Lineage fate of ductular reactions in liver injury and carcinogenesis

Jörs, Simone; Jeliazkova, Petia; Ringelhan, Marc; Thalhammer, Johann G.; Dürl, S; Ferrer, Jorge; Sander, Maike; Heikenwälder, Mathias; Schmid, RM; Siveke, JT; Geisler, Fabian

doi:10.1055/s-0034-1397072

Cited by 22 publications

(30 citation statements)

References 25 publications

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“…In agreement with the data presented here, a recent study using Hnf1b-CreERT labeling of the LPC/biliary compartment found no contribution of this compartment to HCC in DEN-or Mdr2 KO -induced HCC (49), which complements the findings presented here. However, in contrast to our study, the authors did not positively identify the cellular source of HCC.…”

Section: Tracing Of Hepatocytes In Hepatocarcinogenesissupporting

confidence: 92%

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

Español–Suñer

Mederacke

et al. 2015

Journal of Clinical Investigation

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Section: Tracing Of Hepatocytes In Hepatocarcinogenesissupporting

confidence: 92%

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

Español–Suñer

Mederacke

et al. 2015

Journal of Clinical Investigation

183

177

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“…Moreover, JAG1 is coexpressed with CK19 in developing organoids, and the bile duct-like tubules develop within the areas surrounded by JAG1-expressing cells. These findings are consistent with the inhibitory effect that NOTCH1 signaling has on hepatocyte proliferation (58) and in promoting intrahepatic bile duct development (13,59). Given the composition of the cells within the HOs, immune-mediated destruction or inflammation cannot occur within developing organoid cultures.…”

Section: Discussionsupporting

confidence: 74%

Human hepatic organoids for the analysis of human genetic diseases

Guan¹,

Xu²,

Garfin³

et al. 2017

JCI Insight

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“…Oval cells were initially believed to serve as a substitute progenitor compartment for both cholangiocytes and hepatocytes if acute or chronic liver injury compromises selfduplication of the mature epithelial cells. (42) However, recent data demonstrate that the adult liver progenitor compartment within biliary compartment-derived ductular reactions does not function to replenish a significant proportion of hepatocytes, and ductular cells are not the main source of malignant transformation in HCC (43,44) but rather indicate severe liver damage.…”

Section: Discussionmentioning

confidence: 99%

Canonical NF‐κB signaling in hepatocytes acts as a tumor‐suppressor in hepatitis B virus surface antigen‐driven hepatocellular carcinoma by controlling the unfolded protein response

et al. 2016

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Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC).Efficient suppression of HBV viremia and necroinflammation as a result of nucleos(t)ide analogue treatment is able to reduce HCC incidence; nevertheless, hepatocarcinogenesis can occur in the absence of active hepatitis, correlating with high HBV surface antigen (HBsAg) levels. Nuclear factor jB (NF-jB) is a central player in chronic inflammation and HCC development. However, in the absence of severe chronic inflammation, the role of NF-jB signaling in HCC development remains elusive. As a model of hepatocarcinogenesis driven by accumulation of HBV envelope polypeptides, HBsAg transgenic mice, which show no HBV-specific immune response, were crossed to animals with hepatocyte-specific inhibition of canonical NF-jB signaling. We detected prolonged, severe endoplasmic reticulum stress already at 20 weeks of age in NF-jB-deficient hepatocytes of HBsAg-expressing mice. The unfolded protein response regulator binding immunoglobulin protein/78-kDa glucose-regulated protein was down-regulated, activating transcription factor 6, and eIF2a were activated with subsequent overexpression of CCAAT/enhancer binding protein homologous protein. Notably, immune cell infiltrates and liver transaminases were unchanged. However, as a result of this increased cellular stress, insufficient hepatocyte proliferation due to G 1 /S-phase cell cycle arrest with overexpression of p27 and emergence of ductular reactions was detected. This culminated in increased DNA damage already at 20 weeks of age and finally led to 100% HCC incidence due to NF-jB inhibition. Conclusion: The role of canonical NF-jB signaling in HCC development depends on the mode of liver damage; in the case of HBsAg-driven hepatocarcinogenesis, NF-jB in hepatocytes acts as a critical tumor suppressor by augmenting the endoplasmic reticulum stress response. (HEPATOLOGY 2016;63:1592-1607

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Lineage fate of ductular reactions in liver injury and carcinogenesis

Cited by 22 publications

References 25 publications

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment

Human hepatic organoids for the analysis of human genetic diseases

Canonical NF‐κB signaling in hepatocytes acts as a tumor‐suppressor in hepatitis B virus surface antigen‐driven hepatocellular carcinoma by controlling the unfolded protein response

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