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Abstract：
The tumor microenvironment is a complex and dynamic ecosystem composed of various physical cues and biochemical signals that facilitate cancer progression, and tumor-associated macrophages are especially of interest as a treatable target due to their diverse pro-tumorigenic functions. Engineered three-dimensional models of tumors more effectively mimic the tumor microenvironment than monolayer cultures and can serve as a platform for investigating specific aspects of tumor biology within a controlled setting. To study the combinatorial effects of tumor-associated macrophages and microenvironment mechanical properties on osteosarcoma, we co-cultured human osteosarcoma cells with macrophages within biomaterials-based bone tumor niches with tunable stiffness. In the first 24 h of direct interaction between the two cell types, macrophages induced an inflammatory environment consisting of high concentrations of tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 within moderately stiff scaffolds. Expression of Yes-associated protein (YAP), but not its homolog, transcriptional activator with PDZ-binding motif (TAZ), in osteosarcoma cells was significantly higher than in macrophages, and co-culture of the two cells slightly upregulated YAP in both cells, although not to a significant degree. Resistance to doxorubicin treatment in osteosarcoma cells was correlated with inflammation in the microenvironment, and signal transducer and activator of transcription 3 (STAT3) inhibition diminished the inflammation-related differences in drug resistance but ultimately did not improve the efficacy of doxorubicin. This work highlights that the biochemical cues conferred by tumor-associated macrophages in osteosarcoma are highly variable, and signals derived from the immune system should be considered in the development and testing of novel drugs for cancer.
摘要：
肿瘤微环境是一个复杂而动态的生态系统，由促进癌症进展的各种物理线索和生化信号组成，和肿瘤相关的巨噬细胞由于其不同的促肿瘤发生功能而作为可治疗的靶标尤其令人感兴趣。与单层培养物相比，工程化的肿瘤三维模型更有效地模拟肿瘤微环境，并且可以用作在受控环境中研究肿瘤生物学特定方面的平台。研究肿瘤相关巨噬细胞和微环境力学特性对骨肉瘤的联合作用,我们将人骨肉瘤细胞与巨噬细胞共培养在基于生物材料的骨肿瘤壁龛中，刚度可调。在两种细胞类型之间直接相互作用的前24小时内，巨噬细胞在中等坚硬的支架中诱导了由高浓度的肿瘤坏死因子α（TNFα）和白介素（IL）-6组成的炎症环境。Yes相关蛋白(YAP)的表达,但不是它的同系物，具有PDZ结合基序（TAZ）的转录激活因子，骨肉瘤细胞明显高于巨噬细胞，和共培养的两个细胞轻微上调YAP在两个细胞，虽然程度不大。骨肉瘤细胞对多柔比星治疗的抗性与微环境中的炎症相关。信号转导和转录激活因子3（STAT3）抑制减少了与炎症相关的耐药性差异，但最终并未改善阿霉素的疗效。这项工作强调，骨肉瘤中肿瘤相关巨噬细胞赋予的生化线索是高度可变的，在开发和测试新型癌症药物时，应考虑来自免疫系统的信号。
