Circulating tumor cell

A circulating tumor cell (CTC) is a cancer cell from a primary tumor that has shed into the blood of the circulatory system, or the lymph of the lymphatic system. CTCs are carried around the body to other organs where they may leave the circulation and become the seeds for the subsequent growth of secondary tumors. This is known as metastasis, responsible for most cancer-related deaths.

The detection and analysis of CTCs can assist early patient prognoses and determine appropriate tailored treatments. Currently, there is one FDA-approved method for CTC detection, CellSearch, which is used to diagnose breast, colorectal and prostate cancer.

The detection of CTCs, or liquid biopsy, presents several advantages over traditional tissue biopsies. They are non-invasive, can be used repeatedly, and provide more useful information on metastatic risk, disease progression, and treatment effectiveness. For example, analysis of blood samples from cancer patients has found a propensity for increased CTC detection as the disease progresses. Blood tests are easy and safe to perform and multiple samples can be taken over time. By contrast, analysis of solid tumors necessitates invasive procedures that might limit patient compliance. The ability to monitor the disease progression over time could facilitate appropriate modification to a patient's therapy, potentially improving their prognosis and quality of life. The important aspect of the ability to prognose the future progression of the disease is elimination (at least temporarily) of the need for a surgery when the repeated CTC counts are low and not increasing; the obvious benefits of avoiding the surgery include avoiding the risk related to the innate tumor-genicity of cancer surgeries. To this end, technologies with the requisite sensitivity and reproducibility to detect CTCs in patients with metastatic disease have recently been developed. On the other hand, CTCs are very rare, often present as only a few cells per milliliter of blood, which makes their detection challenging. In addition, they often express a variety of markers which vary from patient to patient, which makes it difficult to develop techniques with high sensitivity and specificity.

CTCs that originate from carcinomas (cancers of epithelial origin, which are the most prevalent) can be classified according to the expression of epithelial markers, as well as their size and whether they are apoptotic. In general, CTCs are anoikis-resistant, which means that they can survive in the bloodstream without attaching to a substrate.

Circulating tumor cells are most often present in clusters. CTC clusters are aggregates of two or more circulating tumor cells (CTCs) bound together. These clusters can consist of traditional, small, or cytokeratin-negative CTCs and carry cancer-specific biomarkers that distinguish them from other cells in circulation. Studies have shown that CTC clusters are associated with increased metastatic potential and poor prognosis. For example, research has demonstrated that patients with prostate cancer who have only single CTCs exhibit an eight-fold longer mean survival rate compared to those with CTC clusters. Similar findings have been reported for colorectal cancer as well.

There are two types of circulating tumor cell cluster, one that consists of cancer cells only is termed homotypic. A CTC cluster that also incorporates other cells including white blood cells, fibroblasts, endothelial cells (i.e., cells that line the interior surface of blood vessels), and platelets, is termed heterotypic. Heterotypic clusters are also known as microemboli. It is suggested that these microemboli might enhance metastatic potential.

The cancer exodus hypothesis suggests that CTC clusters remain intact throughout the metastatic process, rather than dissociating into single cells, which was previously assumed. According to this hypothesis, the clusters enter the bloodstream, travel as a cohesive unit, and exit circulation at distant metastatic sites without breaking apart. This allows the clusters to retain their multicellularity, enhancing their metastatic efficiency. The hypothesis posits that the survival advantage provided by intercellular support within clusters increases their metastatic potential compared to single CTCs.

CTC clusters exhibit distinct gene expression profiles, which confer resistance to certain cancer therapies, making them more resilient than individual tumor cells. Their ability to remain multicellular throughout metastasis, may explain their superior survival and metastatic potential.