The study of circulating tumor cells (CTCs) has been largely confounded by the low number of these cells in the blood stream amid billions of other cells. To overcome this challenge numerous methodologies for CTC isolation have been described. Photoacoustic flow cytometry (Nedosekin et al., 2013), dielectrophoresis array (Maltoni et al., 2015) and microfluidics (Warkiani et al., 2015) are among the most sophisticated of these methodologies. However, methods based on immunecapture and immunestaining are still the more frequently utilized, with CellSearch® remaining the most commonly used method to date and the only US FDA approved (Alix-Panabieres and Pantel, 2014). Irrespective of the method of isolation and detection used most studies fail to detect CTCs in the numerous cases. This is particularly unexpected in studies of cases with metastatic disease, in which patients with substantial tumor burden have been found with undetectable CTC levels. The lack of detection of CTCs is usually attributed to limitations on the methodologies utilized such as the conditions of collection and treatment of the samples, the cell size, clustering of CTCs and the high phenotypic plasticity of cancer cells. One common concern is the lack of epithelial markers in disseminating carcinoma cells that experienced epithelial-to-mesenchymal transition (Rao et al., 2005). Moreover, the low number of CTCs usually detected, 1–10 cells in 7.5 ml of blood, is susceptible to stochastic distribution in the sampled blood.
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