Lynch Maureen E, Chiou Aaron E, Lee Min Joon, Marcott Stephen C, Polamraju Praveen V, Lee Yeonkyung, Fischbach Claudia
1 Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University , Ithaca, New York.
2 Department of Mechanical and Industrial Engineering, University of Massachusetts Amherst , Amherst, Massachusetts.
Tissue Eng Part A. 2016 Aug;22(15-16):1006-15. doi: 10.1089/ten.TEA.2016.0153. Epub 2016 Aug 1.
Dynamic mechanical loading is a strong anabolic signal in the skeleton, increasing osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs) and increasing the bone-forming activity of osteoblasts, but its role in bone metastatic cancer is relatively unknown. In this study, we integrated a hydroxyapatite-containing three-dimensional (3D) scaffold platform with controlled mechanical stimulation to investigate the effects of cyclic compression on the interplay between breast cancer cells and BM-MSCs as it pertains to bone metastasis. BM-MSCs cultured within mineral-containing 3D poly(lactide-co-glycolide) (PLG) scaffolds differentiated into mature osteoblasts, and exposure to tumor-derived soluble factors promoted this process. When BM-MSCs undergoing osteogenic differentiation were exposed to conditioned media collected from mechanically loaded breast cancer cells, their gene expression of osteopontin was increased. This was further enhanced when mechanical compression was simultaneously applied to BM-MSCs, leading to more uniformly deposited osteopontin within scaffold pores. These results suggest that mechanical loading of 3D scaffold-based culture models may be utilized to evaluate the role of physiologically relevant physical cues on bone metastatic breast cancer. Furthermore, our data imply that cyclic mechanical stimuli within the bone microenvironment modulate interactions between tumor cells and BM-MSCs that are relevant to bone metastasis.
动态机械负荷是骨骼中一种强大的合成代谢信号，可增加骨髓间充质干细胞（BM-MSCs）的成骨分化并增强成骨细胞的骨形成活性，但其在骨转移性癌症中的作用相对未知。在本研究中，我们将含羟基磷灰石的三维（3D）支架平台与可控机械刺激相结合，以研究循环压缩对乳腺癌细胞与BM-MSCs之间相互作用的影响，因为这与骨转移有关。在含矿物质的3D聚（丙交酯-共-乙交酯）（PLG）支架内培养的BM-MSCs分化为成熟的成骨细胞，而暴露于肿瘤衍生的可溶性因子可促进这一过程。当经历成骨分化的BM-MSCs暴露于从机械加载的乳腺癌细胞收集的条件培养基时，其骨桥蛋白的基因表达增加。当同时对BM-MSCs施加机械压缩时，这种情况会进一步增强，导致骨桥蛋白在支架孔隙内沉积得更均匀。这些结果表明，基于3D支架的培养模型的机械负荷可用于评估生理相关物理线索在骨转移性乳腺癌中的作用。此外，我们的数据表明，骨微环境中的循环机械刺激可调节与骨转移相关的肿瘤细胞与BM-MSCs之间的相互作用。
