Abstract

Circulating Tumor Cells as Liquid Biopsy: Current State & Future Directions

Klaus Pantel, Professor and Founding Director, University Of Hamburg

Sensitive methods have been developed to capture circulating tumor cells (CTCs) in the peripheral blood at the single cell level (Pantel et al., Nature Rev Cancer 2008; Kang & Pantel, Cancer Cell 2013). CTCs are usually detected by immunostaining or RT-PCR assays, and more recently by the EPISPOT assay which measures the number of cells releasing/secreting tumor-associated marker proteins. Interestingly, detection of cell-free nucleic acids released by tumor cells into the blood might become an indirect way to detect micrometastatic disease (Schwarzenbach et al, Nature Rev Cancer 2011). At present, most CTC assays rely on epithelial markers and miss CTCs undergoing an epithelial-mesenchymal transition (EMT). New markers such as the actin bundling protein plastin-3 (Yokobori et al., Cancer Res. 2013) are not downregulated during EMT and not expressed in normal blood cells might overcome this important limitation and, therefore, increase the sensitivity of CTC assays. Recently, in vivo capture of CTCs with an antibody-coated wire placed into the peripheral arm vein has become feasible and allows now the “fishing” for CTCs from approx. 1.5 liters of blood within 30 minutes. CTC enumeration and characterization with certified systems provides reliable information on prognosis and may serve as liquid biopsy (Alix-Panabieres & Pantel, Clin. Chem. 2013; Pantel & Alix-Panabieres, Cancer Res., 2013). Interestingly, the subset of EpCAMlow, CD44high, CD47+, c-Met+ CTCs obtained from the peripheral blood of breast cancer patients might represent metastasis-initiator cells (Baccelli et al, Nature Biotech. 2013). Moreover, monitoring of CTCs before, during and after systemic therapy (e.g., chemotherapy, hormonal therapy, antibody therapy) might provide unique information for the future clinical management of the individual cancer patient. Besides CTCs the analysis of ctDNA and circulating microRNAs may provide complementary information as “liquid biopsy” (Pantel &