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

Abstract

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.