title: EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation.
abstract: 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.
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Hanane
authors.initials: H
authors.lastname: Lanaya
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Natarajan
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Komposch
authors.affiliation: National Center for Liver Cancer. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute / Hospital, Shanghai, 225 Changhai Road, Shanghai 200438, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Amberg
authors.affiliation: National Center for Liver Cancer. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute / Hospital, Shanghai, 225 Changhai Road, Shanghai 200438, P.R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Stefanie K
authors.initials: SK
authors.lastname: Wculek
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Hammer
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Zenz
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sieghart
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: National Center for Liver Cancer. International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute / Hospital, Shanghai, 225 Changhai Road, Shanghai 200438, P.R. China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Sibilia
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004052:Diethylnitrosamine; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000187:drug effects
chemical_list: D053583:Interleukin-1beta; D004052:Diethylnitrosamine; D066246:ErbB Receptors