Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase

Abstract

Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase–DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.

Cells in the liver microenvironment regulate the process of liver metastasis

“…99 Okamoto et al proved that NETs promoted CRC metastasis by releasing NE to activate the ERK signal. 50 NETs can also physically capture tumor cells, which is helpful for their retention in metastatic capillaries. 100 At the same time, NETs encapsulate and cover cancer cells, promote the depletion of T cells, and directly promote the growth of cancer.…”

NETosis: Sculpting tumor metastasis and immunotherapy

“…For instance, citrullinated NETs present significant connections to advanced histopathological tumor grades and lymph node metastasis among colorectal cancer (CRC) patients. Neutrophil extracellular traps enable to elicit filopodia formation and cell motility in CRC cells dependent upon the activation of EMT process, eventually resulting in the metastatic development of CRC 55 . Neutrophil extracellular traps facilitate the growth and metastasis of HCC, which are primarily dominated by enhanced angiogenesis, EMT‐associated cell migration, matrix metalloproteinases (MMPs)‐based extracellular matrix (ECM) degradation, and NET‐elicited cell trapping 56 .…”

Neutrophil serine proteases

“…Abnormal level of release NETs can be associated with the pathogenesis of different disorders, including lung injury [19,21] , nephritis [22] , cardiovascular disease [23] , autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome [18,22] ), as well as lung, breast or pancreatic cancer progression [24,25] . In the tumor microenvironment, the activity of release NE from NETs may also correlate with the formation of breast or colorectal cancer metastases [26,27] . Additionally, recent studies confirm that it is also related to COVID-19 due to SARS-CoV-2 infection can directly induce the increased formation of NETs in neutrophils [28][29][30] .…”