How circulating tumor cluster biology contributes to the metastatic cascade: from invasion to dissemination and dormancy

Abstract

Circulating tumor cells (CTCs) are known to be prognostic for metastatic relapse and are detected in patients as solitary cells or cell clusters. Circulating tumor cell clusters (CTC clusters) have been observed clinically for decades and are of significantly higher metastatic potential compared to solitary CTCs. Recent studies suggest distinct differences in CTC cluster biology regarding invasion and survival in circulation. However, differences regarding dissemination, dormancy, and reawakening require more investigations compared to solitary CTCs. Here, we review the current state of CTC cluster research and consider their clinical significance. In addition, we discuss the concept of collective invasion by CTC clusters and molecular evidence as to how cluster survival in circulation compares to that of solitary CTCs. Molecular differences between solitary and clustered CTCs during dormancy and reawakening programs will also be discussed. We also highlight future directions to advance our current understanding of CTC cluster biology.

Keywords: Cancer dissemination; Cancer dormancy; Circulating tumor cells; Circulating tumor clusters; Metastasis; Tumor microenvironment.

Fig. 1

Distinct advantages of CTC clusters during the metastatic cascade. (1) Intravasation of cancer cells as solitary cells or clusters. (2) CTC clusters are bigger in size, so they travel slower and closer to the endothelium allowing for quicker extravasation. (3) CTC clusters are more resistant to shear stress compared to solitary CTCs through cellular (recruiting platelets) and molecular differences (reshaping cortical dynamics of myosin). (4) CTC clusters are structurally dynamic and can adapt their morphology in tiny capillaries. (5) CTC clusters can bind to other cells like neutrophils enabling extravasation through neutrophil extracellular traps