Metastasis is the main cause of cancer-related deaths. The formation and growth of metastasis is a multistep process. Tumor cells extravasating in the secondary organ are in contact with a new microenvironment and a new extracellular matrix (ECM), called the metastatic niche. Some components of the ECM, such as periostin, can induce tumor cell growth in macrometastasis. In contrast, other components, such as Thrombospondin 1 (TSP-1), can maintain isolated cells in a dormant state. During dormancy, intracellular signaling activation, such as p38, maintains tumor cells arrested in the cell-cycle G0 phase for years. At any moment, stress can induce ECM modifications and binding to their specific receptors (mainly integrins) and reactivate dormant tumor cell growth in macrometastasis. In this review, we describe the tumor microenvironment of the different niches implicated in tumor cell dormancy. The role of ECM components and their associated receptors and intracellular signaling in the reactivation of dormant tumor cells in macrometastasis will be emphasized. We also present the different methodologies and experimental approaches used to study tumor cell dormancy. Finally, we discuss the current and future treatment strategies to avoid late metastasis relapse in patients.
转移是癌症相关死亡的主要原因。转移灶的形成与生长是一个多步骤过程。在次级器官中渗出的肿瘤细胞会接触到一个全新的微环境及细胞外基质（ECM），即转移生态位。ECM中的某些成分（如骨膜蛋白）能够促进大转移灶中肿瘤细胞的生长。相反，其他成分如血小板反应蛋白1（TSP-1）则可使孤立细胞维持在休眠状态。在休眠期间，细胞内信号通路（如p38）的激活可使肿瘤细胞停滞于细胞周期G0期长达数年。任何应激刺激都可能诱导ECM修饰，并通过与其特异性受体（主要为整合素）结合，重新激活大转移灶中休眠肿瘤细胞的生长。本综述将阐述与肿瘤细胞休眠相关的不同生态位中的肿瘤微环境，重点探讨ECM成分及其相关受体与细胞内信号通路在大转移灶休眠肿瘤细胞再激活中的作用。同时，我们将介绍用于研究肿瘤细胞休眠的不同方法学与实验策略。最后，讨论当前及未来避免患者晚期转移复发的治疗策略。
Implication of the Extracellular Matrix in Metastatic Tumor Cell Dormancy
肿瘤(癌症)患者之家