Figure 1.

Schematic illustration of metastasis development via CTCs/CTM. Tumor cells and cell clusters are shed from the primary tumor and intravasate into the circulation, which might involve the process of epithelial-to-mesenchymal transition. The majority of the CTCs are, however, killed via apoptosis and necrosis, releasing debris, cell fragments and intracellular substances (CTMat and CTDNA). CTM, the even rarer species than CTCs in blood, undergo a dynamic life. Tumor cells can dissociate from CTM when subjected to shear force and/or frequent collisions in blood; they can also attach to other tumor or blood cells upon collision due to increased adhesion. The microenvironment established within CTM is unique, protecting the tumor cells inside from damage. CTM are, therefore, believed to be more aggressive than individual CTCs as they proliferate in the vessel and eventually rupture the vessel. Conversely, CTCs have to extravasate in order to form metastasis.