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  1. Article ; Online: EGFR Signaling in Liver Diseases.

    Komposch, Karin / Sibilia, Maria

    International journal of molecular sciences

    2015  Volume 17, Issue 1

    Abstract: The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR ...

    Abstract The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
    MeSH term(s) Animals ; Cell Transformation, Neoplastic/metabolism ; ErbB Receptors ; Humans ; Liver Diseases/metabolism ; Liver Diseases/physiopathology ; Liver Regeneration ; Mice ; Signal Transduction
    Chemical Substances ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2015-12-29
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms17010030
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Hepatocyte-Specific Deletion of EGFR in Mice Reduces Hepatic Abcg2 Transport Activity Measured by [

    Traxl, Alexander / Komposch, Karin / Glitzner, Elisabeth / Wanek, Thomas / Mairinger, Severin / Langer, Oliver / Sibilia, Maria

    Drug metabolism and disposition: the biological fate of chemicals

    2017  Volume 45, Issue 10, Page(s) 1093–1100

    Abstract: The epidermal growth factor receptor (EGFR) regulates cellular expression levels of breast cancer resistance protein (humans: ABCG2, rodents: Abcg2) via its downstream signaling pathways. Drugs that inhibit EGFR signaling (e.g., tyrosine kinase ... ...

    Abstract The epidermal growth factor receptor (EGFR) regulates cellular expression levels of breast cancer resistance protein (humans: ABCG2, rodents: Abcg2) via its downstream signaling pathways. Drugs that inhibit EGFR signaling (e.g., tyrosine kinase inhibitors, antibodies) may lead to ABCG2-mediated drug-drug interactions (DDIs) by changing the disposition of concomitantly administered ABCG2 substrate drugs. In this study, we used positron emission tomography and magnetic resonance imaging to compare disposition of the model Abcg2 substrate [
    Language English
    Publishing date 2017-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 186795-7
    ISSN 1521-009X ; 0090-9556
    ISSN (online) 1521-009X
    ISSN 0090-9556
    DOI 10.1124/dmd.117.077081
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation.

    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

    Nature cell biology

    2014  Volume 16, Issue 10, Page(s) 972–977

    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 ... ...

    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.
    MeSH term(s) Animals ; Blotting, Western ; Carcinoma, Hepatocellular/chemically induced ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; Cells, Cultured ; Diethylnitrosamine ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Hepatocytes/metabolism ; Humans ; Immunohistochemistry ; Interleukin-1beta/pharmacology ; Kupffer Cells/drug effects ; Kupffer Cells/metabolism ; Liver/metabolism ; Liver/pathology ; Liver Neoplasms/chemically induced ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Macrophages/metabolism ; Male ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Knockout ; Mice, Transgenic ; Phosphorylation/drug effects
    Chemical Substances Interleukin-1beta ; Diethylnitrosamine (3IQ78TTX1A) ; ErbB Receptors (EC 2.7.10.1)
    Language English
    Publishing date 2014-08-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/ncb3031
    Database MEDical Literature Analysis and Retrieval System OnLINE

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