Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data.

Deviations of the immune cell landscape between healthy liver and hepatocellular carcinoma.

Tumor-infiltrating immune cells are highly relevant for prognosis and identification of immunotherapy targets in hepatocellular carcinoma (HCC). The recently developed CIBERSORT method allows immune cell profiling by deconvolution of gene expression microarray data. By applying CIBERSORT, we assessed the relative proportions of immune cells in 41 healthy human livers, 305 HCC samples and 82 HCC adjacent tissues.

Impact of glutathione peroxidase 4 on cell proliferation, angiogenesis and cytokine production in hepatocellular carcinoma.

Insufficient supplementation with the micronutrient selenium and persistent hepatic inflammation predispose to hepatocellular carcinoma (HCC). Inflammation-associated reactive oxygen species attack membrane lipids and form lipid hydroperoxides able to propagate oxidative hepatic damage. Selenium-containing enzyme glutathione peroxidase 4 (GPx4) antagonizes this damage by reducing lipid hydroperoxides to respective hydroxides.

Mesenchyme-derived factors enhance preneoplastic growth by non-genotoxic carcinogens in rat liver.

Many frequently prescribed drugs are non-genotoxic carcinogens (NGC) in rodent liver. Their mode of action and health risks for humans remain to be elucidated. Here, we investigated the impact of two model NGC, the anti-epileptic drug phenobarbital (PB) and the contraceptive cyproterone acetate (CPA), on intrahepatic epithelial-mesenchymal crosstalk and on growth of first stages of hepatocarcinogenesis.

The European Registered Toxicologist (ERT): Current status and prospects for advancement.

Following its inception in 1994, the certification of European Registered Toxicologists (ERT) by EUROTOX has been recognized as ensuring professional competence as well as scientific integrity and credibility. Criteria and procedures for registration are contained in the ERT "Guidelines for Registration 2012". The register of ERT currently has over 1900 members.

Proinflammatory mesenchymal effects of the non-genotoxic hepatocarcinogen phenobarbital: a novel mechanism of antiapoptosis and tumor promotion.

Many environmental pollutants and drugs, including steroid hormones, hypolipidemics and antiepileptics, are non-genotoxic carcinogens (NGC) in rodent liver. The mechanism of action and the risk for human health are still insufficiently known. Here, we study the effects of phenobarbital (PB), a widely used model NGC, on hepatic epithelial-mesenchymal crosstalk and the impact on hepatic apoptosis.

Superoxide deficiency attenuates promotion of hepatocarcinogenesis by cytotoxicity in NADPH oxidase knockout mice.

Long-term exposure to carcinogens combined with chronic hepatitis contributes greatly to the worldwide high incidence of hepatocellular carcinoma (HCC). It is still unclear to which extent the release of pro-inflammatory reactive oxygen or nitrogen species contributes to the development of this malignancy. Here, we aim to elucidate the role of superoxide in a model of chemical hepatocarcinogenesis.

Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma.

Recently, we found upregulation of fibroblast growth factor receptor 4 (FGFR4) in a subset of hepatocellular carcinoma (HCC). Here, we provide mechanistic insight into the role of FGFR4-mediated signalling for the aggressive behaviour of HCC cells. To overexpress FGFR4, hepatoma/hepatocarcinoma cells were transfected with a construct coding for FGFR4.

Food-derived peroxidized fatty acids may trigger hepatic inflammation: a novel hypothesis to explain steatohepatitis.

Background & Aims: Obesity and hepatic steatosis are frequently associated with the development of a non-alcoholic steatohepatitis (NASH). The mechanisms driving progression of a non-inflamed steatosis to NASH are largely unknown. Here, we investigated whether ingestion of peroxidized lipids, as being present in Western style diet, triggers the development of hepatic inflammation.

The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells.

To better understand the response of HCC to EGFR inhibition, we analyzed factors connected to the resistance of HCC cells against gefitinib. Sensitive HCC3 cells co-expressed EGFR and ErbB3 but lacked kinase-domain mutations in EGFR. Interestingly, expression of MVP was restricted to resistant cell lines, whereas ABCB1 and ABCC1 showed no association with gefitinib resistance.

Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma.

Unlabelled: Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth.

Inhibin/activin expression in human and rodent liver: subunits α and βB as new players in human hepatocellular carcinoma?

Background: Activins and inhibins belong to the TGFβ-superfamily, which controls cell proliferation and differentiation in many organs. Activin A, the dimer of inhibin βA subunit, acts strongly anti-proliferative in hepatocytes. Little is known on the other activin/inhibin subunits in human liver and hepatocellular carcinoma (HCC).

Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis.

Unlabelled: Fibroblast growth factors (FGFs) and their high-affinity receptors [fibroblast growth factor receptors (FGFRs)] contribute to autocrine and paracrine growth stimulation in several non-liver cancer entities. Here we report that at least one member of the FGF8 subfamily (FGF8, FGF17, and FGF18) was up-regulated in 59% of 34 human hepatocellular carcinoma (HCC) samples that we investigated. The levels of the corresponding receptors (FGFR2, FGFR3, and FGFR4) were also elevated in the great majority of the HCC cases.

Proteomics reveals acute pro-inflammatory and protective responses in rat Kupffer cells and hepatocytes after chemical initiation of liver cancer and after LPS and IL-6.

Inflammation is a key event in the development of liver cancer. We studied early inflammatory responses of Kupffer cells (KCs) and hepatocyte (HC) after cancer initiation. The chemical carcinogen N-nitrosomorpholine (NNM) was used in a rat model.

NORE1B is a putative tumor suppressor in hepatocarcinogenesis and may act via RASSF1A.

Recently, we found epigenetic silencing of the Ras effector genes NORE1B and/or RASSF1A in 97% of the hepatocellular carcinoma (HCC) investigated. This is strong evidence that the two genes are of major significance in hepatocarcinogenesis. Although RASSF1A serves as a tumor suppressor gene, the functions of NORE1B are largely unknown.

Inhalative exposure to vanadium pentoxide causes DNA damage in workers: results of a multiple end point study.

Background: Inhalative exposure to vanadium pentoxide (V(2)O(5)) causes lung cancer in rodents.

Objective: The aim of the study was to investigate the impact of V(2)O(5) on DNA stability in workers from a V(2)O(5) factory.

Methods: We determined DNA strand breaks in leukocytes of 52 workers and controls using the alkaline comet assay.

HB-EGF is a paracrine growth stimulator for early tumor prestages in inflammation-associated hepatocarcinogenesis.

Background/aims: We studied the impact of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on inflammation-driven hepatocarcinogenesis.

Methods: HB-EGF expression was determined by qRT-PCR and immunodetection in hepatocellular adenoma and carcinoma and in mesenchymal (MC) and parenchymal liver cells obtained from different models of inflammation. The functions of HB-EGF in early hepatocarcinogenesis were assessed in co-cultures of unaltered and initiated/premalignant hepatocytes.

Use of four new human-derived liver-cell lines for the detection of genotoxic compounds in the single-cell gel electrophoresis (SCGE) assay.

One of the main problems of in vitro genotoxicity assays is that the lack of adequate representation of drug-metabolising enzymes in indicator cell lines that are currently used in routine testing may lead to false results. In the present study, we investigated the ability of four new human-derived livercell lines to detect the DNA-damaging effects of representatives of different classes of genotoxic carcinogens that require metabolic activation, namely the nitrosamine N-nitrosodimethylamine (NDMA), the heterocyclic aromatic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), the polycyclic aromatic hydrocarbon benzo(a)pyrene (B(a)P) and the mycotoxin aflatoxin B1 (AFB1). Hydrogen peroxide (H2O2) was used in all experimental series as a positive control and parallel experiments were carried out with human HepG2 cells, which have been used in earlier studies.

Review of the toxicology of chlorpyrifos with an emphasis on human exposure and neurodevelopment.

This review examines the large body of toxicological and epidemiological information on human exposures to chlorpyrifos, with an emphasis on the controversial potential for chlorpyrifos to induce neurodevelopmental effects at low doses. The results of this review demonstrate that the use of urinary 3,5,6-trichlorpyridinol (TCPy), a metabolite of chlorpyrifos as a biomarker of nonoccupational exposure is problematic and may overestimate nonoccupational exposures to chlorpyrifos by 10-to 20-fold because of the widespread presence of both TCPy and chlorpyrifos-methyl in the food supply. Current "background" (nonoccupational) levels of exposure to chlorpyrifos are several orders of magnitude lower than those required to inhibit plasma cholinesterase activity, which is a more sensitive target than nervous system cholinesterase.

New cellular tools reveal complex epithelial-mesenchymal interactions in hepatocarcinogenesis.

To enable detailed analyses of cell interactions in tumour development, new epithelial and mesenchymal cell lines were established from human hepatocellular carcinoma by spontaneous outgrowth in culture. We obtained several hepatocarcinoma (HCC)-, B-lymphoblastoid (BLC)-, and myofibroblastoid (MF)-lines from seven cases. In-depth characterisation included cell kinetics, genotype, tumourigenicity, expression of cell-type specific markers, and proteome patterns.

Activins and activin antagonists in hepatocellular carcinoma.

In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor beta (TGFbeta) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo- or heterodimers formed from four different beta subunits termed betaA, betaB, betaC, and betaE, respectively.

Lipid hydroperoxides from processed dietary oils enhance growth of hepatocarcinoma cells.

Linoleic acid, one of the major fatty acid in dietary oils, is an important source for hydroperoxides that may be formed in the presence of oxygen during food processing. Oxidized oils are absorbed in the intestine, transported as chylomicrones to the liver, and may affect unaltered hepatic cells as well as the process of hepatocarcinogenesis. We have studied the effects of linoleic acid hydroperoxides (LOOH) on growth and gene expression of cultured human hepatocellular carcinoma cells (HCC-1.

Effects of coffee and its chemopreventive components kahweol and cafestol on cytochrome P450 and sulfotransferase in rat liver.

Coffee drinking appears to reduce cancer risk in liver and colon. Such chemoprevention may be caused by the diterpenes kahweol and cafestol (K/C) contained in unfiltered beverage. In animals, K/C treatment inhibited the mutagenicity/tumorigenicity of several carcinogens, likely explicable by beneficial modifications of xenobiotic metabolism, particularly by stimulation of carcinogen-detoxifying phase II mechanisms.

Cytotoxicity of the novel spin trapping compound 5-ethoxycarbonyl-3,5-dimethyl-pyrroline N-oxide (3,5-EDPO) and its derivatives.

ESR spin trapping allows detection of superoxide radicals. Novel spin traps forming more stable superoxide adducts (t(1/2) ca. 12-55 min) were tested for their toxicity to cultured cells.