No 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.

Cancer is one of the leading causes of death worldwide. Many treatments have been developed so far, although effective, suffer from severe side effects due to low selectivity. Nanoparticles can improve the therapeutic index of their delivered drugs by specifically transporting them to tumors. However, their exogenous nature usually leads to fast clearance by mononuclear phagocytic system. Recently, cell membrane-camouflaged nanoparticles have been investigated for cancer therapy, taking advantages of excellent biocompatibility and versatile functionality of cell membranes. In this review, we summarized source materials and procedures that have been used for constructing and characterizing biomimetic nanoparticles with a focus on their application in cancer therapy.