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. 2022 Aug 17;10:938289. doi: 10.3389/fcell.2022.938289

FIGURE 2.

FIGURE 2

TAN roles in tumor metastasis. (A) TANs promote tumor-cell invasion; neutrophil-secreted TIMP-1 or IL-17 promote metastasis by inducing the epithelial-mesenchymal transition (EMT). Similarly, TANs cause cancer cells to undergo EMT by activating JAK2/STAT3 signaling. TANs secrete matrix metalloproteinase-9 (MMP-9), cathepsin G, and neutrophil elastase (NE), which degrade the extra-cellular matrix (ECM), thereby allowing tumors to invade adjacent tissues. (B) TANs promote tumor cell vascularization; neutrophils encourage tumor metastasis by releasing proteins such as MMP-9, vascular endothelial growth factor (VEGF), and BV8, which promote tumor angiogenesis. (C) TANs facilitate intravasation and extravasation of tumor cells and the survival of circulating tumor cells (CTCs); HMGB1 is released by tumor cells to recruit neutrophils, which assist tumor cells in invading blood vessels. CTC, CTC-neutrophil, and CTC-platelet clusters shield tumor cells from shear stress and natural killer (NK) cell assault. Hypoxia-inducible factor-1α (HIF-1α) expression is increased in circulating tumor microemboli (CTM) in the lungs. (D) Recurrence of dormant cancer cells; NETs cleave laminin, which results in the generation of an epitope. When a dormant cancer cell recognizes the epitope, signaling encourages tumor cells to awaken and proliferate. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) awaken dormant tumor cells by S100A8/A9.