Coughlin Thomas R, Sana Ali, Voss Kevin, Gadi Abhilash, Basu-Roy Upal, Curtin Caroline M, Mansukhani Alka, Kennedy Oran D
Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10010, USA.
Department of Biomedical Engineering, The City College of New York, Steinman Hall, Room ST-401160 Convent Avenue, New York, NY 1003, USA.
Cancers (Basel). 2021 Jun 23;13(13):3128. doi: 10.3390/cancers13133128.
Osteosarcoma (OS) is an aggressive bone cancer originating in the mesenchymal lineage. Prognosis for metastatic disease is poor, with a mortality rate of approximately 40%; OS is an aggressive disease for which new treatments are needed. All bone cells are sensitive to their mechanical/physical surroundings and changes in these surroundings can affect their behavior. However, it is not well understood how OS cells specifically respond to fluid movement, or substrate stiffness-two stimuli of relevance in the tumor microenvironment. We used cells from spontaneous OS tumors in a mouse engineered to have a bone-specific knockout of pRb-1 and p53 in the osteoblast lineage. We silenced Sox2 (which regulates YAP) and tested the effect of fluid flow shear stress (FFSS) and substrate stiffness on YAP expression/activity-which was significantly reduced by loss of Sox2, but that effect was reversed by FFSS but not by substrate stiffness. Osteogenic gene expression was also reduced in the absence of Sox2 but again this was reversed by FFSS and remained largely unaffected by substrate stiffness. Thus we described the effect of two distinct stimuli on the mechanosensory and osteogenic profiles of OS cells. Taken together, these data suggest that modulation of fluid movement through, or stiffness levels within, OS tumors could represent a novel consideration in the development of new treatments to prevent their progression.
骨肉瘤（OS）是一种起源于间充质谱系的侵袭性骨癌。转移性疾病的预后较差，死亡率约为40%；OS是一种侵袭性疾病，需要新的治疗方法。所有骨细胞都对其机械/物理环境敏感，这些环境的变化会影响它们的行为。然而，目前尚不清楚OS细胞如何具体响应流体运动或基质硬度——这是肿瘤微环境中的两种相关刺激。我们使用了来自在成骨细胞谱系中具有骨特异性pRb-1和p53基因敲除的小鼠自发OS肿瘤的细胞。我们沉默了Sox2（其调节YAP），并测试了流体流动剪切应力（FFSS）和基质硬度对YAP表达/活性的影响——Sox2缺失显著降低了YAP表达/活性，但FFSS可逆转这种影响，而基质硬度则不能。在没有Sox2的情况下，成骨基因表达也降低了，但同样被FFSS逆转，并且在很大程度上不受基质硬度的影响。因此，我们描述了两种不同刺激对OS细胞机械感觉和成骨特征的影响。综上所述，这些数据表明，调节OS肿瘤内的流体运动或硬度水平可能是开发预防其进展的新治疗方法的一个新考虑因素。
