Department of Chemical Engineering, University of Massachusetts, Amherst, Amherst, MA 01003, USA.
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, GA 30332, USA.
Sci Adv. 2020 Mar 11;6(11):eaaz4157. doi: 10.1126/sciadv.aaz4157. eCollection 2020 Mar.
Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, nonproliferative state before reactivation and outgrowth. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system with carefully controlled ECM substrates to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle-arrested, and actively proliferating cells. Cell populations capable of entering dormancy formed an organized, fibrillar fibronectin matrix via αβ and αβ integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation, and cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. We propose this approach as a useful, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation.
肿瘤可以经历长时间的休眠，癌细胞在重新激活和生长之前进入一种主要静止、非增殖状态。为了了解细胞外基质 (ECM) 在调节肿瘤休眠中的作用，我们创建了一个具有精心控制的 ECM 底物的体外细胞培养系统，通过实时成像观察进入和退出休眠。我们发现，能够存活进入长期休眠的细胞群体是异质的，包含静止、细胞周期停滞和活跃增殖的细胞。能够进入休眠的细胞群体通过 αβ 和 αβ 整联蛋白黏附、ROCK 生成的张力和 TGFβ2 刺激形成有组织的纤维连接蛋白纤维基质，休眠后癌症细胞的生长需要 MMP-2 介导的纤维连接蛋白降解。我们提出这种方法是一种有用的、体外研究调控休眠的重要因素的方法，我们在这里用它来阐明纤维连接蛋白沉积和 MMP 激活的作用。
