Characterization of circulating tumor cells as a reflection of the tumor heterogeneity: myth or reality?

•Circulating tumor cells are highly heterogeneous in a spatial and temporal manner.•Circulating-tumor cells are a reflection of the tumor tissue at a fixed time.•Circulating-tumor cells exhibit a dynamic phenotype and genomic profile.•Circulating-tumor cells are the photograph of tumor evolution.•Genomic and downstream RNA analyses of CTCs are promising to monitor the therapeutic response. The current main goal of diagnostic medicine is to detect crucial events in ‘infinitely’ small samples. The key question now is how to determine whether the rare cell events isolated and characterized from these samples reliably reflect the disease and heterogeneity of the tumor. In this review, we provide a short overview of the most recent methods developed for the isolation and characterization of rare cell events in clinical practice, with a specific focus on circulating tumor cells. We discuss the biological value to studying these cells at the single cell level and how these rare cell events can reflect tumor heterogeneity. The potential biomedical applications are also critically discussed in light of precision medicine.