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

doi:10.1016/j.isci.2020.101799

Neutrophil Elastase Facilitates Tumor Cell Intravasation and Early Metastatic Events

iScience. 2020 Nov 13;23(12):101799. doi: 10.1016/j.isci.2020.101799. eCollection 2020 Dec 18.

Authors

Elena Deryugina¹, Alexia Carré¹, Veronica Ardi^{1

2}, Tomoki Muramatsu¹, Jonas Schmidt¹, Christine Pham³, James P Quigley¹

Affiliations

¹ Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
² National University, 9388 Lightwave Avenue, San Diego, CA 92123, USA.
³ Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA.

Abstract

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.

Keywords: Cancer; Cell Biology.