Research ArticleCancer

Reactivation of dormant tumor cells by modified lipids derived from stress-activated neutrophils

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Science Translational Medicine  02 Dec 2020:
Vol. 12, Issue 572, eabb5817
DOI: 10.1126/scitranslmed.abb5817

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Stressed Neutrophils are a Tumor’s Alarm Clock

Tumors can recur years after a seemingly successful treatment, and this may be caused by residual tumor cells remaining dormant throughout the body. In this study, Perego et al. developed a mouse model to investigate the mechanism of tumor cell reactivation, finding that reactivation was dependent on neutrophils and stress hormones such as norepinephrine and cortisol. Inducing stress in mice by immobilizing them resulted in tumor cell reactivation, whereas treating mice with β-blockers to inhibit stress hormone signaling prevented tumor cell reactivation. Last, the authors found an association between serum concentrations of stress-associated proteins and earlier tumor recurrence after surgical resection in a cohort of patients with lung cancer. Thus, pharmacologically inhibiting stress hormone signaling with β-blockers may help to prevent tumor recurrence.

Abstract

Tumor recurrence years after seemingly successful treatment of primary tumors is one of the major causes of mortality in patients with cancer. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using dormancy models of lung and ovarian cancer, we found a specific mechanism, mediated by stress and neutrophils, that may govern this process. Stress hormones cause rapid release of proinflammatory S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase, resulting in accumulation of oxidized lipids in these cells. Upon release from neutrophils, these lipids up-regulate the fibroblast growth factor pathway in tumor cells, causing tumor cell exit from the dormancy and formation of new tumor lesions. Higher serum concentrations of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or β2-adrenergic receptors abrogated stress-induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress and specific neutrophil activation with early recurrence in cancer.

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