Table 1.
List of stimulants known to induce NET formation and the relation to tumor metastasis.
| Stimulus | Potential Mechanisms to Induce NET Formation | The Role of NET in Tumor Progression | Reference | |
|---|---|---|---|---|
| Cytokines | PAF | - | Promotes tumor cell proliferation, neovascularization and immunosuppressive phenotype | [42,43] |
| IL-8 | Activation of the class I isoform of PI3K | Positive correlation with poor outcome in women with breast cancer; enhances angiogenesis and contributes to tumor growth and progression | [18,44,45] | |
| IL-1β | Nuclear localization of ceramide synthase 6 and synthesis of C16-ceramide induce NETs | Promotes abdominal aortic aneurysm formation | [46,47] | |
| GM-CSF | - | Promotes tumor growth and metastasis | [23,24,48,49] | |
| CLL7 | - | - | [25] | |
| Complement factor 5a (C5a) | - | - | [23,50] | |
| TNF-α | - | - | [51] | |
| High-mobility group box 1 protein (HMGB1) | Interactions between HMGB1 and neutrophil-derived TLR4 | Activates TLR9-dependent pathways in cancer cells to promote tumor malignancy | [21,52,53] | |
| IFNs | Induce strong tyrosine phosphorylation of STAT1 in mature neutrophils | - | [50,54] | |
| HIF-1α | - | - | [20] | |
| P-selectin | Promotes NET formation through binding to anti-P-selectin glycoprotein ligand-1 (PSGL-1) | - | [42] | |
| Metabolite | Urate crystals | Interact with lysosomes and result in secretion of IL-1β to induce NADPH oxidase-independent NET formation | - | [27,47] |
| Lactic acid | - | - | [55,56] | |
| Free fatty acid | - | - | [29] | |
| Cholesterol crystal | - | - | [30] | |
| 2-chlorofatty aldehyde and 2-chlorofatty acid | As an MPO product to trigger NET formation following neutrophil activation | - | [31] | |
| High glucose | - | - | [32] | |
| Tumor-derived exosomes | - | KRAS mutation in exosomes causes deterioration of colorectal cancer | [57,58] | |
| Immobilized immune complexes | Induce FcγRIIIb-mediated NADPH oxidase-independent NET formation | - | [59] | |
| Activated platelets | - | - | [60] | |
| Mitochondrial DNA | Triggers TLR9-dependent NET formation | - | [61] | |
|
Physical
stimulation |
Hypoxia | - | - | [20,21] |
| Surgical stress | - | Accelerates development and progression of liver metastatic disease | [21,62] | |
| UV light | NADPH oxide-independent NET formation but requiring mROS | - | [37] | |
| Chemical stimulation | PMA | Triggers assembly and activation of NADPH oxidase and ROS production via the Raf-MEK-ERK pathway | - | [1,34] |
| Hydrogen peroxide (H2O2) | Stimulates activation of NADPH oxidase and the production of ROS | - | [34] | |
| LPS | Induces inflammation, triggers the assembly and activation of NADPH oxidase and the production of ROS via the Raf-MEK-ERK pathway and activates caspase-11 to activate gasdermin D | Activates dormant cancer cells and enhances metastatic proliferation | [16,19] | |
| fMLP | Activates PI3K and MAPK pathways | - | [18,19] | |
| Cigarette smoke extract | - | Converts dormant cancer cells to aggressively growing metastases | [19] | |
| Alkaline pH | Promotes intracellular calcium influx, mROS generation, PAD4-mediated CitH3 formation and histone 4 cleavage | - | [22] | |
| Tamoxifen | Modulates intracellular ceramide via a ceramide/PKCζ-mediated pathway | - | [63] | |
| Nitric oxide (NO) | - | - | [51] | |
| Calcium ionophores | NADPH oxidase-independent NET formation but require mROS | - | [22] | |