Reawakening 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 cancer patients. Reactivation of dormant tumor cells is largely responsible for this phenomenon. Using models of lung and ovarian cancer, we found a specific mechanism that may govern this process mediated by stress and neutrophils. Stress hormones cause rapid release of S100A8/A9 proteins by neutrophils. S100A8/A9 induce activation of myeloperoxidase resulting in accumulation of oxidized lipids. These lipids up-regulate fibroblast growth factor pathway in tumor cells causing tumor cell exit from the dormancy and formation of tumor lesions. Higher serum levels of S100A8/A9 were associated with shorter time to recurrence in patients with lung cancer after complete tumor resection. Targeting of S100A8/A9 or ß2 adrenergic receptors abrogated stress induced reactivation of dormant tumor cells. These observations demonstrate a mechanism linking stress, and specific neutrophils activation with early recurrence in cancer. Overall design: RNA-seq for parental (KRP) and reactivated (KRP.react) by S100A8/9 cells