Lianghan Zhu,Zhaoting Li,Ning Liu,Honghao Sun,Yixin Wang,Minjie Sun
Neutrophil extracellular traps (NETs), consisting of chromatin DNA filaments coated with granule proteins, promote metastasis by enhancing tumor cell migration to distant organs. Recent studies indicate that NETs adhere to cancer cell membranes and enhance cell motility significantly to induce liver metastasis in patients with breast and colon cancers. Herein, a dynamically deformable protein delivery strategy is developed to prevent liver metastasis by disassembling NETs. Specifically, poly amino acid conjugating with polyethylene glycol (PAAP) is explored and synthesized for DNase-1 delivery. Notably, PAAP/DNase-1 degrades chromatin to induce apoptosis, followed by cell membrane rupture and remaining DNase-1 releases to the extracellular. More importantly, the released DNase-1 disassembles NET-DNA to prevent liver metastasis induced by NET. In all, PAAP/DNase-1 treatment not only suppresses tumor growth by degrading intracellular chromatin, but also prevents the liver metastasis by disassembling the NET-NDA. This strategy may provide brand-new inspiration to prevent the liver metastasis fundamentally in patients with metastatic colon and breast cancer.
Neutrophil extracellular traps (NETs) have been shown to promote the metastatic potential of many kinds of tumors. Our study aimed to investigate the role and mechanisms of NETs in lymph node metastasis (LNM) of cervical cancer (CCa), and evaluated the therapeutic value of targeting NETs in CCa. Immunohistochemistry demonstrated that neutrophil infiltration and NETs formation were increased in CCa patients with LNM, as well as confirming a positive correlation between S100A7 expression and neutrophil infiltration in CCa. NETs enhanced the migratory capability of CCa by activating the P38-MAPK/ERK/NFκB pathway through interaction with TLR2. Digesting NETs with deoxyribonuclease 1 (DNase 1) or inhibiting TLR2 with chloroquine eliminated the NETs-induced metastatic potential of CCa. Additionally, NETs promoted lymphangiogenesis and increased the permeability of lymphatic vessels, thus facilitating translymphatic movement of CCa. CCa-derived S100A7 exhibited a chemotactic effect on neutrophils and promoted NETs generation by elevating ROS levels rather than activating autophagy in neutrophils. The mouse model with footpad implantation illustrated that DNase 1 effectively reduced LNM in LPS-induced mice and in mice seeded with S100A7-overexpressing CCa cells. In conclusion, our study reveals a new tumor-promoting mechanism of S100A7, clarifies the crucial role and mechanism of NETs in LNM of CCa, and indicates that the NETs-targeted therapy emerges as a promising anti-metastasis therapy in CCa.
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