Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps

By Juwon Park, R. Wysocki, Zohreh Amoozgar, L. Maiorino, M. Fein, J. Jorns, A. Schott, Yumi Kinugasa-Katayama, Youngseok Lee, N. Won and 9 more. Science Translational Medicine, 2016

868 citations recorded by the source corpus.

Treatment with DNase I–coated nanoparticles prevents metastasis by targeting neutrophil extracellular traps induced by cancer cells in a mouse model. Metastasis caught in a NET Neutrophil extracellular traps, or NETs, are DNA structures that are produced by neutrophils in response to infection and can promote the spread of cancer in the presence of infection. Park et al. discovered that even in the absence of infection, metastatic breast cancer cells can stimulate neutrophils to form NETs, which further support the spread of metastasis. The authors also demonstrated an approach to breaking this vicious cycle using nanoparticles coated with DNase I, an enzyme that breaks down DNA NETs. This treatment was effective in reducing lung metastases in mice, demonstrating the potential of NETs as a therapeutic target. Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil’s DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I–coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.

Subfields: Biomedical Engineering, Immunology

View Paper: https://www.semanticscholar.org/paper/3ccd945ed1636147b459c8f2f8642742e2f3a425

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In Biomedical Engineering

1. Zena Werb
2. M. Egeblad

In Immunology

1. Hugo Gonzalez
2. Zena Werb
3. M. Egeblad
4. C. Hagerling
5. Pengfei Lu

Citations in the corpus

• Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice (2018, methodology): “Immobilization of an enzyme on the surface of nanoparticles can increase enzyme stability, therefore, we also generated and used DNase I–coated nanoparticles, as previously described (22).”
• Roles of the immune system in cancer: from tumor initiation to metastatic progression (2018, background): “Notably, targeting NETs in vivo with DNase I-coated particles reduces metastatic burden (Park et al. 2016).”