Circulating Tumor Cells in Gastrointestinal Cancers: Current Status and Future Perspectives

Abstract

Circulating tumor cells (CTCs), which are now defined as the "break away" cancer cells that derive from primary- or metastatic-tumor sites and present in the bloodstream, are considered to be the precursors of metastases. Considering the key role of CTCs in cancer progression, researchers are committed to analyze them in the past decades and many technologies have been proposed for achieving CTCs isolation and characterization with highly sensitivity and specificity until now. On this basis, clinicians gradually realize the clinical values of CTCs' detection through various clinical studies. As a "liquid biopsy," CTCs' detection and measurement can supply important information for predicting patient's survival, monitoring of response/resistance, assessment of minimal residual disease, evaluating distant metastasis, and sometimes, customizing therapy choices. Nowadays, eliminating CTCs of the blood circulation has been regarded as a promising method to prevent tumor metastasis. However, research on CTCs still faces many challenges. Herein, we present an overview to discuss the current concept of CTCs, summarize the available techniques for CTCs detection, and provide an update on the clinical significance of CTCs in gastrointestinal malignancies, especially focus on gastric and colorectal cancer.

Keywords: circulating tumor cells; clinical application; colorectal cancer; detection; gastric cancer; identification.

Figure 1

Overview of technologies for circulating tumor cells (CTCs) capture, enrichment, and characterization. Immunoaffinity-based enrichment technologies capture CTC by positive or negative selection, typically using antibodies bound to the device surface or to magnetic beads. Positive selection is based on the specific targeting of CTCs epithelial biomarkers, whereas negative selection depletes hematopoietic cells by targeting cell-surface antigens not expressed in CTCs. Functionalized microfluidics platforms can combine the advantages of microfluidic and the characters of positive capture and negative enrichment. Biophysical methods are label-free technologies relying on cell size, shape, density, and electric charge differences between CTC and other blood constituents. Density gradient centrifugation relies in the separation of different cell populations based on their relative densities. Microfiltration consists on size-based cell separation using pores or three-dimensional geometries. Inertial focusing relies on the passive separation of cells by size, through the application of inertial forces that affect positioning within the flow channel in microfluidics devices. Electrophoresis separates cells based on their electrical signatures, using an electric field. The methods of CTCs characterization include immunocytochemistry (ICC)-based approaches and molecular assays. Of which, ICC-based approaches are consist of immunofluorescence and immunohistochemistry technology, and molecular assays are consist of fluorescent in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), genomic analysis, and RNA sequencing.

Figure 2

Overview of the CTCs detection technologies and the potential clinical applications of CTCs in gastric and colorectal cancer.