Circulating Tumor Cells—New Challenges Ahead

Abstract

The presence of circulating tumor cells (CTCs)2 was first described by Thomas Ashworth in 1869 (1). In 1889, Stephen Paget proposed in the first issue of The Lancet the “seed and soil” hypothesis, according to which “metastasis depends on cross-talk between selected cancer cells (the ‘seeds’) and specific organ microenvironments (the ‘soil’),” a hypothesis revisited many years later by Isaiah Fidler [(2); quotation from Fidler]. It took more than a century to recognize the critical role that CTCs play in the metastatic spread of carcinomas, that the detection of CTCs is associated with prognosis for many cancers (such as those of the breast, colon, and prostate), and that their enumeration is useful in follow-up (3). On the basis of these developments, the evaluation of CTCs now represents a promising new diagnostic tool, especially for advanced-stage cancer patients, for whom CTCs can be used as a “liquid biopsy” that allows physicians to follow cancer changes over time and tailor treatment accordingly (3). Given that CTCs are very rare, the very limited amount of available biological sample presents a unique analytical and technical challenge. CTCs can now be isolated, detected, and enumerated with a plethora of highly sensitive analytical methods, such as quantitative reverse-transcription PCR, image-based approaches, and techniques that use microfilter and microchip devices (4). In most cases, the isolation and detection of CTCs depend primarily on their epithelial characteristics, and antibodies to epithelial cell adhesion molecule (EpCAM) and cytokeratins (CKs), respectively, are used for this purpose. At present, the CellSearch® system (Veridex) is the only technology that has been cleared by the US Food and Drug Administration for the detection and enumeration of CTCs in patients with metastatic …