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Neutrophil Elastase Facilitates Tumor Cell Intravasation and Early Metastatic Events.


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, ?1PI. 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.

SUBMITTER: Deryugina E 

PROVIDER: S-EPMC7702017 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Neutrophil Elastase Facilitates Tumor Cell Intravasation and Early Metastatic Events.

Deryugina Elena E   Carré Alexia A   Ardi Veronica V   Muramatsu Tomoki T   Schmidt Jonas J   Pham Christine C   Quigley James P JP  

iScience 20201113 12


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 <i>Elane</i>-negative mice, the lack of  ...[more]

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