Compressive Stress Inhibits Proliferation in Tumor Spheroids through a Volume Limitation
Compressive Stress Inhibits Proliferation in Tumor Spheroids through a Volume Limitation
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DOI：
10.1016/j.bpj.2014.08.031
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发表时间：
2014-10-21
影响因子：
3.4
通讯作者：
Cappello, Giovanni
中科院分区：
文献类型：
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作者：
Delarue, Morgan;Monte, Fabien;Cappello, Giovanni
在大多数情况下，实体瘤的生长发生在受限的环境中，需要空间竞争。机械串扰可由该竞争引起。在这篇文章中，我们剖析了生物力学序列所造成的控制压缩应力对多细胞球体（MCSs）作为一个肿瘤模型系统。在分钟的时间尺度上，我们表明，压缩应力导致MCS体积的减少，与MCS的核心中的细胞体积的减少有关。在小时的时间尺度上，我们观察到从球体的中心到外围的增殖抑制剂p27（KiP1）的可逆诱导。在以天为单位的时间尺度上，我们观察到细胞在细胞周期中在G1晚期检查点（限制点）被阻断。我们发现，压力对增殖的影响可以通过沉默p27（Kip1）来拮抗。最后，我们量化了压力引起的体积变化和球体的生长速率之间的明确相关性。我们研究的压缩诱导的增殖停滞对于五种细胞系是保守的，并且是完全可逆的。它展示了机械应力和细胞周期调控的关键参与者之间的一般串扰。我们的研究结果表明，体积变化对压力的敏感性的作用，和p27（Kip1）是强烈的影响，这种变化。
In most instances, the growth of solid tumors occurs in constrained environments and requires a competition for space. A mechanical crosstalk can arise from this competition. In this article, we dissect the biomechanical sequence caused by a controlled compressive stress on multicellular spheroids (MCSs) used as a tumor model system. On timescales of minutes, we show that a compressive stress causes a reduction of the MCS volume, linked to a reduction of the cell volume in the core of the MCS. On timescales of hours, we observe a reversible induction of the proliferation inhibitor, p27(KiP1), from the center to the periphery of the spheroid. On timescales of days, we observe that cells are blocked in the cell cycle at the late G1 checkpoint, the restriction point. We show that the effect of pressure on the proliferation can be antagonized by silencing p27(Kip1). Finally, we quantify a clear correlation between the pressure-induced volume change and the growth rate of the spheroid. The compression-induced proliferation arrest that we studied is conserved for five cell lines, and is completely reversible. It demonstrates a generic crosstalk between mechanical stresses and the key players of cell cycle regulation. Our results suggest a role of volume change in the sensitivity to pressure, and that p27(Kip1) is strongly influenced by this change.