The biology of circulating tumor cells

Abstract

Metastasis is a biologically complex process consisting of numerous stochastic events which may tremendously differ across various cancer types. Circulating tumor cells (CTCs) are cells that are shed from primary tumors and metastatic deposits into the blood stream. CTCs bear a tremendous potential to improve our understanding of steps involved in the metastatic cascade, starting from intravasation of tumor cells into the circulation until the formation of clinically detectable metastasis. These efforts were propelled by novel high-resolution approaches to dissect the genomes and transcriptomes of CTCs. Furthermore, capturing of viable CTCs has paved the way for innovative culturing technologies to study fundamental characteristics of CTCs such as invasiveness, their kinetics and responses to selection barriers, such as given therapies. Hence the study of CTCs is not only instrumental as a basic research tool, but also allows the serial monitoring of tumor genotypes and may therefore provide predictive and prognostic biomarkers for clinicians. Here, we review how CTCs have contributed to significant insights into the metastatic process and how they may be utilized in clinical practice.

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

“…While their repressive activity on several epithelial genes has been shown to involve a direct binding to promoter regions, their ability to induce mesenchymal genes rather implicates indirect and often unknown mechanisms (6)(7)(8)(9). Closely linking EMT to CTC, the expression of EMT mediators has been detected in CTCs in animal models (2,10) and in subpopulations of CTCs isolated from cancer patients including breast cancer patients, where they associate with poor clinical parameters and to the particularly aggressive "triple-negative breast cancer" (TNBC) subtype (5,11,12). It has thus been suggested that CTCs expressing EMT features could represent a premetastatic population, socalled metastasis-initiating cells (MIC).…”

“…EMT indeed provides epithelial tumor cells with enhanced migratory, invasive, and survival abilities that participate in the liberation of CTCs into the circulation (1,2,4,5). A variety of EMT-inducing extracellular signals and signaling pathways have been shown to converge on the expression of EMT transcription factors including the Snail and ZEB families, Twist, and E47 (6)(7)(8).…”

“…The contribution of epithelial-to-mesenchymal transitions (EMT) to CTCs biology has generated much interest (1)(2)(3)(4)(5). EMT indeed provides epithelial tumor cells with enhanced migratory, invasive, and survival abilities that participate in the liberation of CTCs into the circulation (1,2,4,5).…”

Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy

“…However, new important insights into the biology of CTCs combined with various innovative technologies have been reported ( 31 ), and technical platforms for combined enrichment, detection, and characterization of CTCs are on the horizon.…”

Circulating Tumor Cells: A Review of Non–EpCAM-Based Approaches for Cell Enrichment and Isolation

“…CTCs also have potential for use in evaluating drug resistance mechanisms and may have utility in estimation of the risk of metastatic relapse and progression. Unlike the characterization of primary tumors, which provides only a static view at the time of diagnosis, analyzing CTCs may improve understanding of the different steps involved in the metastatic cascade, from invasion of tumor cells into the bloodstream to the formation of clinically detectable metastases (7 ).…”