Clinical and biological significance of circulating tumor cells in cancer

Abstract

During the process of metastasis, which is the leading cause of cancer-related death, cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize, eventually leading to the formation of metastatic tumors. The migrating tumor cells in circulation, e.g., those found in peripheral blood (PB) or bone marrow (BM), are called circulating tumor cells (CTCs). CTCs in the BM are generally called disseminated tumor cells (DTCs). Many studies have reported the detection and characterization of CTCs to facilitate early diagnosis of relapse or metastasis and improve early detection and appropriate treatment decisions. Initially, epithelial markers, such as EpCAM and cytokeratins (CKs), identified using immunocytochemistry or reverse transcription polymerase chain reaction (RT-PCR) were used to identify CTCs in PB or BM. Recently, however, other markers such as human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and immuno-checkpoint genes also have been examined to facilitate detection of CTCs with metastatic potential. Moreover, the epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs) have also received increasing attention as important CTC markers owing to their roles in the biological progression of metastasis. In addition to these markers, researchers have attempted to develop detection or capture techniques for CTCs. Notably, however, the establishment of metastasis requires cancer-host interactions. Markers from host cells, such as macrophages, mesenchymal stem cells, and bone marrow-derived cells, which constitute the premetastatic niche, may become novel biomarkers for predicting relapse or metastasis or monitoring the effects of treatment. Biological studies of CTCs are still emerging. However, recent technical innovations, such as next-generation sequencing, are being used more commonly and could help to clarify the mechanism of metastasis. Additionally, biological findings are gradually being accumulated, adding to our body of knowledge on CTCs. In this review, we will summarize recent approaches to detect or capture CTCs. Moreover, we will introduce recent studies of the clinical and biological importance of CTCs and host cells.

Keywords: Cancer stem cell; Circulating tumor cells; Epithelial markers; Epithelial-to-mesenchymal transition; Premetastatic niche.

Figure 1

Circulating biomarkers in tumor metastasis. Cancer cells dissociate from primary tumors, migrate to distal sites, and finally colonize at the premetastatic niche, where mesenchymal cells facilitate metastasis by communication between cancer cells and mesenchymal cells using intercellular messengers, such as exosomes.