Title

Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS

UMMS Affiliation

Program in Molecular Medicine; UMass Metabolic Network; Davis Lab

Date

6-12-2017

Document Type

Article

Disciplines

Biochemistry | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Molecular Biology

Abstract

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.

Rights and Permissions

Citation: Cancer Cell. 2017 Jun 12;31(6):771-789.e6. doi: 10.1016/j.ccell.2017.05.006. Link to article on publisher's site

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

Keywords

JNK, Kupffer cell, Tnf, cholastasis, intrahepatic cholangiocarcinoma, mitochondrial dysfunction, pro-inflammatory niche, reactive oxygen species, unfolded protein response

PubMed ID

28609656