Figure 1.

Origin and dissemination of circulating tumor cell (CTC) clusters. Cell aggregates detach from the primary tumor site and metastases by cell jamming to produce homotypic monoclonal or polyclonal tumor clusters. Released cells can also interact with stromal or immune cells in the inflammatory peri-tumoral infiltrate forming heterotypic clusters. Heterotypic cluster formation can also occur in blood vessels by association with circulating immune cells, and possibly with platelets. Intravasation of CTC clusters can occur by invadopodia and macrophage lead or through leaky blood vessels common in tumor microenvironment. In the bloodstream, clustering strengthens CTCs by anoïkis resistance, shear stress resistance, and immune escape and enhances their stemness, resulting in boosted metastatic potential. After extravasation in tissue with favorable microenvironment conditions, clusters can form monoclonal or polyclonal metastasis depending on their initial nature. This figure was performed using free online Servier Medical Art at www.servier.com.