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On-line Access: 2025-11-19
Received: 2024-06-10
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Citations: Bibtex RefMan EndNote GB/T7714
Zhengcheng HE, Haitao HUANG, Jiale FANG, Huiping LIU, Xudong YAO, Hongwei WU. From 2D to 3D: transforming malignant bone tumor research with advanced culture models[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2400288 @article{title="From 2D to 3D: transforming malignant bone tumor research with advanced culture models", %0 Journal Article TY - JOUR
从2D到3D:通过先进培养技术推动恶性骨肿瘤研究的转型1浙江大学医学院附属第四医院骨科,国际医学院,国际健康研究院,再生与衰老中心,中国义乌市,322000 2浙江大学医学院附属第四医院心内科,国际医学院,国际健康研究院,再生与衰老中心,中国义乌市,322000 摘要:骨肉瘤、软骨肉瘤和尤文肉瘤是主要的恶性骨肿瘤,对肿瘤学研究和临床管理提出了重大挑战。传统研究方法(如二维培养的肿瘤细胞和动物模型)无法准确模拟复杂的肿瘤微环境,因此难以有效转化为临床治疗。3D培养技术极大地推动了这一领域的发展,使得构建更贴近体内环境的体外骨肿瘤模型成为可能。这些模型为探索肿瘤生物学、评估治疗反应以及推进个性化医学提供了重要手段。本综述总结了骨肉瘤、软骨肉瘤和尤文肉瘤体外3D肿瘤模型研究的最新进展,并探讨了构建这些模型所采用的多种技术,它们的实际应用以及该领域所面临的挑战与未来发展方向。先进技术的融合和更多细胞类型的引入,有望催生出更复杂且生理相关性更高的模型。随着该领域研究的不断深入,这些模型将在揭示恶性骨肿瘤的复杂性以及加速新疗法的开发方面发挥至关重要的作用。 关键词组: Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article
Reference[1]AndersonWJ, DoyleLA, 2021. Updates from the 2020 World Health Organization classification of soft tissue and bone tumours. Histopathology, 78(5):644-657. ![]() [2]AntunesJ, GasparVM, FerreiraL, et al., 2019. In-air production of 3D co-culture tumor spheroid hydrogels for expedited drug screening. Acta Biomater, 94:392-409. ![]() [3]AranV, DevalleS, MeohasW, et al., 2021. Osteosarcoma, chondrosarcoma and Ewing sarcoma: clinical aspects, biomarker discovery and liquid biopsy. Crit Rev Oncol Hematol, 162:103340. ![]() [4]BrulinB, NolanJC, MarangonT, et al., 2021. Evaluation of the chemotherapy drug response using organotypic cultures of osteosarcoma tumours from mice models and canine patients. Cancers, 13(19):4890. ![]() [5]CersosimoF, LonardiS, BernardiniG, et al., 2020. Tumor-associated macrophages in osteosarcoma: from mechanisms to therapy. Int J Mol Sci, 21(15):5207. ![]() [6]ChenCB, MaQJ, MaXL, et al., 2011. Association of elevated HIF-2α levels with low Beclin 1 expression and poor prognosis in patients with chondrosarcoma. Ann Surg Oncol, 18(8):2364-2372. ![]() [7]ChenH, YuSH, MaRD, et al., 2024. Hypoxia-activated XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of ΔNp63α expression and promote breast cancer metastasis independent of HIF1α. Cell Death Differ, 31(4):447-459. ![]() [8]CilloAR, MukherjeeE, BaileyNG, et al., 2022. Ewing sarcoma and osteosarcoma have distinct immune signatures and intercellular communication networks. Clin Cancer Res, 28(22):4968-4982. ![]() [9]CostaEC, GasparVM, CoutinhoP, et al., 2014. Optimization of liquid overlay technique to formulate heterogenic 3D co-cultures models. Biotechnol Bioeng, 111(8):1672-1685. ![]() [10]Dobaj ŠtiglicA, LacknerF, NagarajC, et al., 2023. 3D-printed collagen‒nanocellulose hybrid bioscaffolds with tailored properties for tissue engineering applications. ACS Appl Bio Mater, 6(12):5596-5608. ![]() [11]DomeniciG, EduardoR, Castillo-EcijaH, et al., 2021. PDX-derived Ewing’s sarcoma cells retain high viability and disease phenotype in alginate encapsulated spheroid cultures. Cancers (Basel), 13(4):879. ![]() [12]DupuyM, LamoureuxF, MullardM, et al., 2023. Ewing sarcoma from molecular biology to the clinic. Front Cell Dev Biol, 11:1248753. ![]() [13]EguchiK, AkibaY, AkibaN, et al., 2018. Insulin-like growth factor binding protein-3 suppresses osteoblast differentiation via bone morphogenetic protein-2. Biochem Biophys Res Commun, 507(1-4):465-470. ![]() [14]ErkizanHV, UverskyVN, ToretskyJA, 2010. Oncogenic partnerships: EWS-FLI1 protein interactions initiate key pathways of Ewing’s sarcoma. Clin Cancer Res, 16(16):4077-4083. ![]() [15]FeigC, JonesJO, KramanM, et al., 2013. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti‒PD-l1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA, 110(50):20212-20217. ![]() [16]FerreiraLP, GasparVM, ManoJF, 2018. Design of spherically structured 3D in vitro tumor models -advances and prospects. Acta Biomater, 75:11-34. ![]() [17]Florencio-SilvaR, da Silva SassoGR, Sasso-CerriE, et al., 2015. Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int, 2015:421746. ![]() [18]FoleyJM, ScholtenII DJ, MonksNR, et al., 2015. Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling. J Transl Med, 13:110. ![]() [19]González DíazEC, LeeAG, SaylesLC, et al., 2022. A 3D osteosarcoma model with bone-mimicking cues reveals a critical role of bone mineral and informs drug discovery. Adv Healthc Mater, 11(17):2200768. ![]() [20]HabanjarO, Diab-AssafM, Caldefie-ChezetF, et al., 2021. 3D cell culture systems: tumor application, advantages, and disadvantages. Int J Mol Sci, 22(22):12200. ![]() [21]HalderJ, PradhanD, KarB, et al., 2022. Nanotherapeutics approaches to overcome P-glycoprotein-mediated multi-drug resistance in cancer. Nanomed Nanotechnol Biol Med, 40:102494. ![]() [22]HauschkaPV, MavrakosAE, IafratiMD, et al., 1986. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-sepharose. J Biol Chem, 261(27):12665-12674. ![]() [23]HawkinsAG, PedersenEA, TreichelS, et al., 2020. Wnt/β-catenin‒activated Ewing sarcoma cells promote the angiogenic switch. JCI Insight, 5(13):e135188. ![]() [24]HouYH, WangWG, BartoloP, 2024. In vitro investigations on the effects of graphene and graphene oxide on polycaprolactone bone tissue engineering scaffolds. Bio-Des Manuf, 7(5):651-669. ![]() [25]HuangBT, YinZF, ZhouFJ, et al., 2023. Functional anti-bone tumor biomaterial scaffold: construction and application. J Mater Chem B, 11(36):8565-8585. ![]() [26]HuangQS, LiangX, RenTT, et al., 2021. The role of tumor-associated macrophages in osteosarcoma progression‒therapeutic implications. Cell Oncol, 44(3):525-539. ![]() [27]JanesPW, VailME, ErnstM, et al., 2021. Eph receptors in the immunosuppressive tumor microenvironment. Cancer Res, 81(4):801-805. ![]() [28]JiangTM, XuGJ, ChenXM, et al., 2019a. Impact of hydrogel elasticity and adherence on osteosarcoma cells and osteoblasts. Adv Healthc Mater, 8(9):1801587. ![]() [29]JiangTM, ZhaoJM, YuS, et al., 2019b. Untangling the response of bone tumor cells and bone forming cells to matrix stiffness and adhesion ligand density by means of hydrogels. Biomaterials, 188:130-143. ![]() [30]Jimenez-AndradeJM, MantyhWG, BloomAP, et al., 2010. Bone cancer pain. Ann N Y Acad Sci, 1198(1):173-181. ![]() [31]KellandLR, 2004. “Of mice and men”: values and liabilities of the athymic nude mouse model in anticancer drug development. Eur J Cancer, 40(6):827-836. ![]() [32]KimJH, LeeSK, 2023. Classification of chondrosarcoma: from characteristic to challenging imaging findings. Cancers (Basel), 15(6):1703. ![]() [33]KirkB, FeehanJ, LombardiG, et al., 2020. Muscle, bone, and fat crosstalk: the biological role of myokines, osteokines, and adipokines. Curr Osteoporos Rep, 18(4):388-400. ![]() [34]KriegM, HaasR, BrauchH, et al., 2000. Up-regulation of hypoxia-inducible factors HIF-1α and HIF-2α under normoxic conditions in renal carcinoma cells by von Hippel-Lindau tumor suppressor gene loss of function. Oncogene, 19(48):5435-5443. ![]() [35]KunduB, BastosARF, BrancatoV, et al., 2019. Mechanical property of hydrogels and the presence of adipose stem cells in tumor stroma affect spheroid formation in the 3D osteosarcoma model. ACS Appl Mater Interfaces, 11(16):14548-14559. ![]() [36]KureshiAK, AfokeA, WohlertS, et al., 2015. 3D culture model of fibroblast-mediated collagen creep to identify abnormal cell behaviour. Biomech Model Mechanobiol, 14(6):1255-1263. ![]() [37]Lamhamedi-CherradiSE, MenegazBA, RamamoorthyV, et al., 2016. IGF-1R and mTOR blockade: novel resistance mechanisms and synergistic drug combinations for Ewing sarcoma. J Natl Cancer Inst, 108(12):djw182. ![]() [38]LawlorER, ScheelC, IrvingJ, et al., 2002. Anchorage-independent multi-cellular spheroids as an in vitro model of growth signaling in Ewing tumors. Oncogene, 21(2):307-318. ![]() [39]LhuissierE, BazilleC, Aury-LandasJ, et al., 2017. Identification of an easy to use 3D culture model to investigate invasion and anticancer drug response in chondrosarcomas. BMC Cancer, 17:490. ![]() [40]LiHX, QiaoY, DaiXL, et al., 2024. 3D bioprinting of tumor models and potential applications. Bio-Des Manuf, 7(6):857-888. ![]() [41]LiWX, ZhouZH, ZhouXY, et al., 2023. 3D biomimetic models to reconstitute tumor microenvironment in vitro: spheroids, organoids, and tumor-on-a-chip. Adv Healthc Mater, 12(18):2202609. ![]() [42]LiuXY, SunSS, WangN, et al., 2022. Therapeutic application of hydrogels for bone-related diseases. Front Bioeng Biotechnol, 10:998988. ![]() [43]LuZY, MiaoXW, ZhangCY, et al., 2024. An osteosarcoma-on-a-chip model for studying osteosarcoma matrix-cell interactions and drug responses. Bioact Mater, 34:1-16. ![]() [44]LuiJH, HansenDV, KriegsteinAR, 2011. Development and evolution of the human neocortex. Cell, 146(1):18-36. ![]() [45]MaYH, ZhangBY, SunHF, et al., 2023. The dual effect of 3D-printed biological scaffolds composed of diverse biomaterials in the treatment of bone tumors. Int J Nanomedicine, 18:293-305. ![]() [46]Maleki DanaP, HallajzadehJ, AsemiZ, et al., 2021. Chitosan applications in studying and managing osteosarcoma. Int J Biol Macromol, 169:321-329. ![]() [47]MaltmanDJ, PrzyborskiSA, 2010. Developments in three-dimensional cell culture technology aimed at improving the accuracy of in vitro analyses. Biochem Soc Trans, 38(4):1072-1075. ![]() [48]MarquesIA, FernandesC, TavaresNT, et al., 2022. Magnetic-based human tissue 3D cell culture: a systematic review. Int J Mol Sci, 23(20):12681. ![]() [49]MeyersPA, FedermanN, DawN, et al., 2024. Open-label, multicenter, phase I/II, first-in-human trial of TK216: a first-generation EWS::FLI1 fusion protein antagonist in Ewing sarcoma. J Clin Oncol, 42(31):3725-3734. ![]() [50]MolinaER, ChimLK, SalazarMC, et al., 2020. 3D tissue-engineered tumor model for Ewing’s sarcoma that incorporates bone-like ECM and mineralization. ACS Biomater Sci Eng, 6(1):539-552. ![]() [51]MonteiroCF, SantosSC, CustódioCA, et al., 2020. Human platelet lysates-based hydrogels: a novel personalized 3D platform for spheroid invasion assessment. Adv Sci, 7(7):1902398. ![]() [52]MonteiroCF, CustódioCA, ManoJF, 2021. Bioengineering a humanized 3D tri-culture osteosarcoma model to assess tumor invasiveness and therapy response. Acta Biomater, 134:204-214. ![]() [53]MonteiroMV, GasparVM, FerreiraLP, et al., 2020. Hydrogel 3D in vitro tumor models for screening cell aggregation mediated drug response. Biomater Sci, 8(7):1855-1864. ![]() [54]NathS, DeviGR, 2016. Three-dimensional culture systems in cancer research: focus on tumor spheroid model. Pharmacol Ther, 163:94-108. ![]() [55]NayakP, BentivoglioV, VaraniM, et al., 2023. Three-dimensional in vitro tumor spheroid models for evaluation of anticancer therapy: recent updates. Cancers, 15(19):4846. ![]() [56]PalubeckaitėI, VennekerS, Briaire-de BruijnIH, et al., 2020. Selection of effective therapies using three-dimensional in vitro modeling of chondrosarcoma. Front Mol Biosci, 7:566291. ![]() [57]PalubeckaitėI, VennekerS, van den AkkerB, et al., 2023. Does PARP inhibition sensitize chondrosarcoma cell lines to chemotherapy or radiotherapy? Results from a three-dimensional spheroid cell model. Clin Orthop Relat Res, 481(3):608-619. ![]() [58]PeelaN, TruongD, SainiH, et al., 2017. Advanced biomaterials and microengineering technologies to recapitulate the stepwise process of cancer metastasis. Biomaterials, 133:176-207. ![]() [59]PellegriniE, DesandoG, PetrettaM, et al., 2022. A 3D collagen-based bioprinted model to study osteosarcoma invasiveness and drug response. Polymers, 14(19):4070. ![]() [60]PerutF, SbranaFV, AvnetS, et al., 2018. Spheroid-based 3D cell cultures identify salinomycin as a promising drug for the treatment of chondrosarcoma. J Orthop Res, 36(8):2305-2312. ![]() [61]PhanN, HongJJ, TofigB, et al., 2019. A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids. Commun Biol, 2:78. ![]() [62]PiconeG, CappadoneC, PasiniA, et al., 2020. Analysis of intracellular magnesium and mineral depositions during osteogenic commitment of 3D cultured Saos2 cells. Int J Mol Sci, 21(7):2368 ![]() [63]PierrevelcinM, FlacherV, MuellerCG, et al., 2022. Engineering novel 3D models to recreate high-grade osteosarcoma and its immune and extracellular matrix microenvironment. Adv Healthc Mater, 11(19):2200195. ![]() [64]PradhanS, ClaryJM, SeliktarD, et al., 2017. A three-dimensional spheroidal cancer model based on PEG-fibrinogen hydrogel microspheres. Biomaterials, 115:141-154. ![]() [65]RadoorS, KarayilJ, JayakumarA, et al., 2024. Recent advances in cellulose- and alginate-based hydrogels for water and wastewater treatment: a review. Carbohydr Polym, 323:121339. ![]() [66]RiggiN, SuvàML, StamenkovicI, 2021. Ewing’s sarcoma. N Engl J Med, 384(2):154-164. ![]() [67]RimannM, LaternserS, GvozdenovicA, et al., 2014. An in vitro osteosarcoma 3D microtissue model for drug development. J Biotechnol, 189:129-135. ![]() [68]RosetiL, ParisiV, PetrettaM, et al., 2017. Scaffolds for bone tissue engineering: state of the art and new perspectives. Mater Sci Eng C, 78:1246-1262. ![]() [69]RossiF, PiconeG, CappadoneC, et al., 2023. Shedding light on osteosarcoma cell differentiation: impact on biomineralization and mitochondria morphology. Int J Mol Sci, 24(10):8559. ![]() [70]SantoroM, Lamhamedi-CherradiSE, MenegazBA, et al., 2015. Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma. Proc Natl Acad Sci USA, 112(33):10304-10309. ![]() [71]SantoroM, MenegazBA, Lamhamedi-CherradiSE, et al., 2017. Modeling stroma-induced drug resistance in a tissue-engineered tumor model of Ewing sarcoma. Tissue Eng Part A, 23(1-2):80-89. ![]() [72]SatoT, VriesRG, SnippertHJ, et al., 2009. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 459(7244):262-265. ![]() [73]ShaoRY, WangYB, LiLF, et al., 2022. Bone tumors effective therapy through functionalized hydrogels: current developments and future expectations. Drug Deliv, 29(1):1631-1647. ![]() [74]SimardFA, RichertI, VandermoetenA, et al., 2017. Description of the immune microenvironment of chondrosarcoma and contribution to progression. Oncoimmunology, 6(2):e1265716. ![]() [75]SinghAK, PramanikK, BiswasA, 2024. Constructing a biofunctionalized 3D-printed gelatin/sodium alginate/chitosan tri-polymer complex scaffold with improvised biological and mechanical properties for bone-tissue engineering. Bio-Des Manuf, 7(1):57-73. ![]() [76]SmithR, OwenLA, TremDJ, et al., 2006. Expression profiling of EWS/FLI identifies NKX2.2 as a critical target gene in Ewing’s sarcoma. Cancer Cell, 9(5):405-416. ![]() [77]SuurmondCA, LeeuwenburghSCG, van den BeuckenJJJP, 2024. Modelling bone metastasis in spheroids to study cancer progression and screen cisplatin efficacy. Cell Prolif, 57(9):e13693. ![]() [78]TebonPJ, WangBW, MarkowitzAL, et al., 2023. Drug screening at single-organoid resolution via bioprinting and interferometry. Nat Commun, 14:3168. ![]() [79]TerashimaJ, SampeiS, IidzukaM, et al., 2016. VEGF expression is regulated by HIF-1α and ARNT in 3D KYSE-70, esophageal cancer cell spheroids. Cell Biol Int, 40(11):1187-1194. ![]() [80]TornínJ, VillasanteA, Solé-MartíX, et al., 2021. Osteosarcoma tissue-engineered model challenges oxidative stress therapy revealing promoted cancer stem cell properties. Free Radical Biol Med, 164:107-118. ![]() [81]TruccoMM, MeyerCF, ThorntonKA, et al., 2018. A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas. Clin Sarcoma Res, 8:21. ![]() [82]TruongDD, WeistuchC, MurgasKA, et al., 2024. Mapping the single-cell differentiation landscape of osteosarcoma. Clin Cancer Res, 30(15):3259-3272. ![]() [83]UgelS, CanèS, de SanctisF, et al., 2021. Monocytes in the tumor microenvironment. Annu Rev Pathol Mech Dis, 16:93-122. ![]() [84]VanderburghJP, GuelcherSA, SterlingJA, 2018. 3D bone models to study the complex physical and cellular interactions between tumor and the bone microenvironment. J Cell Biochem, 119(7):5053-5059. ![]() [85]van OosterwijkJG, AnningaJK, GelderblomH, et al., 2013. Update on targets and novel treatment options for high-grade osteosarcoma and chondrosarcoma. Hematol Oncol Clin North Am, 27(5):1021-1048. ![]() [86]VennekerS, KruisselbrinkAB, Briaire-de BruijnIH, et al., 2019. Inhibition of PARP sensitizes chondrosarcoma cell lines to chemo- and radiotherapy irrespective of the IDH1 or IDH2 mutation status. Cancers (Basel), 11(12):1918. ![]() [87]VerrecchiaF, RédiniF, 2018. Transforming growth factor-β signaling plays a pivotal role in the interplay between osteosarcoma cells and their microenvironment. Front Oncol, 8:133. ![]() [88]VlachogiannisG, HedayatS, VatsiouA, et al., 2018. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, 359(6378):920-926. ![]() [89]VoissiereA, JoubertonE, MaubertE, et al., 2017. Development and characterization of a human three-dimensional chondrosarcoma culture for in vitro drug testing. PLoS ONE, 12(7):e0181340. ![]() [90]WalterSG, KnöllP, EyselP, et al., 2023. Molecular in-depth characterization of chondrosarcoma for current and future targeted therapies. Cancers (Basel), 15(9):2556. ![]() [91]WanL, NeumannCA, LeDucPR, 2020. Tumor-on-a-chip for integrating a 3D tumor microenvironment: chemical and mechanical factors. Lab Chip, 20(5):873-888. ![]() [92]WenY, ChenYS, WuWL, et al., 2023. Hyperplastic human macromass cartilage for joint regeneration. Adv Sci, 10(26):2301833. ![]() [93]WhelanJS, DavisLE, 2018. Osteosarcoma, chondrosarcoma, and chordoma. J Clin Oncol, 36(2):188-193. ![]() [94]WoodLD, EwaldAJ, 2021. Organoids in cancer research: a review for pathologist-scientists. J Pathol, 254(4):395-404. ![]() [95]WuHW, HeZX, LiXN, et al., 2021. Efficient and consistent orthotopic osteosarcoma model by cell sheet transplantation in the nude mice for drug testing. Front Bioeng Biotechnol, 9:690409. ![]() [96]WuSL, WuXM, WangXH, et al., 2023. Hydrogels for bone organoid construction: from a materiobiological perspective. J Mater Sci Technol, 136:21-31. ![]() [97]XiaoY, YuDH, 2021. Tumor microenvironment as a therapeutic target in cancer. Pharmacol Ther, 221:107753. ![]() [98]XuY, QiJQ, ZhouWY, et al., 2022. Generation of ring-shaped human iPSC-derived functional heart microtissues in a Möbius strip configuration. Bio-Des Manuf, 5(4):687-699. ![]() [99]XueYM, NiuW, WangM, et al., 2020. Engineering a biodegradable multifunctional antibacterial bioactive nanosystem for enhancing tumor photothermo-chemotherapy and bone regeneration. ACS Nano, 14(1):442-453. ![]() [100]ZachosTA, 2021. CORR Insights®: do patient-derived spheroid culture models have relevance in chondrosarcoma research? Clin Orthop Relat Res, 479(3):491-492. ![]() [101]ZhangF, ZhangB, WangYY, et al., 2023. An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption. Nature, 622(7984):834-841. ![]() [102]ZhangH, XuHW, AshbyCRJr, et al., 2021. Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp). Med Res Rev, 41(1):525-555. ![]() [103]ZhaoTH, WeiZQ, ZhuW, et al., 2022. Recent developments and current applications of hydrogels in osteoarthritis. Bioengineering (Basel), 9(4):132. ![]() [104]ZöllnerSK, AmatrudaJF, BauerS, et al., 2021. Ewing sarcoma—diagnosis, treatment, clinical challenges and future perspectives. J Clin Med, 10(8):1685. ![]() [105]ZubairH, KhanMA, AnandS, et al., 2022. Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy. 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