Neutrophil Elastase Facilitates Tumor Cell Intravasation and Early Metastatic Events

Functional 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 NEactivity, sensitive to its natural inhibitor, alpha 1PI. In Elane-negativemice, 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 dissemination in 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.