Volume 3,Issue 9
三维模型重构骨肉瘤研究：从类器官到仿生微环境的范式革新
骨肉瘤是一种高度侵袭性的原发性恶性骨肿瘤，其发生、发展及转移进程与其所处微环境的动态互作密切相关。转移性骨肉瘤是临床治疗的主要难题，也是影响患者预后的关键因素，约20%-30% 的初诊患者已发生肺转移，且术后复发患者的五年生存率不足30%，远低于非转移患者的60%-70%， 这凸显了目前治疗策略的局限性。近年来，研究逐步阐明骨微环境通过机械信号传导（如YAP/TAZ 通路）、代谢重编程及免疫抑制等机制在 骨肉瘤转移中的关键调控作用，但针对微环境互作的靶向干预仍面临转化瓶颈。鉴于此，构建仿生三维培养体系以模拟体内生物力学微环境的异质性特征（如细胞外基质刚度、缺氧梯度及流体剪切力）成为研究热点。相较于传统二维模型，仿生三维体系能更真实地再现肿瘤- 基质动态互作、药物响应异质性及转移级联反应，尤其在解析化疗耐药机制与免疫逃逸表型方面展现出显著优势。本综述系统梳理了生物打印、微流控芯片及类器官共培养等前沿技术在骨肉瘤研究中的应用进展，强调其在血管侵袭模拟、耐药机制解析等方面的潜力。尽管标准化构建方案与多中心验证体系亟待完善，但此类技术的跨学科交叉创新有望为骨肉瘤精准医学的转化研究提供新方向，并为开发基于微环境调控的个体化治疗策略奠定理论基石。
[1] Kansara, M., Teng, M. W., Smyth, M. J. & Thomas, D. M. Translational biology of osteosarcoma. Nat Rev Cancer 14, 722–735 (2014).
[2] Gaspar, N. et al. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study.European Journal of Cancer 88, 57–66 (2018).
[3] Meyers, P. A. et al. Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate. JCO 23, 2004–2011 (2005).
[4] Bacci, G. & Lari, S. Current Treatment of High Grade Osteosarcoma of the Extremity: Review. Journal of Chemotherapy 13, 235–243 (2001).
[5] Bishop, M. W., Janeway, K. A. & Gorlick, R. Future directions in the treatment of osteosarcoma. Current Opinion in Pediatrics 28, 26 (2016).
[6] Luetke, A., Meyers, P. A., Lewis, I. & Juergens, H. Osteosarcoma treatment – Where do we stand? A state of the art review. Cancer Treatment Reviews 40, 523–532 (2014).
[7] Paget, S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8, 98–101 (1989).
[8] Alfranca, A. et al. Bone microenvironment signals in osteosarcoma development. Cell Mol Life Sci 72, 3097–3113 (2015).
[9] Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication | Nature Cell Biology. https://www.nature.com/articles/s41556-018-0250-9.
[10] Corre, I., Verrecchia, F., Crenn, V., Redini, F. & Trichet, V. The Osteosarcoma Microenvironment: A Complex But Targetable Ecosystem. Cells 9, 976 (2020).