Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma.

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Neutrophil is one of the most abundant components in human hepatocellular carcinoma (HCC) and has been shown to play important roles in regulating disease progression. But neutrophils are characterized as very short-lived cells in circulation, and mechanisms regulating their accumulation and functions in HCC are not yet fully understood.Monocytes were purified from non-tumor, or paired tumor tissues of patients with hepatocellular carcinoma (HCC), and their production of neutrophil chemokines was evaluated. Mechanisms regulating the expression of CXCL2/8 by tumor monocytes, and the role of tumor monocytes-derived chemokines and cytokines in modulating neutrophil accumulation and functions were studied with both ex vivo analyses and in vitro experiments.we identified monocytes-derived CXCL2 and CXCL8 as main factors in regulating the recruitment of neutrophils into tumor milieus, and these chemokines, in addition to tumor-derived soluble factors, could inhibit the apoptosis and sustain the survival of neutrophils, thus leading to neutrophil accumulation in tumor tissues. Moreover, monocytes-produced TNF-α could synergistically act with tumor-derived soluble factors to induce pro-metastatic factor OSM production in neutrophils. Further observation found that glycolytic switch in tumor infiltrated monocytes mediated their production of CXCL2 and CXCL8 via the PFKFB3-NF-κB signaling pathway. Accordingly, levels of PFKFB3, CXCL2/CXCL8 production in monocytes and infiltration of OSM-producing neutrophils were positively correlated in human HCC tissues.Our results unveiled a previously unappreciated interconnected network between monocytes and neutrophils in human HCC, and provided possible targets that could be therapeutically exploited in the future.


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