Live-imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation.

Abstract

Previous clinical studies and work in mouse models have indicated that platelets and microclots might enable the recruitment of immune cells to the pre-metastatic cancer niche, leading to efficacious extravasation of cancer cells through the vessel wall. Here, we investigated the interaction between platelets, endothelial cells, inflammatory cells, and engrafted human and zebrafish cancer cells by live-imaging studies in translucent zebrafish larvae, and show how clotting (and clot resolution) act as foci and as triggers for extravasation. Fluorescent tagging in each lineage revealed their dynamic behaviour and potential roles in these events, and we tested function by genetic and drug knockdown of the contributing players. Morpholino knockdown of fibrinogen subunit α (fga) and warfarin treatment to inhibit clotting both abrogated extravasation of cancer cells. The inflammatory phenotype appeared fundamental, and we show that forcing a pro-inflammatory, tnfa-positive phenotype is inhibitory to extravasation of cancer cells.