Lee Pilhwa, Wolgemuth Charles W
Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Department of Physics and MCB, University of Arizona, Tucson, Arizona.
Biophys J. 2016 Jul 12;111(1):256-66. doi: 10.1016/j.bpj.2016.05.046.
Whether a tumor is metastatic is one of the most significant factors that influence the prognosis for a cancer patient. The transition from a nonmetastatic tumor to a metastatic one is accompanied by a number of genetic and proteomic changes within the tumor cells. These protein-level changes conspire to produce behavioral changes in the cells: cells that had been relatively stationary begin to move, often as a group. In this study we ask the question of what cell-level biophysical changes are sufficient to initiate evasion away from an otherwise static tumor. We use a mathematical model developed to describe the biophysics of epithelial tissue to explore this problem. The model is first validated against in vitro wound healing experiments with cancer cell lines. Then we simulate the behavior of a group of mutated cells within a sea of healthy tissue. We find that moderate increases in adhesion between the cell and extracellular matrix (ECM) accompanied by a decrease in cell-cell adhesion and/or Rho family of small GTPase activation can cause a group of cells to break free from a tumor and spontaneously migrate. This result may explain why some metastatic cells have been observed to upregulate integrin, downregulate cadherin, and activate Rho family signaling.
肿瘤是否发生转移是影响癌症患者预后的最重要因素之一。肿瘤从非转移性转变为转移性的过程伴随着肿瘤细胞内一系列基因和蛋白质组学的变化。这些蛋白质水平的变化共同导致细胞行为的改变：原本相对静止的细胞开始移动，通常是成群移动。在本研究中，我们提出一个问题：哪些细胞水平的生物物理变化足以引发细胞从原本静止的肿瘤中逃逸。我们使用一个为描述上皮组织生物物理学而开发的数学模型来探索这个问题。该模型首先通过癌细胞系的体外伤口愈合实验进行验证。然后我们模拟一群突变细胞在健康组织海洋中的行为。我们发现，细胞与细胞外基质（ECM）之间的黏附适度增加，同时细胞间黏附减少和/或小GTPase Rho家族激活，可导致一群细胞从肿瘤中脱离并自发迁移。这一结果可能解释了为什么观察到一些转移细胞会上调整合素、下调钙黏蛋白并激活Rho家族信号。
