Implication of the Extracellular Matrix in Metastatic Tumor Cell Dormancy

Abstract

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.

Keywords: dormant tumor cell therapy; extracellular matrix; metastatic niche; tumor cell dormancy; tumor cell reactivation.

Figure 1

Cell composition of the endosteal and perivascular niches. The perivascular and endosteal niches are found in bone marrow, while the perivascular niche seems to be specific for the lung, liver, and brain. However, a large heterogeneity exists between endothelial cells from different organs [47]. Some factors involved in tumor cell dormancy or reactivation are presented. Figure created in BioRender. Redouté-Timonnier, C. (2024) https://BioRender.com/q13u172 (accessed on 1 December 2024).

Figure 2

ECM components implicated in the maintenance of dormant tumor cells (A) or in the reactivation of dormant tumor cells (B). Figure created in BioRender. Redouté-Timonnier, C. (2024) https://BioRender.com/c31p125 (accessed on 1 December 2024).