Wnt/β-Catenin Signaling Pathway Regulates Osteogenesis for Breast Cancer Bone Metastasis: Experiments in an In Vitro Nanoclay Scaffold Cancer Testbed
Wnt/β-Catenin Signaling Pathway Regulates Osteogenesis for Breast Cancer Bone Metastasis: Experiments in an In Vitro Nanoclay Scaffold Cancer Testbed
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Wnt/β-Catenin信号通路调控乳腺癌骨转移的成骨作用：体外纳米粘土支架癌症实验平台的实验
DOI：
10.1021/acsbiomaterials.9b00923
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发表时间：
2020-05-01
影响因子：
5.8
通讯作者：
Katti, Kalpana S.
中科院分区：
文献类型：
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作者：
Kar, Sumanta;Jasuja, Haneesh;Katti, Kalpana S.
乳腺癌与骨有很高的亲和力，导致骨相关并发症，导致临床预后不良。 Wnt/β-连环蛋白信号通路在骨再生过程中的作用已得到充分证实；然而，Wnt/β-连环蛋白通路在乳腺癌骨转移中的调节作用尚不清楚。在此，我们报道Wnt/β-catenin信号通路对乳腺癌骨转移过程中的成骨具有显着影响。在这项研究中，我们使用基于纳米粘土的支架以及成骨分化的人间充质干细胞 (MSC) 和人乳腺癌细胞（MCF-7 和 MDA-MB-231）创建了 3D 体外乳腺癌骨转移微环境。结果显示，与使用 MDA-MB-231 连续培养的 MSC 相比，使用 MCF-7 连续培养的 MSC 中 Wnt 相关因子（Wnt-5a、β-连环蛋白、AXIN2 和 LRPS）的表达上调。 MSC 与 MCF-7 的连续培养物在蛋白质水平上也显示出比 MSC 与 MDA-MB-231 的连续培养物更高的 β-连环蛋白表达。 ET-1 在含有 MCF-7 的 MSC 连续培养物中刺激 Wnt/β-catenin 信号传导导致骨形成增加，而 DKK-1 灭活 Wnt/β-catenin 信号传导则显示骨形成显着减少，类似于乳腺癌患者的骨病变。这些数据共同证明 Wnt/β-连环蛋白信号传导控制肿瘤骨微环境中的成骨，从而导致骨转移。纳米粘土支架为分析癌症转移途径提供了独特的试验台方法。
Breast cancer shows a high affinity toward bone, causing bone-related complications, leading to a poor clinical prognosis. The Wnt/beta-catenin signaling pathway has been well-documented for the bone regenerative process; however, the regulation of the Wnt/beta-catenin pathway in breast cancer bone metastasis is poorly explored. Here, we report that the Wnt/beta-catenin signaling pathway has a significant effect on osteogenesis during breast cancer bone metastasis. In this study, we have created a 3D in vitro breast cancer bone metastatic microenvironment using nanoclay-based scaffolds along with osteogenically differentiated human mesenchymal stem cells (MSCs) and human breast cancer cells (MCF-7 and MDA-MB-231). The results showed upregulation in expressions of Wnt-related factors (Wnt-5a, beta-catenin, AXIN2, and LRPS) in sequential cultures of MSCs with MCF-7 as compared to sequential cultures of MSCs with MDA-MB-231. Sequential cultures of MSCs with MCF-7 also showed higher beta-catenin expression on the protein levels than sequential cultures of MSCs with MDA-MB-231. Stimulation of Wnt/beta-catenin signaling in sequential cultures of MSCs with MCF-7 by ET-1 resulted in increased bone formation, whereas inactivation of Wnt/beta-catenin signaling by DKK-1 displayed a significant decrease in bone formation, mimicking bone lesions in breast cancer patients. These data collectively demonstrate that Wnt/beta-catenin signaling governs osteogenesis within the tumor-harboring bone microenvironment, leading to bone metastasis. The nanoclay scaffold provides a unique testbed approach for analysis of the pathways of cancer metastasis.