Microfluidic platform for studying osteocyte mechanoregulation of breast cancer bone metastasis
Microfluidic platform for studying osteocyte mechanoregulation of breast cancer bone metastasis
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DOI：
10.1093/intbio/zyz008
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发表时间：
2019-04-01
影响因子：
2.5
通讯作者：
You, Lidan
中科院分区：
文献类型：
--
作者：
Mei, Xueting;Middleton, Kevin;You, Lidan
骨转移是乳腺癌常见但严重的并发症。乳腺癌细胞从血管外渗到骨骼，通过与骨细胞相互作用，破坏骨重塑平衡，从而破坏骨质量。虽然运动经常被认为是一种癌症干预策略，并且运动期间的机械负荷可以调节骨重塑，但其在预防骨转移中的作用尚不清楚。我们建立了一种新的体外微流控组织模型来研究骨细胞在乳腺癌骨转移的机械调节中的作用。转移性MDA-MB-231乳腺癌细胞被培养在内衬人脐静脉内皮细胞（HUVECs）的3D微流体管腔中，该管腔毗邻骨细胞样MLO-Y4细胞的通道。生理相关振荡流体流（OFF） （1 Pa, 1 Hz）用于机械刺激骨细胞。两个通道之间的水凝胶填充侧通道允许实时、双向的细胞信号传导和癌细胞外渗超过3天。施加的OFF能够诱导骨细胞内钙反应（82.3%的细胞响应，平均幅度增加3.71倍）。与静态骨细胞（分别为对照组的102.1%和107.3%）相比，机械刺激骨细胞的外渗距离和外渗侧通道百分比均显著减少（分别为对照组的32.4%和53.5%）。这是第一个成功集成刺激骨液流动的微流体装置，并证明机械刺激骨细胞减少乳腺癌外渗。该平台的未来工作将确定骨细胞机制调节乳腺癌骨转移的具体机制，以及其他类型的癌症转移和疾病。
Bone metastasis is a common, yet serious, complication of breast cancer. Breast cancer cells that extravasate from blood vessels to the bone devastate bone quality by interacting with bone cells and disrupting the bone remodeling balance. Although exercise is often suggested as a cancer intervention strategy and mechanical loading during exercise is known to regulate bone remodeling, its role in preventing bone metastasis remains unknown. We developed a novel in vitro microfluidic tissue model to investigate the role of osteocytes in the mechanical regulation of breast cancer bone metastasis. Metastatic MDA-MB-231 breast cancer cells were cultured inside a 3D microfluidic lumen lined with human umbilical vein endothelial cells (HUVECs), which is adjacent to a channel seeded with osteocyte-like MLO-Y4 cells. Physiologically relevant oscillatory fluid flow (OFF) (1 Pa, 1 Hz) was applied to mechanically stimulate the osteocytes. Hydrogel-filled side channels in-between the two channels allowed real-time, bi-directional cellular signaling and cancer cell extravasation over 3 days. The applied OFF was capable of inducing intracellular calcium responses in osteocytes (82.3% cells responding with a 3.71 fold increase average magnitude). Both extravasation distance and percentage of extravasated side-channels were significantly reduced with mechanically stimulated osteocytes (32.4% and 53.5% of control, respectively) compared to static osteocytes (102.1% and 107.3% of control, respectively). This is the first microfluidic device that has successfully integrated stimulatory bone fluid flow, and demonstrated that mechanically stimulated osteocytes reduced breast cancer extravasation. Future work with this platform will determine the specific mechanisms involved in osteocyte mechanoregulation of breast cancer bone metastasis, as well as other types of cancer metastasis and diseases.