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通过机械敏感的Rho-ROCK信号通路,转移性卵巢癌细胞在柔软基质上的恶性程度会增加。

The malignancy of metastatic ovarian cancer cells is increased on soft matrices through a mechanosensitive Rho-ROCK pathway.

作者信息

McGrail Daniel J, Kieu Quang Minh N, Dawson Michelle R

机构信息

School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.

School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA The Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA

出版信息

J Cell Sci. 2014 Jun 15;127(Pt 12):2621-6. doi: 10.1242/jcs.144378. Epub 2014 Apr 16.

Abstract

Although current treatments for localized ovarian cancer are highly effective, this cancer still remains the most lethal gynecological malignancy, largely owing to the fact that it is often detected only after tumor cells leave the primary tumor. Clinicians have long noted a clear predilection for ovarian cancer to metastasize to the soft omentum. Here, we show that this tropism is due not only to chemical signals but also mechanical cues. Metastatic ovarian cancer cells (OCCs) preferentially adhere to soft microenvironments and display an enhanced malignant phenotype, including increased migration, proliferation and chemoresistance. To understand the cell-matrix interactions that are used to sense the substrate rigidity, we utilized traction force microscopy (TFM) and found that, on soft substrates, human OCCs increased both the magnitude of traction forces as well as their degree of polarization. After culture on soft substrates, cells underwent morphological elongation characteristic of epithelial-to-mesenchymal transition (EMT), which was confirmed by molecular analysis. Consistent with the idea that mechanical cues are a key determinant in the spread of ovarian cancer, the observed mechanosensitivity was greatly decreased in less-metastatic OCCs. Finally, we demonstrate that this mechanical tropism is governed through a Rho-ROCK signaling pathway.

摘要

尽管目前针对局限性卵巢癌的治疗方法非常有效,但这种癌症仍然是最致命的妇科恶性肿瘤,这主要是因为它通常在肿瘤细胞离开原发肿瘤后才被检测到。临床医生早就注意到卵巢癌明显倾向于转移到柔软的大网膜。在这里,我们表明这种嗜性不仅归因于化学信号,还归因于机械线索。转移性卵巢癌细胞(OCC)优先粘附于柔软的微环境,并表现出增强的恶性表型,包括迁移、增殖和化疗耐药性增加。为了了解用于感知底物硬度的细胞-基质相互作用,我们利用牵引力显微镜(TFM)发现,在柔软的底物上,人OCC增加了牵引力的大小及其极化程度。在柔软底物上培养后,细胞经历了上皮-间质转化(EMT)特征性的形态伸长,这通过分子分析得到证实。与机械线索是卵巢癌扩散的关键决定因素这一观点一致,在转移较少的OCC中观察到的机械敏感性大大降低。最后,我们证明这种机械嗜性是通过Rho-ROCK信号通路调控的。

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