Circulating tumor cells: biology and clinical significance

Abstract

Circulating tumor cells (CTCs) are tumor cells that have sloughed off the primary tumor and extravasate into and circulate in the blood. Understanding of the metastatic cascade of CTCs has tremendous potential for the identification of targets against cancer metastasis. Detecting these very rare CTCs among the massive blood cells is challenging. However, emerging technologies for CTCs detection have profoundly contributed to deepening investigation into the biology of CTCs and have facilitated their clinical application. Current technologies for the detection of CTCs are summarized herein, together with their advantages and disadvantages. The detection of CTCs is usually dependent on molecular markers, with the epithelial cell adhesion molecule being the most widely used, although molecular markers vary between different types of cancer. Properties associated with epithelial-to-mesenchymal transition and stemness have been identified in CTCs, indicating their increased metastatic capacity. Only a small proportion of CTCs can survive and eventually initiate metastases, suggesting that an interaction and modulation between CTCs and the hostile blood microenvironment is essential for CTC metastasis. Single-cell sequencing of CTCs has been extensively investigated, and has enabled researchers to reveal the genome and transcriptome of CTCs. Herein, we also review the clinical applications of CTCs, especially for monitoring response to cancer treatment and in evaluating prognosis. Hence, CTCs have and will continue to contribute to providing significant insights into metastatic processes and will open new avenues for useful clinical applications.

Fig. 1

The historical milestones of cancer metastasis research

Fig. 2

Multistep process of cancer metastasis. The complex metastatic process includes tumor cell invasion in the primary site, intravasation into circulation, survival in the circulation as CTCs and interaction with blood cells, extravasation from the circulation, attachment to and colonization of the metastatic site. EMT: epithelial to mesenchymal transition, CAF: cancer-associated fibroblast, TAM: tumor-associated macrophage

Fig. 3

CTCs in the blood microenvironment, and their interaction with neutrophils, platelets, CAFs and TAMs. CAFs: cancer-associated fibroblasts, TAMs: tumor-associated macrophages

Fig. 4

Overview of the CTC isolation and detection, characterizations, and clinical applications