Fig. 1

Overview and timeline of CTC-blood interactions during haematogenous dissemination. 1 Invasion: Tumour cells detach from the primary tumour and invade the surrounding tissue. Within the primary tumour, detached CTCs come into contact with platelets and neutrophils within minutes and hours of their dissemination. 2 Intravasation: Degradation of the extracellular matrix and the process of epithelial-to-mesenchymal transition (EMT) resulting from platelet interactions enables the tumour cells to move through the surrounding tissue and finally enter the blood circulation.3 Circulation: CTCs travel though the circulation. Here, they can exist as single cells, doublets or clusters of CTCs and have been shown to express heterotypical surface receptors, making them difficult to isolate using current technologies. CTCs are constantly interacting with circulating immune cells and other factors in the blood (platelets, circulating nucleic acids, EVs). 4 Extravasation: following the arrival to the site of distal metastasis, mesenchymal-to-epithelial transition (MET) occurs. Platelets aid in the recruitment of neutrophils to metastatic niche. Also, disseminated neutrophil-associated CTCs that arrive have enhanced extravasation capabilities. 5 Colonisation: CTC colonises a secondary site, aided and protected by immune cell-rich microthrombi and host EVs. Here, CTCs and CTC clusters can multiply and eventually develop into a metastatic tumour