Emerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from HCC-CAFs with increased expression of CD66b, PDL1, IL8, TNFa, and CCL2, and with decreased expression of CD62L. HCC-CAF-primed neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. We revealed that HCC-CAFs induced the activation of STAT3 pathways in neutrophils, which are essential for the survival and function of activated neutrophils. In addition, we demonstrated that HCC-CAF-derived IL6 was responsible for the STAT3 activation of neutrophils. Collectively, our results suggest that HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade, which presents a novel mechanism for the role of CAFs in remodeling the cancer niche and provides a potential target for HCC therapy.

Background/Aims: Systemic inflammatory response (SIR) is widely considered as a preoperative risk factor for hepatocellular carcinoma (HCC) outcomes. The neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR), two of the prognostic indices, have been investigated in post-therapeutic recurrence and survival of HCC. Here, we quantify the prognostic value of these two biomarkers and evaluate their consistency in different HCC therapies. Methods: A systematic review of electronic database of the Web of Science, Embase, PubMed and the Cochrane Library was conducted to search for associations between the NLR and PLR in the blood and clinical outcomes of HCC. Overall survival (OS) and recurrence-free survival (RFS) were the primary outcomes, and hazard ratios (HRs) and 95% confidence intervals (95% CIs) were explored as effect measures. Subgroup analyses were performed to explore the heterogeneity of different therapies. Results: A total of 24 articles comprising 6318 patients were included in the meta-analysis. Overall, the pooled outcomes revealed that a high NLR before treatment predicted a poor OS (HR: 1.54, 95% CI: 1.34 to 1.76, p<0.001) and poor RFS (HR: 1.45, 95% CI: 1.16 to 1.82, p=0.001). Moreover, an increased PLR predicted a poor OS (HR: 1.63, 95% CI: 1.34 to 1.98, p<0.001) and earlier HCC recurrence (HR: 1.52, 95% CI: 1.21 to 1.91, p<0.001). In addition, both the NLR and PLR were identified as independent risk factors for predicting OS and RFS in HCC patients in a subgroup analysis of different treatment types, including curative or palliative therapy; however, these results were not found in the sorafenib subgroup due to limited clinical research. Conclusion: An increased NLR or PLR indicated poor outcomes for patients with HCC. The NLR and PLR may be considered as reliable and inexpensive biomarkers for making clinical decisions regarding HCC treatment.

BackgroundThe role of exosomal circular RNAs (circRNAs) in Hepatocellular carcinoma (HCC) cells with high metastatic potential has been little studied.MethodsExosomal circRNA from cells with non-metastatic (HepG2), low metastatic (97L), and high metastatic (LM3) potential were sequencing. Metastatic-related circRNAs in serum from HCC patients were measured and their association with clinical prognosis was evaluated. Furthermore, candidate functional circRNAs in LM3-derived exosomes was assessed.FindingsLM3 exosomes enhanced the cell migration and invasion potential of HepG2 and 97 L cells. CircPTGR1, a circRNA with three isoforms, was specifically expressed in exosomes from 97 L and LM3 cells, upregulated in serum exosomes from HCC patients and was associated with the clinical stage and prognosis. Knockdown of circPTGR1 expression suppressed the migration and invasion of HepG2 and 97L cells induced by co-culturing with LM3 exosomes. Bioinformatics, co-expression analysis, and a luciferase assay indicated that circPTGR1 competed with MET to target miR449a.InterpretationHigher metastatic HCC cells can confer this potential on those with lower or no metastatic potential via exosomes with circPTGR1, resulting in increased migratory and invasive abilities in those cells.FundNational Natural Science Foundation of China (No. 81470870, 81670601, 81570593), Guangdong Natural Science Foundation (No. 2015A030312013, 2015A030313038), Sci-tech Research Development Program of Guangdong Province (2014B020228003), Sci-tech Research Development Program of Guangzhou City (No. 201508020262, 201400000001-3, 201604020001, 201607010024), Innovative Funds for Small and Medium-Sized Enterprises of Guangdong Province (2016A010119103), Pearl River S&T Nova Program of Guangzhou (201710010178), and National 13th Five-Year Science and Technology Plan Major Projects of China (No. 2017ZX10203205-006-001).

Mesenchymal stem cells (MSCs) have been reported to exert therapeutic effects on immunoregulation, tissue repair, and regeneration from the bench to the bedside. Increasing evidence demonstrates that extracellular vesicles (EVs) derived from MSCs could contribute to these effects and are considered as a potential replacement for stem cell‐based therapies. However, the efficacy and underlying mechanisms of EV‐based treatment in hepatic ischemia‐reperfusion injury (IRI) remain unclear. Here, we demonstrated that human umbilical cord MSC‐EVs (huc‐MSC‐EVs) could protect against IRI‐induced hepatic apoptosis by reducing the infiltration of neutrophils and alleviating oxidative stress in hepatic tissue in vivo. Meanwhile, huc‐MSC‐EVs reduced the respiratory burst of neutrophils and prevented hepatocytes from oxidative stress‐induced cell death in vitro. Interestingly, we found that the mitochondria‐located antioxidant enzyme, manganese superoxide dismutase (MnSOD), was encapsulated in huc‐MSC‐EVs and reduced oxidative stress in the hepatic IRI model. Knockdown of MnSOD in huc‐MSCs decreased the level of MnSOD in huc‐MSC‐EVs and attenuated the antiapoptotic and antioxidant capacities of huc‐MSC‐EVs, which could be partially rescued by MnSOD mimetic manganese (III) 5,10,15,20‐tetrakis (4‐benzoic acid) porphyrin (MnTBAP). In summary, these findings provide new clues to reveal the therapeutic effects of huc‐MSC‐EVs on hepatic IRI and evaluate their preclinical application.—Yao, J., Zheng, J., Cai, J., Zeng, K., Zhou, C., Zhang, J., Li, S., Li, H., Chen, L., He, L., Chen, H., Fu, H., Zhang, Q., Chen, G., Yang, Y., Zhang, Y. Extracellular vesicles derived from human umbilical cord mesenchymal stem cells alleviate rat hepatic ischemia‐reperfusion injury by suppressing oxidative stress and neutrophil inflammatory response. FASEB J. 33, 1695–1710 (2019). http://www.fasebj.org