Department of Biological Sciences, Wayne State University, Detroit, MI 48202, USA.
J Cell Biochem. 2011 Nov;112(11):3151-8. doi: 10.1002/jcb.23241.
The process of metastasis requires a metastatic cancer cell to invade a variety of micro-environments of variable stiffnesses. Unlike metastatic cells, normal cell function and viability is dependent on the stiffness of the environment and used as a cue to maintain cell health and proper tissue organization. In this study we have asked if metastatic cells can ignore the parameter of stiffness and if this ability is gradually acquired and if so, through what mechanism. Using a panel of mouse mammary tumor cells derived from the same parental tumor, but possessing different metastatic abilities, we cultured the cells on hard and soft substrates conjugated with collagen or fibronectin. Normal and non-metastatic tumor cells responded to changes in stiffness on fibronectin, but not collagen. However, the more metastatic cells ignored the change in stiffness on fibronectin-coated substrates. This lack of response on fibronectin correlated with a change in the expression level of the α3 integrin subunit, activation of the β1 subunit, and phosphorylation of FAKpY397. We conclude that through fibronectin, changes in the activation and tethering of the beta-1 integrin provides a mechanism for metastatic cells to disregard changes in compliance to survive and navigate in environments of different stiffness.
转移的过程需要转移性癌细胞侵入各种硬度不同的微环境。与转移性细胞不同，正常细胞的功能和活力依赖于环境的硬度，并将其作为维持细胞健康和组织正常的线索。在这项研究中，我们询问转移性细胞是否可以忽略硬度这一参数，以及这种能力是否是逐渐获得的，如果是，通过什么机制。我们使用一组源自同一亲本肿瘤但具有不同转移能力的小鼠乳腺肿瘤细胞，在与胶原蛋白或纤维连接蛋白结合的硬基底和软基底上培养这些细胞。正常和非转移性肿瘤细胞对纤维连接蛋白上硬度的变化有反应，但对胶原蛋白没有反应。然而，更具转移性的细胞忽略了纤维连接蛋白涂层基底上的硬度变化。这种在纤维连接蛋白上缺乏反应与α3 整合素亚基表达水平的变化、β1 亚基的激活以及 FAKpY397 的磷酸化有关。我们得出结论，通过纤维连接蛋白，β1 整合素的激活和连接的变化为转移性细胞提供了一种机制，使其能够无视顺应性的变化，从而在不同硬度的环境中存活和迁移。
