Mechanical regulation of breast cancer migration and apoptosis via direct and indirect osteocyte signaling
Mechanical regulation of breast cancer migration and apoptosis via direct and indirect osteocyte signaling
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DOI：
10.1002/jcb.26745
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发表时间：
2018-07-01
影响因子：
4
通讯作者：
You, Lidan
中科院分区：
文献类型：
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作者：
Ma, Yu-Heng V.;Lam, Candy;You, Lidan
65-80%的晚期乳腺癌患者发生骨转移，即癌症向骨骼的转移。转移的癌细胞与骨吸收破骨细胞等细胞相互作用，改变骨重塑。运动通常被认为是癌症患者的干预手段，通过骨细胞调节骨重塑。骨细胞也向内皮细胞发出信号，这可能影响癌细胞外渗。因此，我们假设机械刺激的骨细胞可以调节乳腺癌骨转移过程。为了验证这一点，我们使用平行板流动室将骨细胞暴露在体外振荡流体中。我们观察到，流动刺激骨细胞的条件培养基增加了乳腺癌细胞的迁移（45%），减少了凋亡（12%）。在流动骨细胞条件培养基中调节的破骨细胞的条件培养基减少了癌细胞的迁移（47%），增加了癌细胞的凋亡（55%）。在流动的骨细胞条件培养基中，癌细胞跨内皮迁移减少了34%。ICAM-1或IL-6中和抗体消除了这种差异。内皮细胞条件培养基在流动骨细胞条件培养基中使癌细胞凋亡增加29%。总之，本研究证明机械刺激的骨细胞不仅通过直接信号传导影响乳腺癌细胞，而且通过破骨细胞和内皮细胞影响乳腺癌细胞。由于骨细胞比破骨细胞和内皮细胞离转移的癌细胞更远，因此间接信号的抗转移潜力特别令人兴奋。未来对骨机械负荷对转移的影响及其机制的研究将有助于设计降低骨转移风险的癌症干预方案。
Bone metastases, the migration of cancers to bone, occur in 65-80% of patients with advanced breast cancer. Metastasized cancer cells interact with cells such as the bone-resorbing osteoclasts to alter bone remodeling. Exercise, often suggested as an intervention for cancer patients, regulates bone remodeling via osteocytes. Osteocytes also signal to endothelial cells, which may affect cancer cell extravasation. Therefore, we hypothesize that mechanically stimulated osteocytes can regulate processes in breast cancer bone metastasis. To test this, we exposed osteocytes to oscillatory fluid flow in vitro using parallel-plate flow chambers. We observed that conditioned medium from flow-stimulated osteocytes increased migration (by 45%) and reduced apoptosis (by 12%) of breast cancer cells. Conditioned medium from osteoclasts conditioned in flowed osteocytes' conditioned medium reduced migration (by 47%) and increased apoptosis (by 55%) of cancer cells. Cancer cell trans-endothelial migration was reduced by 34% toward flowed osteocytes' conditioned medium. This difference was abolished with ICAM-1 or IL-6 neutralizing antibodies. Conditioned medium from endothelial cells conditioned in flowed osteocytes' conditioned medium increased cancer cell apoptosis by 29%. To summarize, this study demonstrated mechanically stimulated osteocytes' potential to affect breast cancer cells not only through direct signaling, but also through osteoclasts and endothelial cells. The anti-metastatic potential of the indirect signalings is particularly exciting since osteocytes are further away from metastasizing cancer cells than osteoclasts and endothelial cells. Future studies into the effect of bone mechanical loading on metastases and its mechanism will assist in designing cancer intervention programs that lowers the risk for bone metastases.