Editors' ChoiceMETASTASIS

Nothing but NET

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Science Translational Medicine  28 Aug 2013:
Vol. 5, Issue 200, pp. 200ec143
DOI: 10.1126/scitranslmed.3007311

Neutrophils comprise over half of the white blood cells circulating in our bodies. They are the first responders charged with fighting off infection; in response to inflammatory stimuli, they enter tissues to engulf and kill bacteria. It is long established that as part of this process, neutrophils degranulate to release an array of antimicrobial agents. More recently, neutrophils have been found to also secrete chromatin- and neutrophil elastase–rich webs called neutrophil extracellular traps (NETs) that bind and effectively kill bacteria.

Infections occur frequently after surgical removal of tumors, leading in some cancers to more rapid metastatic relapse and death. The cellular basis for this association remains a mystery, but Cools-Lartigue et al. hypothesized that NETs deposited in response to infection may unwittingly promote metastasis by ensnaring circulating tumor cells (CTCs). The authors tested this hypothesis by inducing sepsis in mice by means of cecal ligation and puncture (CLP), ectopically implanting lung cancer cells, and monitoring dissemination and metastatic outgrowth within the lung and liver. CLP induced the formation of NET-like structures within the liver and lung microvasculature, increased retention of CTCs twofold, and led to a stunning increase in the number and size of liver metastases. In each case, treatment with deoxyribonuclease (DNAse) or neutrophil elastase inhibitor to dissolve NETs or inhibit their function impaired CLP-induced metastasis.

Why NETs seemingly trap tumor cells selectively is unknown. For instance, the authors note that red blood cells are impervious to NETs. Are leukocytes as well? What cell surface moieties bind NETs? And although the authors demonstrated that NETs promote tumor cell adhesion and transendothelial migration, how these functions manifest in an ostensible increase in CTC survival and retention needs to be elucidated.

In terms of treatment, this study offers strong evidence that anti-NET therapies should be devised to follow up surgical interventions in cancer patient populations. Whether DNAse and/or neutrophil elastase inhibitors will prove to be safe and effective enough, or novel NET-targeting agents need to be developed, remains to be seen.

J. Cools-Lartigue et al., Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. J. Clin. Invest. 123, 3446–3458 (2013). [Full text]

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