Efficient extravasation of tumor-repopulating cells depends on cell deformability.
Efficient extravasation of tumor-repopulating cells depends on cell deformability.
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DOI：
10.1038/srep19304
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发表时间：
2016-01-20
影响因子：
4.6
通讯作者：
Wang N
中科院分区：
文献类型：
--
作者：
Chen J;Zhou W;Jia Q;Chen J;Zhang S;Yao W;Wei F;Zhang Y;Yang F;Huang W;Zhang Y;Zhang H;Zhang Y;Huang B;Zhang Z;Jia H;Wang N
癌症转移是癌症进展中最致命的阶段。尽管在过去的几十年里做出了巨大的努力，但为什么只有极小部分的癌细胞能够产生微转移和转移定植，仍然难以捉摸。最近，我们发现肿瘤再生细胞（TRC）是一种高度致瘤性的小鼠黑色素瘤细胞亚群，可以通过在 3D 软纤维蛋白凝胶中培养和生长来选择。在这里，我们表明，当注射到 Tg（fli1:EGFP 或 kdrl:mCherry）斑马鱼受精后 2 天（dpf）胚胎的卵黄中时，TRC 比在硬质塑料上生长的对照黑色素瘤细胞更能有效地在各个次生位点存活和生长，从而产生微转移和转移定植。 TRCs的转移依赖于自我更新基因Sox2的存在，沉默Sox2会导致TRC转移的抑制。次要部位 TRC 的高分辨率 3D 共焦图像表明，TRC 的外渗和微转移形成比对照细胞更有效。值得注意的是，TRC 在体内的有效外渗和体外的迁移是由 TRC 的变形能力决定的，这是低 Cdc42 和高 Sox2 的结果。我们的研究结果表明，肿瘤细胞变形性是控制转移过程中外渗动力学的关键因素。
Cancer metastasis is the most deadly stage in cancer progression. Despite significant efforts over the past decades, it remains elusive why only a very small fraction of cancer cells is able to generate micrometastasis and metastatic colonization. Recently we have shown that tumor-repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, can be selected by being cultured and grown in 3D soft fibrin gels. Here we show that when injected into the yolk of a 2 day-post-fertilization (dpf) embryo of Tg (fli1:EGFP or kdrl:mCherry) zebrafish, TRCs are much more efficient in surviving and growing at various secondary sites to generate micrometastasis and metastatic colonization than control melanoma cells that are grown on rigid plastic. The metastasis of TRCs is dependent on the presence of Sox2, a self-renewal gene, and silencing Sox2 leads to the inhibition of TRC metastasis. High-resolution of 3D confocal images of the TRCs at the secondary sites show that extravasation and formation of micrometastases by TRCs are more efficient than by the control cells. Remarkably, efficient extravasation of TRCs in vivo and transmigration in vitro are determined by TRC deformability, as a result of low Cdc42 and high Sox2. Our findings suggest that tumor cell deformability is a key factor in controlling extravasation dynamics during metastasis.