Promotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4
By D. Dapito, Ali A. Mencin, G. Gwak, J. Pradère, M. Jang, I. Mederacke, J. Caviglia, Hossein Khiabanian, Adebowale Adeyemi, R. Bataller and 6 more. Cancer Cell, 2012
1,240 citations recorded by the source corpus.
SUMMARY Increased translocation of intestinal bacteria is a hallmark of chronic liver disease and contributes to hepatic inflammation and fibrosis. Here we tested the hypothesis that the intestinal microbiota and Toll-like receptors (TLRs) promote hepatocellular carcinoma (HCC), a long-term consequence of chronic liver injury, inflammation and fibrosis. Hepatocarcinogenesis in chronically injured livers depended on the intestinal microbiota, and TLR4 activation in non-bone marrow-derived resident liver cells. TLR4 and the intestinal microbiota were not required for HCC initiation but for HCC promotion, mediating increased proliferation, expression of the hepatomitogen epiregulin, and prevention of apoptosis. Gut sterilization restricted to late stages of hepatocarcinogenesis reduced HCC suggesting that the intestinal microbiota and TLR4 represent therapeutic targets for HCC prevention in advanced liver disease.
Subfields: Epidemiology, Molecular Biology, Oncology
View Paper: https://www.semanticscholar.org/paper/f0fae94d834839031129cab9f7bda38dd85d4335
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Citations in the corpus
- Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “Liver cancer and NASH/fibrosis which underlies HCC development are actively promoted by intestinal bacteria and their products (Dapito et al., 2012; Shalapour et al., 2017) and recent studies highlight the role of lung microbiota in induction of inflammation and tumorigenesis (Greathouse et al.”
- Hepatic Stellate Cells and Liver Fibrosis (2013, neutral): “growth of both primary and metastatic tumors (47, 134, 209).”
- The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer (2016, background): “In the chronically injured liver, epiregulin is predominantly expressed by activated HSCs and strongly upregulated by LPS (70).”
- Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma (2018, background): “15 Notably, the decrease of Verrucomicrobia is likely attributed to the decrease of Akkermansia in the early HCC. Akkermansia muciniphila is a Gram-negative anaerobic commensal that uses host-derived mucins as carbon and nitrogen source 43 and promotes barrier function partly by enhancing mucus…”
- Interaction between microbiota and immunity in health and disease (2020, background): “Recent studies also demonstrated carcinogenic effects of microbiome-derived small molecules via regulation of immune responses in liver malignancy, including secondary bile acid mediating upregulation of hepatic NKT cells,(189) deoxycholic acid modulating the inflammatory secretome,(235) lipoteichoi”
- Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. (2019, background): “…in humans), this strategy can reduce bacterial translocation and KC activation through TLR4 and improve experimental steatohepatitis (in a CX3CR1-dependent way) (Schneider et al., 2015), fibrosis (TLR4 is expressed by activated HSC/MFs) (Seki et al., 2007) and carcinogenesis (Dapito et al., 2012).”
- The microbiome and cancer (2018, background): “Bone marrow from TLR4 wild-type animals was not able to restore the oncogenic effect of the microbiota in a TLR4 knockout host, pointing to resident cells in the liver driving the oncogenic effect of the microbiota [74].”