Fig. 2

Molecular mechanisms of NETs in tumor metastasis. HMGB1, released by NETs, promotes tumor metastasis by binding to TLR9 to activate p38/MAPK signaling. HMGB1 also facilitates metastasis by binding to TLR4 or by regulating the degradation of VE-cadherin (CD144), followed by increased expression of EMT-associated genes, ZEB1 and Snail. The NETs component, NE, directly regulates mitochondrial metabolism via the TLR4-p38-PGC1-α pathway and promotes tumor proliferation and metastasis. NETs-derived NE and MMP-9 proteases are required for reactivating dormant cancer cells through degradation of the extracellular matrix (ECM) through the cleavage of laminin. In several cancer cells, NET-DNA directly binds to CCDC25, resulting in tumor metastasis.