPR Screening Reveals ERCC6 as a Determinant of Cisplatin Resistance in Osteosarcoma","volume":"12","author":"Xu","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"101015","DOI":"10.1016\/j.tranon.2021.101015","article-title":"3D Bioprinted cancer models: Revolutionizing personalized cancer therapy","volume":"14","author":"Augustine","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1021\/acsbiomaterials.3c01569","article-title":"Applications of 3D Bioprinting Technology to Brain Cells and Brain Tumor Models: Special Emphasis to Glioblastoma","volume":"10","author":"Ozbek","year":"2024","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"150339","DOI":"10.1016\/j.bbrc.2024.150339","article-title":"Advances in tumor microenvironment: Applications and challenges of 3D bioprinting","volume":"730","author":"Dong","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"115670","DOI":"10.1016\/j.addr.2025.115670","article-title":"Patient-Derived 3D-Bioprinted Models of Pancreatic Cancer: Toward Personalized Therapy and Overcoming Tumor Microenvironment Challenges","volume":"225","author":"Krinsky","year":"2025","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"118471","DOI":"10.1016\/j.biopha.2025.118471","article-title":"Three-dimensional preclinical models for Osteosarcoma: Advances and translational prospects","volume":"191","author":"Puce","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"a031559","DOI":"10.1101\/cshperspect.a031559","article-title":"Biology of Bone: The Vasculature of the Skeletal System","volume":"8","author":"Watson","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature10144","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nature"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1002\/adhm.201600505","article-title":"Hierarchical Fabrication of Engineered Vascularized Bone Biphasic Constructs via Dual 3D Bioprinting: Integrating Regional Bioactive Factors into Architectural Design","volume":"5","author":"Cui","year":"2016","journal-title":"Adv. Healthc. Mater."},{"key":"ref_123","first-page":"57","article-title":"Key components of engineering vascularized 3-dimensional bioprinted bone constructs","volume":"216","author":"Shahabipour","year":"2020","journal-title":"Transl. Res. J. Lab. Clin. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"110905","DOI":"10.1016\/j.msec.2020.110905","article-title":"3D-bioprinted functional and biomimetic hydrogel scaffolds incorporated with nanosilicates to promote bone healing in rat calvarial defect model","volume":"112","author":"Liu","year":"2020","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_125","doi-asserted-by":"crossref","unstructured":"Fischetti, T., Di Pompo, G., Baldini, N., Avnet, S., and Graziani, G. (2021). 3D Printing and Bioprinting to Model Bone Cancer: The Role of Materials and Nanoscale Cues in Directing Cell Behavior. Cancers, 13.","DOI":"10.3390\/cancers13164065"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"5053","DOI":"10.1002\/jcb.26774","article-title":"3D bone models to study the complex physical and cellular interactions between tumor and the bone microenvironment","volume":"119","author":"Vanderburgh","year":"2018","journal-title":"J. Cell. Biochem."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41413-018-0008-9","article-title":"Engineering 3D approaches to model the dynamic microenvironments of cancer bone metastasis","volume":"6","author":"Qiao","year":"2018","journal-title":"Bone Res."},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Mattar, M., McCarthy, C.R., Kulick, A.R., Qeriqi, B., Guzman, S., and de Stanchina, E. (2018). Establishing and Maintaining an Extensive Library of Patient-Derived Xenograft Models. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00019"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"12174","DOI":"10.1038\/s41598-019-48634-y","article-title":"Bone sarcoma patient-derived xenografts are faithful and stable preclinical models for molecular and therapeutic investigations","volume":"9","author":"Nanni","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/BF03033741","article-title":"Human osteosarcoma xenografts and their sensitivity to chemotherapy","volume":"10","author":"Bruheim","year":"2004","journal-title":"Pathol. Oncol. Res. POR"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nature23647","article-title":"Orthotopic patient-derived xenografts of paediatric solid tumours","volume":"549","author":"Stewart","year":"2017","journal-title":"Nature"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1158\/2159-8290.CD-17-1152","article-title":"Genome-Informed Targeted Therapy for Osteosarcoma","volume":"9","author":"Sayles","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.diff.2015.10.012","article-title":"Subrenal capsule grafting technology in human cancer modeling and translational cancer research","volume":"91","author":"Wang","year":"2016","journal-title":"Differentiation"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/978-1-0716-1020-6_18","article-title":"Ewing Sarcoma PDX Models","volume":"2226","author":"Surdez","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1023\/A:1018456911823","article-title":"A novel spontaneous metastasis model of human osteosarcoma developed using orthotopic transplantation of intact tumor tissue into tibia of nude mice","volume":"15","author":"Crnalic","year":"1997","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s10585-015-9738-x","article-title":"An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis","volume":"32","author":"Goldstein","year":"2015","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"4200","DOI":"10.1158\/1078-0432.CCR-13-2574","article-title":"Toward a drug development path that targets metastatic progression in osteosarcoma","volume":"20","author":"Khanna","year":"2014","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s10585-005-0365-9","article-title":"An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis","volume":"22","author":"Luu","year":"2005","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12967-015-0497-x","article-title":"Establishment of a patient-derived orthotopic osteosarcoma mouse model","volume":"13","author":"Blattmann","year":"2015","journal-title":"J. Transl. Med."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1007\/s11999.0000000000000291","article-title":"Intratibial Injection Causes Direct Pulmonary Seeding of Osteosarcoma Cells and Is Not a Spontaneous Model of Metastasis: A Mouse Osteosarcoma Model","volume":"476","author":"Maloney","year":"2018","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1038\/ng.3967","article-title":"Patient-derived xenografts undergo mouse-specific tumor evolution","volume":"49","author":"Ha","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_142","doi-asserted-by":"crossref","unstructured":"Landuzzi, L., Manara, M.C., Lollini, P.L., and Scotlandi, K. (2021). Patient Derived Xenografts for Genome-Driven Therapy of Osteosarcoma. Cells, 10.","DOI":"10.3390\/cells10020416"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s13073-014-0116-0","article-title":"Assessment of patient-derived tumour xenografts (PDXs) as a discovery tool for cancer epigenomics","volume":"6","author":"Guilhamon","year":"2014","journal-title":"Genome Med."},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Wang, H., Zhu, T., Yang, K., Xu, C., Zhang, Z., Liu, G., and Ren, H. (2025). Decoding the immune microenvironment in osteosarcoma: New insights into checkpoints, vaccines, and CAR-T cells. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1702219"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/s42003-025-07992-2","article-title":"The tumor microenvironment of metastatic osteosarcoma in the human and canine lung","volume":"8","author":"McGee","year":"2025","journal-title":"Commun. Biol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s00262-025-04051-x","article-title":"Osteosarcoma cell-derived CCL2 facilitates lung metastasis via accumulation of tumor-associated macrophages","volume":"74","author":"Kondo","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1177\/15353702231171900","article-title":"A new insight of immunosuppressive microenvironment in osteosarcoma lung metastasis","volume":"248","author":"He","year":"2023","journal-title":"Exp. Biol. Med."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1186\/s13046-023-02886-9","article-title":"Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling","volume":"42","author":"Almeida","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"e37070","DOI":"10.1016\/j.heliyon.2024.e37070","article-title":"AOC3 accelerates lung metastasis of osteosarcoma by recruiting tumor-associated neutrophils, neutrophil extracellular trap formation and tumor vascularization","volume":"10","author":"Qi","year":"2024","journal-title":"Heliyon"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1007\/s11914-023-00803-9","article-title":"Advances in Osteosarcoma","volume":"21","author":"Heymann","year":"2023","journal-title":"Curr. Osteoporos. Rep."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/2909\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T08:14:52Z","timestamp":1788941692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/2909"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,9]]},"references-count":150,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18182909"],"URL":"https:\/\/doi.org\/10.3390\/cancers18182909","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,9]]}}}