Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells.
Micro-environmental mechanical stress controls tumor spheroid size and morphology by suppressing proliferation and inducing apoptosis in cancer cells.
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DOI：
10.1371/journal.pone.0004632
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Munn LL
中科院分区：
文献类型：
--
作者：
Cheng G;Tse J;Jain RK;Munn LL
在限制基质中生长过程中产生的压缩机械应力限制了肿瘤球体的大小，但对应力积累的动力学、应力如何影响癌细胞表型或所涉及的分子途径知之甚少。我们将单个癌细胞与荧光微珠共包埋在琼脂糖凝胶中，并使用共聚焦显微镜记录了生长中的球体周围微珠的3D分布。然后将微珠密度的变化转换为凝胶中的应变，由此我们估计了球体周围的压应力的空间分布。我们发现球体周围的固体应力分布与球体形状有很强的相关性，这是高机械应力区域抑制细胞增殖和诱导细胞死亡的结果。通过压缩由过表达抗凋亡基因的癌细胞组成的球体，我们证明了机械应激诱导的细胞凋亡是通过线粒体途径发生的。我们的结果提供了对微环境机械应力在肿瘤球体生长动力学中的作用的详细的、定量的洞察，并提示了肿瘤如何在固体应力水平变高的受限位置生长。一个重要的含义是，通过线粒体途径诱导的细胞凋亡可能参与了肿瘤的休眠，在这种休眠中，肿瘤的生长受到细胞凋亡和增殖的平衡的控制。
Compressive mechanical stress produced during growth in a confining matrix limits the size of tumor spheroids, but little is known about the dynamics of stress accumulation, how the stress affects cancer cell phenotype, or the molecular pathways involved. We co-embedded single cancer cells with fluorescent micro-beads in agarose gels and, using confocal microscopy, recorded the 3D distribution of micro-beads surrounding growing spheroids. The change in micro-bead density was then converted to strain in the gel, from which we estimated the spatial distribution of compressive stress around the spheroids. We found a strong correlation between the peri-spheroid solid stress distribution and spheroid shape, a result of the suppression of cell proliferation and induction of apoptotic cell death in regions of high mechanical stress. By compressing spheroids consisting of cancer cells overexpressing anti-apoptotic genes, we demonstrate that mechanical stress-induced apoptosis occurs via the mitochondrial pathway. Our results provide detailed, quantitative insight into the role of micro-environmental mechanical stress in tumor spheroid growth dynamics, and suggest how tumors grow in confined locations where the level of solid stress becomes high. An important implication is that apoptosis via the mitochondrial pathway, induced by compressive stress, may be involved in tumor dormancy, in which tumor growth is held in check by a balance of apoptosis and proliferation.
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影响因子：
4.8
作者：
Zhou, Q;Snipas, S;Salvesen, GS
通讯作者：
Salvesen, GS
影响因子：
46.9
作者：
Helmlinger, G;Netti, PA;Jain, RK
通讯作者：
Jain, RK
肿瘤生长的动力学。
影响因子：
8.8
作者：
LAIRD, A K
通讯作者：
LAIRD, A K
影响因子：
7.3
作者：
EAVES, G
通讯作者：
EAVES, G
影响因子：
82.9
作者：
HOLMGREN, L;OREILLY, MS;FOLKMAN, J
通讯作者：
FOLKMAN, J