Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.
Cancer Cell, 2012/4/17;21(4):504-16.
Dapito DH[1], Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, Lefkowitch JH, Bower M, Friedman R, Sartor RB, Rabadan R, Schwabe RF
Affiliations
PMID: 22516259DOI: 10.1016/j.ccr.2012.02.007
Impact factor: 38.585
Abstract
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.
MeSH terms
Animals; Apoptosis; Bacterial Translocation; Cell Proliferation; Epidermal Growth Factor; Epiregulin; Humans; Intestines; Liver Diseases; Liver Neoplasms, Experimental; Mice; Mice, Inbred C57BL; Toll-Like Receptor 4; Tumor Cells, Cultured
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