Fig. 3

Roles of NETs in promoting malignant progression and awakening dormant cancer cells. The neutrophil extracellular trap (NET) is composed of neutrophil-derived DNA strands and enzymes such as NE and MMP9. NETs exist in the circulation as well as in the tumor microenvironment. A In the circulation, G-CSF derived from cancer cells acts in an endocrine manner to stimulate mobilization of neutrophils from the bone marrow to the bloodstream, leading to neutrophilia. In addition, tumor-released EVs (including exosomes) interact with the circulating neutrophils favoring the formation of NETs. NETs in the circulation promote cancer progression through several interrelated ways: (1) stimulating the formation of cancer-associated thrombosis; (2) promoting endothelial damage and organ dysfunction; (3) facilitating cancer cell survival; and (4) promoting cancer cell metastasis. In the tumor microenvironment, NE and MMP9 contained in NETs cleave laminin in the extracellular matrix, resulting in the exposure of cryptic epitopes on laminin. Exposed laminin epitopes trigger the proliferation of cancer cells through activation of the α3β1 integrin-mediated signaling pathway, leading to the awakening of dormant cancer cells