Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase

Abstract

Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer (PCa) and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here it is reported that granulocytic myeloid-derived suppressor cells (MDSCs) are the predominant tumor infiltrating cells in PCa xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their pro-tumorigenic actions in part through neutrophil elastase (ELA2/NE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in PCa xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated mitogen-activated protein kinase (MAPK) signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in PCa cells. Functionally, NE stimulated proliferation, migration, and invasion of PCa cells in vitro. Immunohistochemistry (IHC) on human PCa clinical biopsies revealed co-expression of NE and infiltrating CD33+ MDSCs.

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…Other studies have focused on targeting NE, which contributes to cancer progression through enhanced proliferation, invasion and metastasis ( 31 – 33 , 35 – 37 , 207 , 208 ). Suppression of NE activity by the small molecule sivelestat resulted in reduced tumor growth in murine models of colorectal and prostate cancer ( 207 , 208 ). The NE inhibitor sivelestat sodium hydrate has been successfully applied in esophageal cancer patients, although this study did not focus on tumor progression ( 209 ).…”

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural Insights from a Computational Model

“…Experimental [27] and model simulations ( (Fig 7) through chemotaxis (Fig 8) and haptotaxis (Fig 9). TAN-induced signaling pathways of NET and NE were shown to actively induce tumor invasion and metastasis [42,151,152]. On the other hand, the presence of inhibitors of NET/NEs and MMPs was shown both experimentally to block tumor invasion [10,27].…”

PLAG Exerts Anti-Metastatic Effects by Interfering with Neutrophil Elastase/PAR2/EGFR Signaling in A549 Lung Cancer Orthotopic Model

“…Neutrophil elastase released from activated neutrophils is one of the major components that promote tumor metastasis [11,12,50]. The endogenous neutrophil elastase inhibitor is involved in inflammation-mediated tumor progression [51].…”

“…Tumor-infiltrating neutrophils (TINs) play vital roles in the abnormal growth and metastasis via activates specific signaling pathways [8][9][10]. Especially, signaling pathways stimulated by elements from TINs such as neutrophil elastase was known to actively induce cancerous process and metastatic activity [11,12]. For this reason, tumor tissues recruited neutrophils into the tissues through various pathways.…”