Endotoxin Accumulation Prevents Carcinogen-Induced Apoptosis and Promotes Liver Tumorigenesis in Rodents

Abstract

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-jB 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 DENinduced cytokine production and compensatory proliferation, whereas in vivo LPS prechallenge promotes hepatocyte proliferation. Conclusion: 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. (HEPATOLOGY 2010;52:1322-1333

Intracellular Osteopontin Inhibits Toll-like Receptor Signaling and Impedes Liver Carcinogenesis

“…TLR4 is the major receptor recognizing endogenous ligands released from damaged or dying cells; it participates in cytokine expression mainly in myeloid cells and promotes liver tumorigenesis (47). Mice deficient in MyD88 or TLR4 had a significant reduction in tumor incidence in DENinduced liver cancer (24,48). These findings suggest that in DENinduced HCC, production of cytokines by resident liver macrophages is mainly via the TLR4/MyD88 signaling.…”

Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein

“…To demonstrate the success of BMT in mice, the blood and bone marrow of the chimeric mice were collected and genomic DNA was extracted. The presence of the Tlr4 gene was measured by means of quantitative PCR 14 . The Tlr4 primers were: forward: 5 0 -GCAACTTGG ACCTG-3 0 ; reverse: 5 0 -ATCTGTGAGCGTGTAT-3 0 .…”

“…Immunoblotting analysis was performed as described previously 14 . The primary antibody anti-HMGB1 (1:1,000) were purchased from Abcam, UK; the anti-b-actin antibody (1:200) were obtained from Santa Cruz Biotechnology, Inc.; and the anti-TSG101 antibody (1:1,000) were obtained from ABclonal Biotech Co., Ltd.…”

“…Depending on the composition of the cells in the microenvironment and stage of disease, activation of TLR4 signalling can either stimulate 14 or inhibit 15 tumour development. Studies focusing on the endotoxin and tumour cell TLR4 have already shown that endotoxin is a potent promoter of tumour metastasis when infused systemically 16 , and that tumour cell TLR4 activation by endotoxin resulted in EMT of tumour cells and augmented metastasis 17 .…”

TLR2 Limits Development of Hepatocellular Carcinoma by Reducing IL18-Mediated Immunosuppression

“…Although the role of TLRs in tumorigenesis has been extensively studied (10)(11)(12)(13)(14), the role of TLR2 in particular remains obscure. For example, TLR2 was reported to promote gastric tumorigenesis due to STAT3 activation (15), and blocking TLR2 attenuated pulmonary metastases of melanoma and increased both the survival rate and recovery of tumor-killing cells (16).…”