Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma
| Autor: | Hao-Fan Guo, Meng-Meng Zhou, Wan-Ru Ning, Yan Wu, Ze-Zhou Jiang, Yu-Fan Huang, Zhi-Peng Peng, Jin-Hua Huang, Limin Zheng |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Chemokine Carcinoma Hepatocellular Neutrophils Biology Monocytes 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Cell Line Tumor Humans Interleukin 8 Retrospective Studies Tumor microenvironment Hepatology Liver Neoplasms NF-κB CXCL2 030104 developmental biology chemistry Disease Progression Cancer research biology.protein Female 030211 gastroenterology & hepatology Tumor necrosis factor alpha Signal transduction Glycolysis Signal Transduction |
| Zdroj: | Journal of Hepatology. 73:906-917 |
| ISSN: | 0168-8278 |
| Popis: | Background & Aims Neutrophils are one of the most abundant components in human hepatocellular carcinoma (HCC) and have been shown to play important roles in regulating disease progression. However, neutrophils are very short-lived cells in circulation, and mechanisms regulating their accumulation and functions in HCC are not yet fully understood. Methods Monocytes were purified from non-tumor or paired tumor tissues of patients with HCC, and their production of neutrophil-attracting chemokines was evaluated. Mechanisms regulating the expression of CXCL2/8 by tumor monocytes, and the role of tumor monocyte-derived chemokines and cytokines in modulating neutrophil accumulation and functions were studied with both ex vivo analyses and in vitro experiments. Results Monocyte-derived CXCL2 and CXCL8 were major factors in regulating the recruitment of neutrophils into tumor milieus. These chemokines, in addition to tumor-derived soluble factors, could inhibit apoptosis and sustain survival of neutrophils, thus leading to neutrophil accumulation in tumor tissues. Moreover, monocyte-derived TNF-α acted synergistically with tumor-derived soluble factors to induce the production of the pro-metastasis factor OSM by neutrophils. Further, the glycolytic switch in tumor-infiltrating 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. Conclusions Our results unveiled a previously unappreciated link between monocytes and neutrophils in human HCC, identifying possible targets that could be therapeutically exploited in the future. Lay summary Neutrophils constitute a major but poorly understood component of human hepatocellular carcinoma (HCC). Herein, we unveil a novel mechanism by which metabolic switching in monocytes promotes the accumulation of neutrophils in the tumors of patients with HCC. Both monocyte-produced chemokines and signals from the tumor microenvironment promote the production of the pro-metastatic factor OSM by neutrophils. These data identify potential targets for immune-based anticancer therapies for HCC. |
| Databáze: | OpenAIRE |
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