EGFR has a tumour-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...

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Published inNature cell biology Vol. 16; no. 10; pp. 972 - 981
Main Authors Lanaya, Hanane, Natarajan, Anuradha, Komposch, Karin, Li, Liang, Amberg, Nicole, Chen, Lei, Wculek, Stefanie K, Hammer, Martina, Zenz, Rainer, Peck-Radosavljevic, Markus, Sieghart, Wolfgang, Trauner, Michael, Wang, Hongyang, Sibilia, Maria
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 01.10.2014
Subjects
Animals
Apoptosis
Blotting, Western
Cancer
Carcinoma, Hepatocellular - chemically induced
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - metabolism
Cells, Cultured
Cytokines
Development and progression
Diethylnitrosamine
Epidermal growth factor
ErbB Receptors - genetics
ErbB Receptors - metabolism
Gastroenterology
Genetic aspects
Hepatitis
Hepatocytes - metabolism
Hepatology
Hepatoma
Humans
Immunohistochemistry
Interleukin-1beta - pharmacology
Kupffer Cells - drug effects
Kupffer Cells - metabolism
Liver - metabolism
Liver - pathology
Liver cancer
Liver Neoplasms - chemically induced
Liver Neoplasms - genetics
Liver Neoplasms - metabolism
Macrophages - metabolism
Male
Medical prognosis
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Mice, Transgenic
Oncology, Experimental
Phosphorylation - drug effects
Signal transduction
Tumors
Austria
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Summary: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.
Bibliography:AUTHOR CONTRIBUTION AN designed, performed and analyzed in vivo tumor experiments with the EGFRΔhep, EGFRΔMx and EGFRΔMx* mice. HL designed, performed and analyzed in vitro experiments, some Western Blot analysis and performed in vivo tumor experiments with EGFRΔhep/Δmac and EGFRΔmac mice. KK performed in vivo analyses with EGFRΔhep/Δmac and EGFRΔmac mice, in vitro analyses with Kupffer cells including Western blot analysis. NA helped with histology, immunohistochemistry and immunofluorescence. SKW helped with qRT-PCRs, MH helped with histology, mouse colony and animal experiments. LL and LC performed stainings on all human samples (Chinese and European cohorts) and analyzed the Chinese cohort with the supervision of HW. WS analyzed the European cohort together with MT and MPR. RZ and MS wrote the manuscript with the input from HL, AN, NA, WS, MT, MPR, HW and with major contributions during the revision phase from KK. MS conceived and supervised the whole project.
ISSN:1465-7392
1476-4679
DOI:10.1038/ncb3031