Department of Biomedical Engineering, University of California, Davis, California, USA.
Department of Orthopaedic Surgery, UC Davis Health, Sacramento, California, USA.
Cancer Med. 2024 Sep;13(18):e70239. doi: 10.1002/cam4.70239.
Osteosarcoma (OS) survival rates and outcome have not improved in 50 years since the advent of modern chemotherapeutics. Thus, there is a critical need for an improved understanding of the tumor microenvironment to identify better therapies. Extracellular matrix (ECM) deposition and hypoxia are known to abrogate the efficacy of various chemical and cell-based therapeutics. Here, we aim to mechanistically investigate the combinatorial effects of hypoxia and matrix deposition with the use of OS spheroids.
We use two murine OS cell lines with differential metastatic potential to form spheroids. We form spheroids of two sizes, use ascorbate-2-phosphate supplementation to enhance ECM deposition, and study cell response under standard (21% O) and physiologic (5% O) oxygen tensions. Finally, we examine chemotherapeutic responses to doxorubicin treatment.
ECM production and oxygen tension are key determinants of spheroid size through cell organization based on nutrient and oxygen distribution. Interestingly, highly metastatic OS is more susceptible to chemotherapeutics compared to less metastatic OS when matrix production increases. Together, these data suggest that dynamic interactions between ECM production and oxygen diffusion may result in distinct chemotherapeutic responses despite inherent tumor aggressiveness.
This work establishes OS spheroids as a valuable tool for early OS tumor formation investigation and holds potential for novel therapeutic target and prognostic indicator discovery.
自现代化疗药物问世以来，骨肉瘤（OS）的存活率和治疗效果 50 年来并没有改善。因此，迫切需要更好地了解肿瘤微环境，以确定更好的治疗方法。已知细胞外基质（ECM）的沉积和缺氧会降低各种化学和细胞治疗的疗效。在这里，我们旨在使用 OS 球体来深入研究缺氧和基质沉积的组合效应对肿瘤的影响。
我们使用两种具有不同转移潜力的鼠骨肉瘤细胞系来形成球体。我们形成两种大小的球体，使用抗坏血酸-2-磷酸补充剂来增强 ECM 的沉积，并在标准（21%O）和生理（5%O）氧张力下研究细胞反应。最后，我们检查了阿霉素治疗的化疗反应。
ECM 的产生和氧张力是通过基于营养物质和氧气分布的细胞组织来决定球体大小的关键因素。有趣的是，与转移性较低的 OS 相比，当基质生成增加时，高度转移性的 OS 对化疗药物更敏感。这些数据表明，尽管肿瘤具有侵袭性，但 ECM 产生和氧气扩散之间的动态相互作用可能导致不同的化疗反应。
这项工作确立了 OS 球体作为早期骨肉瘤肿瘤形成研究的有价值的工具，并具有发现新的治疗靶点和预后指标的潜力。
