Show simple item record

dc.contributor.authorTechnische Universitat München
dc.contributor.authorDavis, Roger J.
dc.contributor.authorHeikenwalder, Mathias
dc.date2022-08-11T08:09:19.000
dc.date.accessioned2022-08-23T16:26:32Z
dc.date.available2022-08-23T16:26:32Z
dc.date.issued2017-06-12
dc.date.submitted2017-07-20
dc.identifier.citationCancer Cell. 2017 Jun 12;31(6):771-789.e6. doi: 10.1016/j.ccell.2017.05.006. <a href="https://doi.org/10.1016/j.ccell.2017.05.006">Link to article on publisher's site</a>
dc.identifier.issn1535-6108 (Linking)
dc.identifier.doi10.1016/j.ccell.2017.05.006
dc.identifier.pmid28609656
dc.identifier.urihttp://hdl.handle.net/20.500.14038/36585
dc.description<p>Full author list omitted for brevity. For the full list of authors, see article.</p>
dc.description.abstractIntrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=28609656&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttps://doi.org/10.1016/j.ccell.2017.05.006
dc.subjectJNK
dc.subjectKupffer cell
dc.subjectTnf
dc.subjectcholastasis
dc.subjectintrahepatic cholangiocarcinoma
dc.subjectmitochondrial dysfunction
dc.subjectpro-inflammatory niche
dc.subjectreactive oxygen species
dc.subjectunfolded protein response
dc.subjectBiochemistry
dc.subjectCancer Biology
dc.subjectCell Biology
dc.subjectCellular and Molecular Physiology
dc.subjectMolecular Biology
dc.titleKupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS
dc.typeJournal Article
dc.source.journaltitleCancer cell
dc.source.volume31
dc.source.issue6
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/metnet_pubs/103
dc.identifier.contextkey10458187
html.description.abstract<p>Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.</p>
dc.identifier.submissionpathmetnet_pubs/103
dc.contributor.departmentDavis Lab
dc.contributor.departmentUMass Metabolic Network
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages771-789.e6


Files in this item

Thumbnail
Name:
Publisher version

This item appears in the following Collection(s)

Show simple item record