Neutrophil Elastase Facilitates Tumor Cell Intravasation and Early Metastatic Events
Elena Deryugina,
Alexia Carré,
Veronica Ardi,
Tomoki Muramatsu,
Jonas Schmidt,
Christine Pham,
James P. Quigley
Affiliations
Elena Deryugina
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Corresponding author
Alexia Carré
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Veronica Ardi
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; National University, 9388 Lightwave Avenue, San Diego, CA 92123, USA
Tomoki Muramatsu
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Jonas Schmidt
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Christine Pham
Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA
James P. Quigley
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; Corresponding author
Summary: 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 NE activity, sensitive to its natural inhibitor, α1PI. In Elane-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 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.
