Neutrophil elastase in the tumor microenvironment

Abstract

Myeloid cell production within the bone marrow is accelerated in the setting of cancer, and the numbers of circulating and infiltrating neutrophils and granulocytic myeloid derived suppressor cells (MDSCs) correlate with tumor progression and patient survival. Cancer is therefore able to hijack the normally host-protective immune system and use it to further fuel growth and metastasis. Myeloid cells secrete neutrophil elastase and neutrophil extracellular traps (NETs) in response to cues within the tumor microenvironment, thereby leading to enhanced activity in a variety of cancer types. Neutrophil elastase may indeed be a driver of tumorigenesis, since genetic deletion and pharmacological inhibition markedly reduces tumor burden and metastatic potential in numerous preclinical studies. In this review, we examine the current evidence for neutrophil elastase as a stimulatory factor in cancer, focusing on precise mechanisms by which it facilitates primary tumor growth and secondary organ metastasis. We conclude with a brief overview of neutrophil elastase inhibitors and discuss their potential use in cancer therapy.

Keywords: Myeloid derived suppressor cells (MDSC); Neutrophil elastase; Prostate cancer; Tumor microenvironment.

Figure 1

Infiltrating immune cells, including neutrophils and myeloid derived suppressor cells (MDSC), secrete neutrophil elastase into the tumor microenvironment. Neutrophil elastase then mediates important pathways involved in primary tumor growth, such as direct induction of proliferation, inactivation of tumor suppressors, and stimulation of angiogenesis. Neutrophil elastase also facilitates key steps in the metastatic cascade, including epithelial to mesenchymal transition (EMT), migration, invasion, and eventual homing to distant sites of metastasis.