Promotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4

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 c...

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Bibliographic Details
Published in:Cancer cell 2012-04, Vol.21 (4), p.504-516
Main Authors: Dapito, Dianne H., Mencin, Ali, Gwak, Geum-Youn, Pradere, Jean-Philippe, Jang, Myoung-Kuk, Mederacke, Ingmar, Caviglia, Jorge M., Khiabanian, Hossein, Adeyemi, Adebowale, Bataller, Ramon, Lefkowitch, Jay H., Bower, Maureen, Friedman, Richard, Sartor, R. Balfour, Rabadan, Raul, Schwabe, Robert F.
Format: Article
Language:English
Subjects:
Animals
Apoptosis - genetics
Bacterial Translocation
Cell Proliferation
Epidermal Growth Factor - metabolism
Epiregulin
Humans
Intestines - microbiology
Liver Diseases - complications
Liver Diseases - microbiology
Liver Neoplasms, Experimental - genetics
Liver Neoplasms, Experimental - microbiology
Liver Neoplasms, Experimental - pathology
Mice
Mice, Inbred C57BL
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - physiology
Tumor Cells, Cultured
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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. ► The gut microbiota and TLR4 play a role in HCC promotion but not in HCC initiation ► Gut sterilization, germfree status or TLR4 inactivation reduce HCC by 80%–90% ► Gut sterilization efficiently suppresses hepatocarcinogenesis even when given late ► Resident liver cells but not BM-derived cells promote HCC through TLR4
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2012.02.007