A narrative review of circulating tumor cells clusters: A key morphology of cancer cells in circulation promote hematogenous metastasis

Abstract

Circulating tumor cells (CTCs) that survive in the blood are playing an important role in the metastasis process of tumor. In addition, they have become a tool for tumor diagnosis, prognosis and recurrence monitoring. CTCs can exist in the blood as individual cells or as clumps of aggregated cells. In recent years, more and more studies have shown that clustered CTCs have stronger metastasis ability compared to single CTCs. With the deepening of studies, scholars have found that cancer cells can combine not only with each other, but also with non-tumor cells present in the blood, such as neutrophils, platelets, etc. At the same time, it was confirmed that non-tumor cells bound to CTCs maintain the survival and proliferation of cancer cells through a variety of ways, thus promoting the occurrence and development of tumor. In this review, we collected information on tumorigenesis induced by CTC clusters to make a summary and a discussion about them. Although CTC clusters have recently been considered as a key role in the transition process, many characteristics of them remain to be deeply explored. A detailed understanding of their vulnerability can prospectively pave the way for new inhibitors for metastasis.

Keywords: CTC cluster; circulating tumor cells; hematogenous metastasis; heterotypic type; homotypic type.

Figure 1

Metastasis of circulating tumor cells (CTCs) and CTC clusters Cancer cells fall off from the primary sites and enter the blood circulation. They can exist by the form of single cells or aggregated cell clusters. There are various factors in peripheral blood (PB) that are not conducive to the survival of cancer cells. Cancer cells will be attacked by fluid shear stress and immune system, and signal CTCs also induce apoptosis due to the loss of intercellular contact. Finally, they reach distant organs and continue to spread, and CTC clusters have stronger metastatic potential compared to signal CTCs.

Figure 2

Characteristics of homotypic circulating tumor cell (CTC) clusters After CTCs gather into CTCT clusters, they will create favorable living conditions conducive to their own survival in a variety of ways. Cancer cells maintain important intercellular junction molecules, such as CD44, ICAM1, plakoglobin and so on, to resist anoikis. The aggregation of cancer cells can lead to hypomethylation of transcription factor binding sites related to stem cells and proliferation. CTC clusters keep hypoxic environment and the expression of PD–L1 increases significantly. They evade immune surveillance by these two ways. In addition, CTC clusters have a mixed epithelial/mesenchymal phenotype. When encountering small diameter vessels, they will be arranged in chains. All these characteristics lead to the stronger metastatic ability of CTC clusters.

Figure 3

Formation of heterotypic circulating tumor cell (CTC) clusters. In the blood circulation, CTCs forms cell clusters with other non–tumor cells, such as neutrophils, platelets, macrophages, MDSCs and CAFs. These non–tumor cells can combine with cancer cells through key adhesion molecules to prevent apoptosis, and maintain the survival of CTCs in vivo through multiple ways. They can release some cytokines to strengthen the invasion and proliferation of cancer cells, and be more resistant to fluid shear stress (FSS). In addition, cancer cells also release related substances to act on non–tumor cells and recruit them to adhere to CTCs. In short, they jointly promote the occurrence and development of cancer in the blood system.