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

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 beta 2-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.