Fig. 1

Multicellular interactions between neutrophils, tumor cells, platelets and endothelial cells result in NETosis. Shapes are color coded by their cell or granule of origin: neutrophil nucleus and NETs (dark blue), tumor (green), platelet (lavender), and endothelium (red). (a) The primary tumor site releases extracellular vesicles (EVs), various ROS generating proinflammatory factors (indicated by “ROS”), and specific pro-NETotic factors into the circulation. (b) Tissue factor (TF) released from tumor cells activates platelets, provoking the release of HMGB1 and further ROS generation. Compounding this, tumor released proinflammatory factors may provoke the endothelium as well, dependent on tumor phenotype. (c) Factors released from the tumor, activated platelets, and activated endothelium bind to their respective receptors on the neutrophil, causing NET release. Activated platelets can also directly bind to the neutrophil surface through P-selectin (P-SEL)/P-selectin glycoprotein ligand 1 (PSGL-1) interactions to generate NETosis. Furthermore, tumor-derived EVs may also promote NET release through neutrophil phagocytosis of the tumor membrane fragments and encapsulated factors. The neutrophil flattens and adheres to the endothelium during this process. (d) Released NETs are decorated with citH3, NE, and MPO and further activate and entrap platelets, leading to the potential for venous thromboembolism. NETs may also capture circulating tumor cells, promoting the formation of metastases. (e) NETs damage endothelial cells via proteolytic components such as NE and MPO, causing the release of inflammatory factors, including IL-8, which can further promote NET release and neutrophil recruitment. Arrested tumor cells further damage endothelial cells as they extravasate. The now highly inflammatory, crowded environment forms the pre-metastatic niche.