The biology and clinical potential of circulating tumor cells

Abstract

Background Tumor cells can shed from the tumor, enter the circulation and travel to distant organs, where they can seed metastases. These cells are called circulating tumor cells (CTCs). The ability of CTCs to populate distant tissues and organs has led us to believe they are the primary cause of cancer metastasis. The biological properties and interaction of CTCs with other cell types during intravasation, circulation in the bloodstream, extravasation and colonization are multifaceted and include changes of CTC phenotypes that are regulated by many signaling molecules, including cytokines and chemokines. Considering a sample is readily accessible by a simple blood draw, monitoring CTC levels in the blood has exceptional implications in oncology field. A method called the liquid biopsy allows the extraction of not only CTC, but also CTC products, such as cell free DNA (cfDNA), cell free RNA (cfRNA), microRNA (miRNA) and exosomes. Conclusions The clinical utility of CTCs and their products is increasing with advances in liquid biopsy technology. Clinical applications of liquid biopsy to detect CTCs and their products are numerous and could be used for screening of the presence of the cancer in the general population, as well as for prognostic and predictive biomarkers in cancer patients. With the development of better CTC isolation technologies and clinical testing in large prospective trials, increasing clinical utility of CTCs can be expected. The understanding of their biology and interactions with other cell types, particularly with those of the immune system and the rise of immunotherapy also hold great promise for novel therapeutic possibilities.

Keywords: CTC; cancer; circulating tumor cells; disseminated tumor cells; liquid biopsy; metastasis.

Figure 1

Circulating tumor cells (CTCs) can enter the blood vessel via active intravasation involving epithelial-mesenchymal transition (EMT) or by passive shedding due to compromised tumor vasculature. CTCs can exist in different phenotypes- epithelial, mesenchymal or both- hybrid epithelial/ mesenchymal phenotype (hybrid E/M). CTCs can be found in the form of individual cells or cell clusters; the latter show increased metastatic potential compared to individual CTCs. Platelet-CTC interaction in the blood vessel acts as a shield against the shear stress of blood flow, immune attack and also enables the adhesion to the blood vessel wall and extravasation. After the arrest of CTCs in the bone marrow or distant organ, they can extravasate and remain in the target tissue in the form of disseminated tumor cell (DTC).

Figure 2

Clinical applications of CTCs.