Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response

Abstract

Background: The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value. Methods: The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays.Results: NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model. Conclusions:NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.

NETs By-products and Extracellular DNA May Play a Key Role in COVID-19 Pathogenesis: Incidence on Patient Monitoring and Therapy

“…It is widely accepted that naturally-occurring DNase-1 digests extracellular chromatin and NETs (Yang et al, 2020). As such it displays a vital physiological regulation of NETs in the host and the adequate clearance of NETs.…”

“…However, modulation of pH does not appear to explain the inhibition of TLR7 and 9 signaling either by AT791, E6446, or by the anti-malarials chloroquine or hydroxychloroquine. Hydroxychloroquine (HCQ), a well-applied anti-inflammation drug with TLR-pathway blockage capacity, could effectively abrogate COX2 through activating TLR4/9 (Yang et al, 2020). HCQ has multiple mechanisms of action that may differ according to the pathogen studied (Deveaux et al, 2020).…”

The Value of C-Reactive Protein, C-Reactive Protein Kinetics and C-reactive Protein to Albumin Ratio on Prognosis in Newly Diagnosed Indolent B-cell Non-Hodgkin Lymphoma

“…These MSCs promote tumor growth, progression, and metastasis, leading to the formation of a vicious cycle. In ammation has also been reported promoting development and progression of cholangiocarcinoma and hepatocellular carcinoma [41][42][43]. IL-6, as the main inducers of CRP synthesis, was proved promote the progression of cholangiocarcinoma and other cancers [44][45][46][47].…”

Netting Liver Disease: Neutrophil Extracellular Traps in the Initiation and Exacerbation of Liver Pathology

“…78 Furthermore, once adherent, metastatic cells have been shown to internalize fragments of NETs, driving TLR9 activation and leading to NFκB and COX2-mediated signaling, ultimately resulting in increased cell survival and enhanced tumor establishment. 79 It is argued that this inflammation/NET-mediated tumor cell trapping may partly explain postsurgical metastasis of colon carcinoma to the liver. Resection of the primary colon tumor is believed to release PAMPs such as LPS into the circulation, triggering NET production in the liver and facilitating the trapping of circulating tumor cells that may have been liberated by the surgical process.…”