Circulating tumor cells: overcoming challenges of detecting a needle in a haystack

Circulating tumor cells (CTCs) are cancer cells that are detached from the primary and metastatic tumor site and invade the bloodstream. Most importantly, CTCs are the key players in the development of metastasis. As one of the main components of liquid biopsy, they may significantly contribute to improvements in early cancer diagnosis, monitoring response to therapy, and predicting recurrence of the disease. Although identifying and analyzing CTCs offers the potential for a real-time liquid biopsy, their detection is associated with a number of challenges, which mainly stem from three sources: complexity of the CTCs, complexity of the media (blood), and performance of the detection assays. Particularly, low concentration of the CTCs and the presence of a vast population of hematopoietic cells in the blood make their detection technically complex. The heterogeneity of the target cells and not enough sensitivity of the measuring platforms are also among major technical challenges in CTC detection. Therefore, this review aims to give an update on various methods developed for CTC isolation, including chip-based assays and biosensors. The work will elucidate various challenges associated with the isolation and detection of CTCs and showcase the studies that aimed to tackle them. A number of available commercial platforms for CTC detection and hurdles associated with their widespread applications in clinical settings will also be discussed.