EGFR has a tumor-promoting role in liver macrophages during hepatocellular carcinoma formation

Hepatocellular carcinoma (HCC) is a frequent cancer with limited treatment options and poor prognosis. Tumorigenesis has been linked with macrophage-mediated chronic inflammation and diverse signalling pathways, including the epidermal growth factor receptor (EGFR) pathway. The precise role of EGFR in HCC is unknown, and EGFR inhibitors have shown disappointing clinical results. Here we discover that EGFR is expressed in liver macrophages in both human HCC and in a mouse HCC model. Mice lacking EGFR in macrophages show impaired hepatocarcinogenesis, whereas mice lacking EGFR in hepatocytes unexpectedly develop more HCC owing to increased hepatocyte damage and compensatory proliferation. Mechanistically, following interleukin-1 stimulation, EGFR is required in liver macrophages to transcriptionally induce interleukin-6, which triggers hepatocyte proliferation and HCC. Importantly, the presence of EGFR-positive liver macrophages in HCC patients is associated with poor survival. This study demonstrates a tumour-promoting mechanism for EGFR in non-tumour cells, which could lead to more effective precision medicine strategies.

• Publication year

  2014

• Venue

  Nature Cell Biology

• Publication date

  2014-07-31

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncb3031PMID 25173978PMCID 4183558
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Clinical practice guidelines: Management of Hepatocellular Carcinoma

  2014cited by this paper
• miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β.

  2013cited by this paper
• miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-β He-Ping Li*,†, Xian-Cheng Zeng1,†, Bing Zhang2,†, Jian-Ting Long3, Bo Zhou, Guo-Sheng Tan, Wei-Xia Zeng4, Wei Chen and Jian-Yong Yang

  2013cited by this paper
• Targeted therapies in medical oncology: successes, failures and next steps

  2013cited by this paper
• EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.

  2012cited by this paper
• EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.

  2012cited by this paper
• Transactivation of EGFR by LPS Induces COX-2 Expression in Enterocytes

  2012cited by this paper
• Imiquimod clears tumors in mice independent of adaptive immunity by converting pDCs into tumor-killing effector cells.

  2012cited by this paper
• Phosphorylated p38 and JNK MAPK proteins in hepatocellular carcinoma

  2012cited by this paper
• Osteopontin expression predicts overall survival after liver transplantation for hepatocellular carcinoma in patients beyond the Milan criteria.

  2011cited by this paper
• NF-κB in liver cancer: the plot thickens.

  2011cited by this paper
• Global cancer statistics

  2011cited by this paper
• NF-κB and STAT3 – key players in liver inflammation and cancer

  2011cited by this paper
• The role of JNK in the development of hepatocellular carcinoma.

  2011cited by this paper
• The role of signaling pathways in the development and treatment of hepatocellular carcinoma

  2010cited by this paper
• Overexpression of aspartyl‐(asparaginyl)‐β‐hydroxylase in hepatocellular carcinoma is associated with worse surgical outcome

  2010cited by this paper
• Immunity, inflammation, and cancer.

  2010cited by this paper
• The plot thickens: hemoconcentration, renal function, and survival in heart failure.

  2010cited by this paper
• Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development.

  2010cited by this paper
• Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma.

  2008cited by this paper
• Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation.

  2008cited by this paper
• Contradictory functions of NF-kappaB in liver physiology and cancer.

  2008cited by this paper
• Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis.

  2008cited by this paper
• p38α MAPK inhibits JNK activation and collaborates with IκB kinase 2 to prevent endotoxin‐induced liver failure

  2008cited by this paper
• p38α suppresses normal and cancer cell proliferation by antagonizing the JNK–c-Jun pathway

  2007cited by this paper
• Gender Disparity in Liver Cancer Due to Sex Differences in MyD88-Dependent IL-6 Production

  2007cited by this paper
• The EGF receptor is required for efficient liver regeneration

  2007cited by this paper
• Correction for Natarajan et al., The EGF receptor is required for efficient liver regeneration

  2007cited by this paper
• Deletion of NEMO/IKKγ in Liver Parenchymal Cells Causes Steatohepatitis and Hepatocellular Carcinoma

  2007cited by this paper
• Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma.

  2007cited by this paper
• Genetics of hepatocellular tumors

  2006cited by this paper
• Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation.

  2006cited by this paper
• Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis

  2005cited by this paper
• ADAMs: key components in EGFR signalling and development

  2005cited by this paper
• IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis.

  2005cited by this paper
• Management of hepatocellular carcinoma

  2005cited by this paper
• Early molecular and genetic determinants of primary liver malignancy.

  2004cited by this paper
• Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma.

  2004cited by this paper
• Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53.

  2003cited by this paper
• Cellular origin of hepatocellular carcinomas.

  2002cited by this paper
• Inflammation and cancer

  2002cited by this paper
• The High Mobility Group (Hmg) Boxes of the Nuclear Protein Hmg1 Induce Chemotaxis and Cytoskeleton Reorganization in Rat Smooth Muscle Cells

  2001cited by this paper
• The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development.

  2000cited by this paper
• Conditional gene targeting in macrophages and granulocytes using LysMcre mice

  1999cited by this paper
• Fully localized brane intersections - the plot thickens

  1999cited by this paper
• Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.

  1996cited by this paper
• Management of hepatocellular carcinoma.

  1992cited by this paper
• Preparation of Pure Hepatocytes and Reticuloendothelial Cells in High Yield From a Single Rat Liver by Means of Percoll Centrifugation and Selective Adherence

  1985cited by this paper
• [Inflammation and cancer].

  1974cited by this paper

• Signaling Pathway Remodeling and Molecular Regulation in the HCC TME: Dynamic Evolution and Clinical Therapeutic Advances.

  2026cites this paper
• Uncovering the antiproliferative effects of magnolol in liver cancer: a multi-omics study integrating computational chemistry, network pharmacology, bioinformatics and in vitro experimental validations.

  2026cites this paper
• EGFR: New Insights on Its Activation and Mutation in Tumor and Tumor Immunotherapy

  2025cites this paper
• LTA4H improves the tumor microenvironment and prevents HCC progression via targeting the HNRNPA1/LTBP1/TGF-β axis

  2025cites this paper
• Network pharmacology-based identification of key pharmacological pathways of epimedium acting on hepatocellular carcinoma

  2025cites this paper
• Investigating the Anticancer Effect of Purified rCec-B Peptide in a DEN Murine Model: Insights into Tumorigenesis Prevention, Bioavailability, and Molecular Mechanisms.

  2025cites this paper
• CCA-1.1 Destabilizes MYC proteins to induce irreversible anti-proliferative effects in hepatocellular carcinoma

  2025cites this paper
• CIMT 2025: Report on the 22nd Annual Meeting of the Association for Cancer Immunotherapy

  2025cites this paper
• TYK2 Promotes Immunosurveillance of Colorectal Cancer Liver Metastasis

  2025cites this paper
• Synthesis, anticancer and anti-inflammatory evaluation of novel quinoxaline-1,3,4-oxadiazole derivatives as EGFR and COX-2 inhibitors

  2025cites this paper
• Protocol for assessing the effect of diesel particulate matter on the liver in vivo through hydrodynamic tail vein injection in mice

  2025cites this paper
• Prevention of liver cancer in the era of next-generation antivirals and obesity epidemic.

  2025cites this paper
• EGF receptor in organ development, tissue homeostasis and regeneration

  2025cites this paper
• Research progress of epidermal growth factor receptor in metabolic dysfunction‐associated steatotic liver disease and related diseases

  2025cites this paper
• Early boosting of p38 MAPK signaling pathway by lycorine hydrochloride potently inhibits PRRSV proliferation in primary and established cells

  2025cites this paper
• Antioxidant and anticancer properties of fucoidan isolated from Saccharina Japonica brown algae

  2025cites this paper
• Antiviral effects of mogroside V against porcine reproductive and respiratory syndrome virus in vitro

  2025cites this paper
• Integrated Network Pharmacology and Experimental Validation Reveal EGFR/p53/Bcl-2-Mediated Anti-Hepatocellular Carcinoma Effects of Zedoary Turmeric Oil.

  2025cites this paper
• EGFR controls transcriptional and metabolic rewiring in KRASG12D colorectal cancer

  2025cites this paper
• Radiation-induced amphiregulin drives tumour metastasis

  2025cites this paper
• PSMD9 promotes the malignant progression of hepatocellular carcinoma by interacting with c-Cbl to activate EGFR signaling and recycling

  2024cites this paper
• Kurarinol restrains non-alcoholic fatty liver disease-associated hepatocellular carcinoma (HCC) progression by suppressing EGFR signaling

  2024cites this paper
• ORF virus causes tumor-promoting inflammation in sheep and goats

  2024cites this paper
• Current and emerging strategies for the prevention of hepatocellular carcinoma

  2024cites this paper
• Machine learning based ultrasomics noninvasive predicting EGFR expression status in hepatocellular carcinoma patients

  2024cites this paper
• Targeting tumorous Circ-E-Cadherinencoded C-E-Cad inhibits the recruitment and function of breast cancer-associated myeloid-derived suppressor cells.

  2024cites this paper
• Resistance to Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma (HCC): Clinical Implications and Potential Strategies to Overcome the Resistance

  2024cites this paper
• Progress of research on the relationship between efferocytosis and tumor

  2024cites this paper
• Calotropis procera: Network Pharmacology-based Virtual Screening and Molecular Mechanism Exploration against Hepatocellular Carcinoma

  2024cites this paper
• Intelligent Modular DNA Lysosome-Targeting Chimera Nanodevice for Precision Tumor Therapy.

  2024cites this paper
• Inhibition of EGFR Pathway Suppresses M1 Macrophage Polarization and Osteoclastogenesis, Mitigating Titanium Particle-Induced Bone Resorption

  2024cites this paper
• CT-guided high dose rate brachytherapy can induce multiple systemic proteins of proliferation and angiogenesis predicting outcome in HCC

  2024cites this paper
• Design and synthesis of magnesium and palladium hybrid nanoparticles using Cyperus rotundus: An assessment of antimicrobial and anticancer applications

  2024cites this paper
• Coumarin-furo[2,3-d]pyrimidone hybrid molecules targeting human liver cancer cells: synthesis, anticancer effect, EGFR inhibition and molecular docking studies.

  2024cites this paper
• EGF-receptor phosphorylation and downstream signaling are activated by genistein during subacute liver damage

  2023cites this paper
• EGFR alterations in glioblastoma play a role in antitumor immunity regulation

  2023cites this paper
• Immunosuppressive mechanisms of oncofetal reprogramming in the tumor microenvironment: implications in immunotherapy response

  2023cites this paper
• Impact of Synthesized Indoloquinoline Analog to Isolates from Cryptolepis sanguinolenta on Tumor Growth Inhibition and Hepatotoxicity in Ehrlich Solid Tumor-Bearing Female Mice

  2023cites this paper
• Multi‐omic network analysis identified betacellulin as a novel target of omega‐3 fatty acid attenuation of western diet‐induced nonalcoholic steatohepatitis

  2023cites this paper
• Immuno-Desorption Electrospray Ionization Mass Spectrometry Imaging Identifies Functional Macromolecules by Using Microdroplet-Cleavable Mass Tags.

  2023cites this paper
• New and Old Key Players in Liver Cancer

  2023cites this paper
• Shp2 Deficiency in Kupffer Cells and Hepatocytes Aggravates Hepatocarcinogenesis by Recruiting Non-Kupffer Macrophages

  2023influential citation
• Hope and Challenges: Immunotherapy in EGFR-Mutant NSCLC Patients

  2023cites this paper
• EGFR mediates epithelial‑mesenchymal transition through the Akt/GSK-3β/Snail signaling pathway to promote liver cancer proliferation and migration

  2023cites this paper
• A highly oxidized germacranolide from elephantopus tomentosus inhibits the growth of hepatocellular carcinoma cells by targeting EGFR in vitro and in vivo.

  2023cites this paper
• The S100 calcium binding protein A11 promotes liver fibrogenesis by targeting TGF-β signaling.

  2022cites this paper
• In silico, in vitro screening of antioxidant and anticancer potentials of bioactive secondary metabolites from an endophytic fungus (Curvularia sp.) from Phyllanthus niruri L

  2022cites this paper
• Bleeding complications and possible resistance patterns of anti-angiogenesis treatments in recurrent/metastatic head-and-neck squamous cell carcinoma – Reflections from a phase II study of pazopanib in recurrent/metastatic head-and-neck squamous cell carcinoma

  2022cites this paper
• Short-course pembrolizumab and continuous afatinib therapy for recurrent or metastatic head and neck squamous cell carcinoma: a real-world data analysis

  2022cites this paper
• Toosendanin activates caspase-1 and induces maturation of IL-1β to inhibit type 2 porcine reproductive and respiratory syndrome virus replication via an IFI16-dependent pathway

  2022cites this paper
• Heparin binding epidermal growth factor–like growth factor is a prognostic marker correlated with levels of macrophages infiltrated in lung adenocarcinoma

  2022cites this paper
• In silico development and experimental validation of a novel 7-gene signature based on PI3K pathway-related genes in bladder cancer

  2022cites this paper
• Lack of EGFR catalytic activity in hepatocytes improves liver regeneration following DDC‐induced cholestatic injury by promoting a pro‐restorative inflammatory response

  2022cites this paper
• Melatonin alleviates alcoholic liver disease via EGFR–BRG1–TERT axis regulation

  2022cites this paper
• Melanoma differentiation associated gene‐9/syndecan binding protein promotes hepatocellular carcinoma

  2022cites this paper
• Liver Immunology, Immunotherapy, and Liver Cancers: Time for a Rethink?

  2022cites this paper
• Reprogramming the tumor microenvironment by genome editing for precision cancer therapy

  2022cites this paper
• Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology

  2022cites this paper
• Suppression of Betacellulin expression is a key mechanism for omega-3 fatty acid mediated attenuation of nonalcoholic steatohepatitis

  2022cites this paper
• Autocrine Osteopontin is involved in maintaining the growth and metastasis of Echinococcus multilocularis.

  2022cites this paper
• Local and systemic effects of interleukin‐6 (IL‐6) in inflammation and cancer

  2021cites this paper
• Molecular mechanisms underlying the effect of diacerein on trichloroacetic acid–induced hepatic pre-neoplastic lesions in rats

  2021cites this paper
• Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics

  2021cites this paper
• Representing Tumor-Associated Macrophages as the Angiogenesis and Tumor Microenvironment Regulator

  2021cites this paper
• Lepidium sativum Secondary Metabolites (Essential Oils): In Vitro and In Silico Studies on Human Hepatocellular Carcinoma Cell Lines

  2021influential citation
• Bringing Macrophages to the Frontline against Cancer: Current Immunotherapies Targeting Macrophages

  2021cites this paper
• The role of ADAM17 during liver damage

  2021cites this paper
• Induction of PI3K/Akt-Mediated Apoptosis in Osteoclasts Is a Key Approach for Buxue Tongluo Pills to Treat Osteonecrosis of the Femoral Head

  2021cites this paper
• RNF144A deficiency promotes PD-L1 protein stabilization and carcinogen-induced bladder tumorigenesis.

  2021cites this paper
• Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies

  2021cites this paper
• Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses

  2021cites this paper
• T cell derived HB-EGF prevents Th17 cell differentiation in an autocrine way

  2021cites this paper
• A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma

  2021cites this paper
• The two facets of gp130 signalling in liver tumorigenesis

  2021cites this paper
• Functional interaction between macrophages and hepatocytes dictate the outcome of liver fibrosis

  2021cites this paper
• Signaling pathways in hepatocellular carcinoma.

  2021cites this paper
• Lymphotoxin-β-receptor (LTβR) signaling on hepatocytes is required for liver regeneration after partial hepatectomy

  2021cites this paper
• The quinazoline derivative, 04NB-03, induces cell cycle arrest and apoptosis in hepatocellular carcinoma cells in a reactive oxygen species-dependent manner.

  2021cites this paper
• Antitumour immunity regulated by aberrant ERBB family signalling

  2021cites this paper
• Low Inorganic Phosphate Stress Inhibits Liver Cancer Progression: from In Vivo to In Vitro

  2021cites this paper
• METTL1‐m7G‐EGFR/EFEMP1 axis promotes the bladder cancer development

  2021cites this paper
• Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome.

  2021cites this paper
• PATZ1 (MAZR) Co-occupies Genomic Sites With p53 and Inhibits Liver Cancer Cell Proliferation via Regulating p27

  2021cites this paper
• Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer

  2020cites this paper
• Establishment of a low-tumorigenic MDCK cell line and study of differential molecular networks.

  2020cites this paper
• Interleukin-6 signalling in health and disease

  2020cites this paper
• A novel prognostic index of hepatocellular carcinoma based on immunogenomic landscape analysis

  2020cites this paper
• Correction: Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway

  2020cites this paper
• Relevance of EGFR Between Serum VEGF and MMP-9 in Primary Hepatocellular Carcinoma Patients with Transarterial Chemoembolization

  2020cites this paper
• Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis

  2020cites this paper
• ADAM-Mediated Signalling Pathways in Gastrointestinal Cancer Formation

  2020cites this paper
• Annona senegalensis extract demonstrates anticancer properties in N-diethylnitrosamine-induced hepatocellular carcinoma in male Wistar rats.

  2020cites this paper
• Cisplatin promotes the expression level of PD-L1 in the microenvironment of hepatocellular carcinoma through YAP1

  2020cites this paper
• PDF AhR controls redox homeostasis and shapes the tumour microenvironment in BRCA1-associated breast cancer

  2020cites this paper
• Hepatobiliary Tumors: Immunopathology and Immunotherapy

  2020cites this paper
• IL-1 Signaling in Tumor Microenvironment.

  2020cites this paper
• Bile Acids as Signaling Molecules

  2020cites this paper
• Interleukin-6 signalling in health and disease [version 1; peer review: 3 approved]

  2020cites this paper
• Cetuximab enhances the anti-tumor function of macrophages in an IL-6 dependent manner.

  2020cites this paper
• Cell Proliferation, Survival, Necrosis and Apoptosis

  2020cites this paper