Fig. 8

Proposed mechanism for the extravasation and dissemination of CTC clusters involving a switch from a cooperative phenotype to a single-celled stage (mediated by platelet-derived TGF-β1; paracrine signalling) capable of extravasation and dissemination (involving autocrine TGF-β1 signalling). In the bloodstream, CTC clusters recruit platelets that become attached to the cluster. In response to the TGF-β1 released from platelets (paracrine signalling), CTC clusters dissociate and individual CTCs adhere to the endothelial wall. Once adherent, these cells secrete their own TGF-β1 that induces a mesenchymal-like state (autocrine signalling) with invasion capabilities, which allows them (at least initially) to individually extravasate and disseminate into the adjacent tissues. Paracrine signalling among nearby individual CTCs is also possible, if clusters are composed of cells that differ in their ability to secrete TGF-β1. Lastly, although not shown here, extravasated cells could also aggregate through homotypic interactions in the perivascular space and/or undergo collective migration and invasion (see text for discussion). Diagram created with Servier Medical Art at www.smart.servier.com