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Nat Cell Biol & J Immunol:癌细胞对机械力的反应可促进癌症转移

来源:生物谷 2014-04-11 00:03

2014年4月11日 讯 /生物谷BIOON/ --近日,来自北卡罗来纳大学莱恩伯格综合癌症中心等处的研究人员通过研究揭示了癌细胞对于机械操作产生反应的分子机制,这对于揭示癌症及其它疾病发病的原因非常关键,相关研究成果刊登在了国际杂志Nature Cell BiologyThe Journal of Immunology上。

研究者Burridge表示,在癌症中机械力非常重要,因为肿瘤细胞可以产生机械力并且随着机械力而扩散到其它组织中。刊登在Nature Cell Biology上的研究论文中,研究者Christophe Guilluy和其同时通过研究揭示,癌细胞的细胞核可以对机械力产生反应,利用2.8-4微米,包被有可结合细胞核外表面蛋白质的金属颗粒,研究者就可以产生一定的磁性脉冲,在每一个脉冲下癌细胞的细胞核都会慢慢移动一部分,最后细胞核就会僵硬来应对机械力。

此前研究中研究者认为细胞仅会对来自细胞表面和细胞核周围细胞骨架的物理操作产生反应,Burridge表示,这项研究中我们首次发现离体的细胞器也可以对机械力产生反应,这对于研究细胞生物学将是一大进步。

而刊登在国际杂志the Journal of Immunology上的研究论文中,研究者Elizabeth Lessey-Morillon检测了机体血管中细胞变硬以及松弛用以促进免疫细胞顺利通过血管的方式,他们认为癌症转移细胞可以模拟白细胞随血液流动的情况。

研究者利用磁珠吸附到血管中的内皮细胞来进行研究,结果发现对细胞的作用力可以促进其变硬,这种反应可以激活由蛋白质RhoA和LARG介导的信号路径。当阻断该路径后,细胞的僵硬程度就会减缓,由于该途径在癌症转移中扮演着重要角色,因此这就为后期开发治疗癌症的新型靶向疗法提供了一定的研究依据。(生物谷Bioon.com)

Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus

Christophe Guilluy, Lukas D. Osborne, Laurianne Van Landeghem, Lisa Sharek, Richard Superfine, Rafael Garcia-Mata & Keith Burridge

Mechanical forces influence many aspects of cell behaviour. Forces are detected and transduced into biochemical signals by force-bearing molecular elements located at the cell surface, in adhesion complexes or in cytoskeletal structures1. The nucleus is physically connected to the cell surface through the cytoskeleton and the linker of nucleoskeleton and cytoskeleton (LINC) complex, allowing rapid mechanical stress transmission from adhesions to the nucleus2. Although it has been demonstrated that nuclei experience force3, the direct effect of force on the nucleus is not known. Here we show that isolated nuclei are able to respond to force by adjusting their stiffness to resist the applied tension. Using magnetic tweezers, we found that applying force on nesprin-1 triggers nuclear stiffening that does not involve chromatin or nuclear actin, but requires an intact nuclear lamina and emerin, a protein of the inner nuclear membrane. Emerin becomes tyrosine phosphorylated in response to force and mediates the nuclear mechanical response to tension. Our results demonstrate that mechanotransduction is not restricted to cell surface receptors and adhesions but can occur in the nucleus.

doi:10.4049/​jimmunol.1302525
The RhoA Guanine Nucleotide Exchange Factor, LARG, Mediates ICAM-1–Dependent Mechanotransduction in Endothelial Cells To Stimulate Transendothelial Migration

Elizabeth C. Lessey-Morillon*, Lukas D. Osborne†, Elizabeth Monaghan-Benson*, Christophe Guilluy*, E. Timothy O’Brien†, Richard Superfine† and Keith Burridge*,‡§

RhoA-mediated cytoskeletal rearrangements in endothelial cells (ECs) play an active role in leukocyte transendothelial cell migration (TEM), a normal physiological process in which leukocytes cross the endothelium to enter the underlying tissue. Although much has been learned about RhoA signaling pathways downstream from ICAM-1 in ECs, little is known about the consequences of the tractional forces that leukocytes generate on ECs as they migrate over the surface before TEM. We have found that after applying mechanical forces to ICAM-1 clusters, there is an increase in cellular stiffening and enhanced RhoA signaling compared with ICAM-1 clustering alone. We have identified that leukemia-associated Rho guanine nucleotide exchange factor (LARG), also known as Rho GEF 12 (ARHGEF12) acts downstream of clustered ICAM-1 to increase RhoA activity, and that this pathway is further enhanced by mechanical force on ICAM-1. Depletion of LARG decreases leukocyte crawling and inhibits TEM. To our knowledge, this is the first report of endothelial LARG regulating leukocyte behavior and EC stiffening in response to tractional forces generated by leukocytes.

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