Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents.
Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation.


CONCLUSIONS
Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC.
Yu
Le-Xing
LX
International Cooperation Laboratory on Signal Transduction, Liver Centre of SMMU, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Yan
He-Xin
HX
Liu
Qiong
Q
Yang
Wen
W
Wu
Hong-Ping
HP
Dong
Wei
W
Tang
Liang
L
Lin
Yan
Y
He
Ya-Qin
YQ
Zou
Shan-Shan
SS
Wang
Chao
C
Zhang
Hui-Lu
HL
Cao
Guang-Wen
GW
Wu
Meng-Chao
MC
Wang
Hong-Yang
HY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002273:Carcinogens / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004052:Diethylnitrosamine / Q000633:toxicity; D007422:Intestines / Q000382:microbiology; D008070:Lipopolysaccharides / Q000097:blood / Q000494:pharmacology*; D008103:Liver Cirrhosis / Q000150:complications; D008113:Liver Neoplasms / Q000209:etiology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009355:Neomycin / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D002273:Carcinogens; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004052:Diethylnitrosamine; D009355:Neomycin; D011112:Polymyxin B