Department of Biomedical Engineering, Chemistry and Biological Sciences, Stevens Institute of Technology, Hoboken, NJ, USA.
Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, USA.
Sci Rep. 2018 Dec 19;8(1):17975. doi: 10.1038/s41598-018-36424-x.
Prostate cancer (PCa) is the second leading cause of cancer deaths among American men. Unfortunately, there is no cure once the tumor is established within the bone niche. Although osteocytes are master regulators of bone homeostasis and remodeling, their role in supporting PCa metastases remains poorly defined. This is largely due to a lack of suitable ex vivo models capable of recapitulating the physiological behavior of primary osteocytes. To address this need, we integrated an engineered bone tissue model formed by 3D-networked primary human osteocytes, with conditionally reprogrammed (CR) primary human PCa cells. CR PCa cells induced a significant increase in the expression of fibroblast growth factor 23 (FGF23) by osteocytes. The expression of the Wnt inhibitors sclerostin and dickkopf-1 (Dkk-1), exhibited contrasting trends, where sclerostin decreased while Dkk-1 increased. Furthermore, alkaline phosphatase (ALP) was induced with a concomitant increase in mineralization, consistent with the predominantly osteoblastic PCa-bone metastasis niche seen in patients. Lastly, we confirmed that traditional 2D culture failed to reproduce these key responses, making the use of our ex vivo engineered human 3D bone tissue an ideal platform for modeling PCa-bone interactions.
前列腺癌（PCa）是美国男性癌症死亡的第二大主要原因。不幸的是，一旦肿瘤在骨龛内建立，就没有治愈的方法。尽管成骨细胞是骨稳态和重塑的主要调节者，但它们在支持 PCa 转移中的作用仍未得到明确界定。这主要是由于缺乏能够重现原代成骨细胞生理行为的合适的体外模型。为了满足这一需求，我们整合了由 3D 网络原代人成骨细胞形成的工程化骨组织模型，与条件重编程（CR）的原代人 PCa 细胞。CR PCa 细胞诱导成骨细胞中成纤维细胞生长因子 23（FGF23）的表达显著增加。Wnt 抑制剂骨硬化素和 dickkopf-1（Dkk-1）的表达表现出相反的趋势，其中骨硬化素减少，而 Dkk-1 增加。此外，碱性磷酸酶（ALP）被诱导，同时矿化增加，与患者中观察到的主要成骨细胞 PCa-骨转移龛相一致。最后，我们证实传统的 2D 培养无法重现这些关键反应，因此我们的体外工程化人 3D 骨组织是模拟 PCa-骨相互作用的理想平台。
