• cancer epigenetics
• cancer metabolism

• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/metabolism
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/metabolism
• Liver Neoplasms/genetics
• Tumor-Associated Macrophages/metabolism
• Tumor-Associated Macrophages/pathology
• Tumor-Associated Macrophages/immunology
• Tumor Microenvironment
• Animals
• Macrophages/metabolism

• Drug delivery
• Hepatocellular carcinoma
• Immunotherapy
• Nanomedicine
• Tumor immunosuppressive microenvironment

• Humans
• Carcinoma, Hepatocellular/drug therapy
• Liver Neoplasms/drug therapy
• Nanomedicine
• Combined Modality Therapy
• Immune Checkpoint Inhibitors
• Immunosuppressive Agents
• Tumor Microenvironment

• angiogenesis
• cancer stem cells
• carcinoma cell proliferation
• hepatic fibrosis
• hepatocellular carcinoma
• invasion and migration
• tumor microenvironment
• tumor-associated macrophages

• National Natural Science Foundation of China
• Science and Technology Department of Xinjiang Uygur Autonomous Region

• Immunotherapy
• Liver Neoplasms
• Macrophages
• Tumor Biomarkers
• Tumor Microenvironment

• Animals
• Mice
• Carcinoma, Hepatocellular/therapy
• CD8-Positive T-Lymphocytes
• Liver Neoplasms/therapy
• Immunotherapy
• Immunosuppressive Agents
• Tumor Microenvironment

• Shanghai Shen Kang Hospital Development Center New Frontier Technology Joint Project
• Special Foundation for Science and Technology Basic Research Program
• National Natural Science Foundation of China
• Sino-German Mobility Program
• Shanghai Sailing Program
• China Postdoctoral Science Foundation

• immunology
• diseases

• KiSS1
• angiogenesis
• epithelial mesenchymal transition
• hepatocellular carcinoma
• kisspeptin
• metastasis

• Animals
• Humans
• Mice
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Movement/genetics
• Cell Proliferation/genetics
• Epithelial-Mesenchymal Transition/genetics
• Gene Expression Regulation, Neoplastic
• Kisspeptins/genetics
• Kisspeptins/metabolism
• Liver Neoplasms/pathology
• Vascular Endothelial Growth Factor A/genetics

• ALPPS
• corosolic acid
• liver regeneration
• macrophage polarisation
• tumour growth

• Animals
• Hepatectomy/methods
• Liver Neoplasms/surgery
• Liver Regeneration/physiology
• Portal Vein/surgery
• Programmed Cell Death 1 Receptor
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor beta
• Triterpenes

Macrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ^+/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ^+/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ^+/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ^+/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ^+/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ^+/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.

• Bevacizumab
• Glioblastoma
• MMP9
• Neutrophils
• Predictive biomarker

• hepatic inflammatory microenvironment
• hepatocellular carcinoma
• intrahepatic metastasis
• sorafenib resistance

• Animals
• Antineoplastic Agents/pharmacology
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cellular Microenvironment
• Cytokines/metabolism
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Humans
• Inflammation Mediators
• Liver Cirrhosis/complications
• Liver Cirrhosis/metabolism
• Liver Cirrhosis/pathology
• Liver Neoplasms/drug therapy
• Liver Neoplasms/etiology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Mice
• Protein Kinase Inhibitors/pharmacology
• STAT3 Transcription Factor/metabolism
• Sorafenib/pharmacology
• Xenograft Model Antitumor Assays

• 201704020128 Science and Technology Program of Guangzhou, China
• 81672320 National Natural Science Foundation of China
• 81871987 National Natural Science Foundation of China
• 81802423 National Natural Science Foundation of China
• 2017M622741 China Postdoctoral Science Foundation
• 1201561579 Yangcheng Scholar Program
• 1201410075 Municipal University Science and Technology Program of Guangzhou Education Bureau
• National Natural Science Foundation of China
• China Postdoctoral Science Foundation

Current understanding of fibrosis remains incomplete despite the increasing burden of related diseases. Preclinical models are used to dissect the pathogenesis and dynamics of fibrosis, and to evaluate anti-fibrotic therapies. These studies require objective and accurate measurements of fibrosis. Existing histological quantification methods are operator-dependent, organ-specific, and/or need advanced equipment. Therefore, we developed a robust, minimally operator-dependent, and tissue-transposable digital method for fibrosis quantification. The proposed method involves a novel algorithm for more specific and more sensitive detection of collagen fibers stained by picrosirius red (PSR), a computer-assisted segmentation of histological structures, and a new automated morphological classification of fibers according to their compactness. The new algorithm proved more accurate than classical filtering using principal color component (red-green-blue; RGB) for PSR detection. We applied this new method on established mouse models of liver, lung, and kidney fibrosis and demonstrated its validity by evidencing topological collagen accumulation in relevant histological compartments. Our data also showed an overall accumulation of compact fibers concomitant with worsening fibrosis and evidenced topological changes in fiber compactness proper to each model. In conclusion, we describe here a robust digital method for fibrosis analysis allowing accurate quantification, pattern recognition, and multi-organ comparisons useful to understand fibrosis dynamics.

• collagen proportionate area
• digital analysis
• fibrosis
• fibrosis pattern
• picrosirius red
• region-of-interest
• whole section

• Algorithms
• Animals
• Azo Compounds
• Collagen/analysis
• Collagen/metabolism
• Disease Models, Animal
• Fibrosis/classification
• Fibrosis/metabolism
• Fibrosis/pathology
• Image Processing, Computer-Assisted/methods
• Kidney/metabolism
• Kidney/pathology
• Liver/metabolism
• Liver/pathology
• Lung/metabolism
• Lung/pathology
• Male
• Mice, Inbred C57BL
• Pattern Recognition, Automated/methods
• Staining and Labeling

• / Fonds de Recherche Clinique (Saint-Luc)

• Cancer
• immune response
• immune system
• immunosuppression
• inflammation
• solid tumor

• Animals
• Cell Transformation, Neoplastic/immunology
• Cell Transformation, Neoplastic/pathology
• Humans
• Immunity/immunology
• Inflammation/immunology
• Inflammation/pathology
• Neoplasms/immunology
• Neoplasms/pathology
• Prognosis

• Wroclaw Medical University

• Hepatocellular carcinoma
• Immunotherapy
• Macrophage
• Tumor microenvironment

• Key Technologies Research and Development Program
• National Natural Science Foundation of China
• Special Funds for National Key Sci-Tech Sepcial Project of China
• Shanghai Science and Technology Development Foundation
• Science Fund for Creative Research Groups

The study examines the expression and function of hypoxia-inducible gene 2 (HIG2) in hepatocellular carcinoma (HCC) tissues and cells.

Forty patients with HCC were included in the study. Bioinformatic analysis was used to analyze the clinical relevance of HIG2 expression in HCC tissue samples. Immunohistochemistry was employed to determine the expression of target proteins in tumor tissues. Hepatic HepG2 and SMMC-7721 cells were transfected with HIG2-targeting siRNA with Lipofectamine 2000. qRT-PCR was carried out to determine gene expression levels, while Western blotting was used to determine protein expression. A CCK-8 assay was performed to detect proliferation of cells, while migration and invasion of cells were studied by Transwell assay. Flow cytometry was carried out to detect surface markers and effector molecules in Nature killercells, as well as the killing effect of NK cells.

HIG2 expression was upregulated in HCC. Silencing of HIG2 suppressed HCC cell migration and invasion. The killing effect of NK cells on HCC cells was enhanced after HIG2 was silenced in HCC cells. Conditioned media from HIG2-silenced SMMC-7721 cells inhibited the phenotype and function of NK cells. HCC cells with silenced expression of HIG2 modulated the activity of NK cells via STAT3. HIG2 promoted the evasion of HCC cells from killing by NK cells through upregulation of IL-10 expression.

The study demonstrates that HIG2 activates the STAT3 signaling pathway in NK cells by promoting IL-10 release by HCC cells, thereby inhibiting the killing activity of NK cells, and subsequently promoting the recurrence and metastasis of HCC.

• Hepatocellular carcinoma
• Hypoxia-inducible gene 2
• IL-10
• Nature killer cells
• STAT3

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.

• Hepatocellular carcinoma
• Viral/non-viral hepatitis
• Alcohol consumption
• Epithelial-mesenchymal transition
• Tumor-stromal interactions
• Tumor microenvironment
• Cancer stem cells
• Circulating tumor cells
• Immunomodulation
• Neural regulation

• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Disease Progression
• Humans
• Liver/pathology
• Liver Neoplasms/etiology
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Prognosis
• Risk Factors

Control of homeostasis and rapid response to tissue damage in the liver is orchestrated by crosstalk between resident and infiltrating inflammatory cells. A crucial role for myeloid cells during hepatic injury and repair has emerged where resident Kupffer cells, circulating monocytes, macrophages, dendritic cells and neutrophils control local tissue inflammation and regenerative function to maintain tissue architecture. Studies in humans and rodents have revealed a heterogeneous population of myeloid cells that respond to the local environment by either promoting regeneration or driving the inflammatory processes that can lead to hepatitis, fibrogenesis, and the development of cirrhosis and malignancy. Such plasticity of myeloid cell responses presents unique challenges for therapeutic intervention strategies and a greater understanding of the underlying mechanisms is needed. Here we review the role of myeloid cells in the establishment and progression of liver disease and highlight key pathways that have become the focus for current and future therapeutic strategies.

• circulating monocytes
• cirrhosis
• fibrosis
• hepatitis (general)
• hepatocellular carcinoma
• macrophage
• myeloid derived suppressor cell (MDSC)
• neutrophil (PMN)

Royal jelly (RJ) is a glandular secretion produced by worker honeybees and is a special food for the queen honeybee. It results in a significant prolongation of the lifespan of the queen honeybee compared with the worker honeybees through anti-inflammatory, anti-oxidant and anti-microbial activities. Consequently, RJ is used as cosmetic and dietary supplement throughout the world. In addition, in vitro studies and animal experiments have demonstrated that RJ inhibits cell proliferation and stimulates apoptosis in various types of malignant cells and affects the production of various chemokines, anti-oxidants and growth factors and the expression of cancer-related molecules in patients with malignancies, especially in patients treated with anti-cancer agents. Therefore, RJ is thought to exert anti-cancer effects on tumor growth and exhibit protective functions against drug-induced toxicities. RJ has also been demonstrated to be useful for suppression of adverse events, the maintenance of the quality of life during treatment and the improvement of prognosis in animal models and patients with malignancies. To understand the mechanisms of the beneficial effects of RJ, knowledge of the changes induced at the molecular level by RJ with respect to cell survival, inflammation, oxidative stress and other cancer-related factors is essential. In addition, the effects of combination therapies of RJ and other anti-cancer agents or natural compounds are important to determine the future direction of RJ-based treatment strategies. Therefore, in this review, we have covered the following five issues: (1) the anti-cancer effects of RJ and its main component, 10-hydroxy-2-decenoic acid; (2) the protective effects of RJ against anti-cancer agent-induced toxicities; (3) the molecular mechanisms of such beneficial effects of RJ; (4) the safety and toxicity of RJ; and (5) the future directions of RJ-based treatment strategies, with a discussion on the limitations of the study of the biological activities of RJ.

• 10-hydroxy-2-decenoic acid
• anti-cancer effects
• malignancies
• royal jelly
• toxicities

Ninety percent of hepatocarcinoma (HCC) develops in a chronically damaged liver. Interactions between non‐tumor stromal components, especially macrophages, and cancer cells are still incompletely understood. Our aim was to determine whether a chronically injured liver represents a favorable environment for the seeding and growth of HCC cells, and to evaluate the potential roles of macrophages infiltrated within the tumor. HCC cells were injected into the liver in healthy mice (healthy liver group [HL]) and in mice chronically treated with carbon tetrachloride (CCl₄) for 7 weeks (CCl₄ 7w group). Livers were examined for the presence of tumor 2 weeks post‐injection. Tumor and non‐tumor tissues were analyzed for macrophage infiltration, origin (monocytes‐derived vs resident macrophages) and polarization state, and MMP production. Fifty‐three percent of mice developed neoplastic lesion in the HL group whereas a tumor lesion was found in all livers in the CCl₄ 7w group. Macrophages infiltrated more deeply the tumors of the CCl₄ 7w group. Evaluation of factors involved in the recruitment of macrophages and of markers of their polarization state was in favor of prominent infiltration of M2 pro‐tumor monocyte‐derived macrophages inside the tumors developing in a chronically injured liver. MMP‐2 and ‐9 production, attributed to M2 pro‐tumor macrophages, was significantly higher in the tumors of the CCl₄ 7w group. In our model, chronic liver damage promotes cancer development. Our results suggest that an injured background favors the infiltration of M2 pro‐tumor monocyte‐derived macrophages. These secrete MMP‐2 and MMP‐9 that promote tumor progression.

• hepatocarcinoma
• inflammation
• liver fibrosis
• macrophage
• matrix metalloproteinase