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Challenges in circulating tumour cell research

Abstract

During the past ten years, circulating tumour cells (CTCs) have received enormous attention as new biomarkers and the subject of basic research. Although CTCs are already used in numerous clinical trials, their clinical utility is still under investigation. Many issues regarding the detection and characterization of CTCs remain unknown. In this Opinion article, we propose a conceptual framework of CTC assays and point out current challenges of CTC research, which might structure this dynamic field of translational cancer research.

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Figure 1: Circulating tumour cell (CTC) enrichment technologies.
Figure 2: Circulating tumour cell (CTC) detection technologies.
Figure 3: Current concept of cellular and molecular characteristics of circulating tumour cells CTCs).

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Acknowledgements

C.A.-P. is supported by Grant “INCa-DGOS-Inserm 6045”, Institut National du Cancer (INCa) national grants; K.P. is supported by European Research Council Investigator Grant “DISSECT” (no. 269081); K.P. and C.A.-P. are both supported by the ERA-NET on Translational Cancer Research (TRANSCAN) grant “CTC-SCAN”.

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Correspondence to Klaus Pantel.

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C.A.P. received honoraria from Sanofi and grants from Janssen and Roche; K.P. received honoraria from Janssen, Alere and Gilupi.

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Glossary

BEAMing PCR

A combination of emulsion digital PCR and flow cytometry: beads, emulsions, amplification and magnetics (BEAMing) are combined to achieve the necessary level of sensitivity.

Cancer stem cells

Cancer cells with self-renewing capacity and the ability to create or sustain a tumour cell population.

Castration-resistant prostate cancer

(CRPC). Prostate cancer that no longer responds to androgen deprivation therapy.

CellSearch® system

US Food and Drug Administration (FDA)-cleared technology that allows a sensitive positive capture of CTCs by antibodies against epithelial cell adhesion molecule (EPCAM) coated with ferrofluids: tumour cells are identified by positive immunostaining for antibodies against cytokeratins (CK8, CK18 and CK19), negative immunostaining for the common leukocyte antigen CD45 to exclude leukocytes, and positive DAPI staining as a measure of nuclear integrity.

Clinical utility

The capacity to diagnose and to facilitate a decision to adopt or reject a therapeutic action: the risks and benefits result from test use.

Clinical validity

The predictive value of a test for a given clinical outcome (for example, in cancer, a primary tumour or metastasis will develop in a patient with a positive test): a test identifies the clinical status of a patient.

Dielectrophoresis

(DEP). A phenomenon in which a force is exerted on a dielectric particle when it is subjected to a non-uniform electric field. As biological cells have diverse dielectric properties, DEP can be used to manipulate, transport, separate and sort different types of particles (for example, circulating tumour cells).

Digital PCR

A refinement of conventional PCR methods that can be used to directly quantify and clonally amplify nucleic acids, including DNA, cDNA or RNA that occur at very low frequencies.

Epithelial-to-mesenchymal transition

(EMT). Conversion from an epithelial to a mesenchymal phenotype, which is a normal component of embryonic development. In carcinomas, this transformation results in altered cell morphology, the expression of mesenchymal proteins and increased invasiveness.

Leukapheresis

A process by which a large amount of blood is withdrawn from a vein, white blood cells and circulating tumour cells are selectively removed, and the remaining blood (red blood cells in platelet- and leukocyte-poor plasma) is transfused back into the donor.

Microfluidic devices

The integration of one or different laboratory functions on a single chip of only millimetres to a few square centimetres in size, in which extremely small fluid volumes (down to <picolitres) are handled.

Parallel progression

Tumour cells leave the primary tumour and home to secondary sites many years before the diagnosis and surgical resection of the primary tumour. These disseminated tumour cells can develop mutations that are independent from the mutational landscape of the primary tumour.

Photoacoustic flow cytometry

The irradiation of individual cells in blood and lymph flow with one or a few focused laser beams operating at different wavelengths, followed by the use of an ultrasound transducer attached to the skin to record laser-induced acoustic waves.

Tumour, node, metastasis cancer staging

(TNM cancer staging). A staging system for classifying cancers that was originally developed by the American Joint Committee on Cancer (AJCC) and that grades cancer by tumour, lymph node and metastatic status.

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Alix-Panabières, C., Pantel, K. Challenges in circulating tumour cell research. Nat Rev Cancer 14, 623–631 (2014). https://doi.org/10.1038/nrc3820

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