A conduit to metastasis: circulating tumor cell biology

Abstract

Advances in the enrichment and analysis of rare cells from the bloodstream have allowed for detection and characterization of circulating tumor cells (CTCs) from patients with cancer. The analysis of CTCs has provided significant insight into the metastatic process. Studies on the biology of CTCs have begun to elucidate the molecular mechanisms of CTC generation, intravasation, survival, interactions with components of the blood, extravasation, and colonization of distant organs. Additionally, the study of CTCs has exposed dramatic intrapatient and interpatient heterogeneity and their evolution over time. In this review, we focus on the current knowledge of CTC biology and the potential clinical implications.

Keywords: blood-based diagnostics; cancer metastasis; circulating tumor cells.

Figure 1.

Tumor cell intravasation and the generation of CTCs: Tumor cells from primary and metastatic tumors intravasate either as single cells directly into blood or potentially as tumor cell clusters into the lymphatics, lymph nodes, and blood. The tumor cells can be shed passively into the circulation after a blood vessel is compromised or can actively intravasate without loss of blood vessel integrity. Macrophages in the tissue aid in the entry of CTCs into the bloodstream. VEGF, FGF, and other cytokines produced by macrophages and tumor cells lead to the loss of vascular junctions and increase permeability of the blood vessels. Invadopodia formation dependent on N-WASP in the tumor cell facilitates invasion through the endothelium.

Figure 2.

Feature of CTCs in the circulation: CTCs that have accessed the circulation are coated with platelets, which may protect them from the deleterious effects of the immune cells, including natural killer cells and lymphocytes (A); are subjected to the cytotoxic effects of reactive oxygen species (B); and/or travel as CTC clusters with increased metastatic propensity (C). These factors, together with other unknown mechanisms, affect the survival of CTCs in the blood.

Figure 3.

Extravasation of CTCs: CTCs that survive in the circulation can actively extravasate through the walls of the blood vessels or become lodged in branch points and capillaries. Lodged tumor cells can extravasate through compromised vessel walls. Other CTCs can form an initial interaction with E-selectin, expressed on the endothelial cells, that arrests the CTCs and allows them to form more stable interactions with MUC1, CD44, and integrins. Production of TGF-β by the tumor cells or platelets can facilitate opening of the endothelial tight junctions, allowing the CTCs to transverse the vessel wall. Extravasated CTCs can colonize and remain dormant or proliferate, giving rise to metastatic tumors.