Liquid biopsy. In cancer, the liquid biopsy term describes the minimally invasive analysis of analytes released by or related to the primary and/or metastatic tumors. These analytes can be found in any physiological or pathological body liquid (e.g., blood, ascites) [20]. This is an extension of the tissue biopsy, and many cancer biomarkers of clinical utility can be found also in liquid biopsy samples. Moreover, new biomarkers can be easily identified in liquid biopsy analytes because they are thought to represent more accurately cancer progression (i.e., the metastatic cascade), and cancer heterogeneity than tissue biopsy samples [21]. Some examples of liquid biopsy analytes are: circulating tumor cells (CTCs), circulating-free nucleic acids (cfNA: DNA or RNA), extracellular vesicles (EVs), tumor-educated platelets, and their possible combination with other protein tumor makers [22]. Although all these analytes have biological significance during the metastatic cascade and provide useful clinical information, currently, the most studied analytes are CTCs and cfNA. As CTCs are the main drivers of the metastatic cascade, it is reasonable to suggest that the biological cycles might influence their biological behavior, as observed in cancer. Consequently, these observations have implications for the current and future clinical applications of CTCs as liquid biopsy
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