The Crosstalk Between Cancer Cells and Neutrophils Enhances Hepatocellular Carcinoma Metastasis via Neutrophil Extracellular Traps-Associated Cathepsin G Component: A Potential Therapeutic Target

Abstract

Background: Emerging evidences have highlighted the roles of neutrophils, as the major host microenvironment component, in the development of hepatocellular carcinoma (HCC). Neutrophils extracellular traps (NETs) produced in the infection can strengthen the behavior of cancer metastasis. Here, we investigated the roles of NETs in HCC metastasis and further explore the underlying mechanism of how NETs interact with cancer. Methods: The neutrophils were isolated from whole blood of HCC patients and used to evaluate the formation of NETs. NET markers were detected in tissue samples, plasma and cell climbing slice. Mouse models were used to evaluate the roles of NETs in HCC metastasis in vivo, and the corresponding mechanisms were explored using in vivo and in vitro assays. Results: An increase in the release of NETs in patients with HCC, particularly those with portal vein tumor thrombosis (PVTT). The presence of NETs in HCC tumor tissues closely correlated with a poor prognosis. Functionally, the invasion ability of HCC cells was enhanced by coculture with HCC neutrophils, through NETs formation, while the neutrophils from a healthy donor (HD) exhibited the inhibition of the invasion ability. Furthermore, we observed an enhanced ability of forming NETs in neutrophils from HCC patients in vitro, especially patients with PVTT or extra-hepatic metastasis. An in-vivo animal study demonstrated that neutrophils of HCC facilitated the metastatic behavior towards the lung. The further mechanistic investigation unveiled that HCC cells-derived cytokine IL-8 triggered NETs formation in an NADPH oxidasedependent manner, and NETs-associated cathepsin G (cG) promoted HCC metastasis in vitro as well as vivo. Clinically, the expression of the cG protein in tumor tissues displayed a close correlation with the disease prognosis of HCC patients. Conclusion:Our findings implicated that the induction of NETs by HCC cells is a critical metastasis-supporting cancer-host interaction and that NETs may serve as an immune-based potential therapeutic target against HCC progression.

Neutrophil Extracellular Traps in Cancer Therapy Resistance

“…Pre-clinical and clinical evidence directly implicating CG in resistance to therapy is scant, yet the protein is known to drive ECM remodeling and angiogenesis, which are mechanisms associated with cancer progression and resistance to therapy ( Figure 1 ) [ 3 , 114 , 115 ]. Furthermore, there exists evidence associating cathepsin G expression with an aggressive neoplastic phenotype that is associated with treatment resistance [ 116 , 117 ]. Further research is needed, however, to elaborate any cathepsin G-dependent processes that may influence such resistance to therapy.…”

Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options

“…The presence of TANs supports the development of HCC via direct crosstalk with cancer cells. They release neutrophil extracellular traps (NETs), which support tumor growth by secretion of MMP-9 and cathepsin G, as well as the induction of metastasis of HCC cells [ 105 ]. Therefore, NETs can be potential targets for the new treatment options in HCC [ 106 ].…”

The Significance of Neutrophil Extracellular Traps in Colorectal Cancer and Beyond: From Bench to Bedside

“…In a study, NETs were found to drive the transformation of typical epithelial morphology to the mesenchymal phenotype and increase the expression of tumor stem cell-related markers in human breast cancer MCF7 cells, which was accompanied by enhanced invasion and migration ability ( 8 ). In addition, NET-associated cathepsin G has been reported to facilitate the invasion and metastasis of HCC cells both in vitro and in vivo ( 69 ). The DNA component of NETs can directly act on the CCDC25 receptor on the surface of cancer cells and activates the ILK–β-parvin cascade to enhance the motor capacity of cells ( 70 ).…”