摘要：SummaryFunctional roles of neutrophil elastase (NE) have not been examined in distinct steps of the metastatic cascade. NE, delivered to primary tumors as a purified enzyme or within intact neutrophils or neutrophil granule content, enhanced human tumor cell intravasation and subsequent dissemination via NE-mediated formation of dilated intratumoral vasculature. These effects depended on picomole range of NE activity, sensitive to its natural inhibitor, α1PI. InElane-negative mice, the lack of NE decreased lung retention of human tumor cells in experimental metastasis. Furthermore, NE was essential for spontaneous metastasis of murine carcinoma cells in a syngeneic orthotopic model of oral cancer. NE also induced tumor cell survival and migration via Src/PI3K-dependent activation of Akt signaling, vital for tumor cell disseminationin vivo. Together, our findings implicate NE, a potent host enzyme specific for first-responding innate immune cells, as directly involved in early metastatic events and a potential target for therapeutic intervention.Graphical AbstractDisplay OmittedHighlights•NE enhances human carcinoma cell intravasation and spontaneous metastasis•NE mediates formation of dilated intratumoral vasculature supporting cell intravasation•NE-KO mice exhibit decreased lung retention and spontaneous metastasis of tumor cells•NE induces tumor cell survival and migration via activation of Src/PI3K/Akt pathwayCell Biology; Cancer
