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王璟, 杨根, 刘峰

Application of physics in the study of cell polarity during tumor cell migration

Wang Jing, Yang Gen, Liu Feng
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  • 肿瘤细胞和所处微环境的物理性质, 以及它们之间的相互物理作用对于肿瘤的产生、发展与转移都有极大的影响, 这使得从物理学角度探索肿瘤研究成为了必然趋势. 肿瘤转移是癌症致死的最大因素, 而肿瘤细胞迁移中的极化是肿瘤转移的重要一步. 本文总结了物理学实验和模型在揭示细胞迁移和极化机理方面的贡献. 实验上应用最新的微流控芯片技术与表面微模型化技术等手段, 研究空间维度、黏附行为、机械力等物理信号对于细胞极性的建立与保持以及细胞迁移行为的影响后, 发现物理信号与生化反应之间的相互耦合对于细胞迁移有着至关重要的作用; 理论上基于扩散反应方程, 已经建立了一系列表征细胞极化的模型. 今后的研究将结合物理实验建立肿瘤细胞迁移中的极化模型, 进而发展针对肿瘤细胞感知物理信号的新的治疗肿瘤转移方法.
    Investigation of tumors from a physics perspective has attracted more and more attention since the initiation, development, and metastasis of tumors are strongly influenced by the physical interactions between the tumor cells and their microenvironments. Since tumor metastasis accounts for more than 90% of cancer-associated death, one of the focuses is to understand its underlying mechanism, especially how tumor cells polarize during their migration. Cell polarization directs tumor-cell migration in response to a spatial stimulus, e.g., the gradient of chemokine or oxygen molecules. It forms the front and back edges of cells by estiblishing asymmetric distributions of cell polarity proteins such as the Rho family GTPases and organelles such as Golgi. This paper reviews how the experimental and theoretical studies combining physics with biology reveal the underlying mechanisms of cell migration and cell polarity. Experimental results demonstrate that the physics clues including extracellular matrix's mechanical properties, dimensionality, and topography are strongly coupled with the biochemical reactions to establish and maintain the cell polarity and direct cell migration. The cell migration mode in a more physiological three-dimensional (3D) matrix is different from that in a two-dimensional(2D) system. Moreover, the membrane tension is suggested to maitain cell polarity by inhibiting polarization processes outside the front edge. On the other hand, a series of reaction diffusion models have been developed to characterize cell polarity. Representative examples inculding Turing-type model, local-excitation and global-inhibition (LEGI) model, and wave-pinning model can capture certain features of cell polarization, however none of them takes the physical factors, such as the membrane tension, into account hence fails to explain previous published experimental results about the membrane tension with cell polarization. To further improve our understanding of the mechanism of cell polarity, in the future study it is experimentally important to estiblish 3D tumor systems and study the gene regulation network that can control cell polariztion by advanced microscope; theroetically it is of importance to build mathematical models for the chemical reaction diffusion systems coupled with the mechanical factors such as membarne tension. These studies will reveal the molecular mechanism of cell polarization and cell migration under a more physiological relevant condition. They may also help us understand how the higher deformation ability of cancer stem cells provides the higher migration capability compared with the normal cancer cells. Ultimately, they will facilitate developing new therapeutic strategy against tumor metastasis by targeting the signaling of tumor cells in response of physical stimuli.
      • 基金项目:国家自然科学基金(批准号: 11434001)和科技部重大仪器专项(批准号: 2012YQ030142)资助的课题.
      • Funds:Project supported by the National Natural Science Foundation of China (Grant No. 11434001), and the Deparment of Science of China (Grant No. 2012YQ030142).
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    出版历程
    • 收稿日期:2014-12-02
    • 修回日期:2015-02-06
    • 刊出日期:2015-03-05

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