Extrahepatic Carcinogenesis Research Articles

Doença hepática gordurosa não-alcoólica e neoplasias extra-hepáticas: uma revisão narrativa

ABSTRACT Background: Recently, significant associations between non-alcoholic fatty liver disease (NAFLD) and extra-hepatic cancer have been reported. Objective: To carry out a comprehensive review of the current evidence in the literature on the association between NAFLD and extra-hepatic cancer. Methods: A narrative literature review was performed through an online search for the MeSH terms “fatty liver” and “cancer” in MEDLINE (via PubMed) and LILACS (via BVS). Original studies that described the impact of NAFLD on different types of extra-hepatic malignancies were included. Results: After careful analysis, nine prospective cohort studies, one retrospective cohort study, three case-control studies, and three cross-sectional studies were selected. Conclusion: There is consistent evidence on the association between NAFLD and extra-hepatic carcinogenesis, especially in relation to colorectal, gastric, pancreatic, breast, prostate, and bladder cancers.

Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis.

Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes. This article is highlighted in the In This Issue feature, p. 1501.

Serum Nutritional Markers as Prognostic Factors for Hepatic and Extrahepatic Carcinogenesis in Japanese Patients with Nonalcoholic Fatty Liver Disease

Serum zinc (Zn) levels and the branched chain amino acid/tyrosine molar ratio (BTR) were reported to decrease with the progression of various chronic liver diseases. We investigated the impact of BTR and Zn on the incidence of malignancies in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). A total of 179 Japanese NAFLD patients who underwent liver biopsy were enrolled. Hepatocellular carcinoma (HCC) and extrahepatic malignancies developed in 7 (3.9%) and 10 (5.6%) patients, respectively, during the follow-up period (median 7.9 years). Patients with low BTR levels (<5.0) and Zn deficiency (<70 μg/dL) had significantly higher incidences of HCC and extrahepatic malignancies (P < 0.001 and 0.026), respectively. Multiple logistic regression analyses revealed the following risk factors: liver fibrosis (F3–4) (hazard ratio [HR] 24.292, 95% confidence interval [CI] 2.802–210.621, P = 0.004) and BTR < 5.0 (HR 5.462, 95% CI 1.095–27.253, P = 0.038) for HCC, and serum Zn level <70 μg/dL (HR 3.504, 95% CI 1.010–12.157, P = 0.048) and liver inflammation (A2–3) (HR 3.445, 95% CI 0.886–13.395, P = 0.074) for extra-hepatic malignancies. In conclusion, serum BTR and Zn levels were useful for predicting HCC and extrahepatic malignancies in NAFLD, respectively.

THU-314-Serum Zinc levels as a prognostic factor for extra-hepatic carcinogenesis in Japanese patients with non-alcoholic liver disease

THU-314-Serum Zinc levels as a prognostic factor for extra-hepatic carcinogenesis in Japanese patients with non-alcoholic liver disease

Anti-idiotypic nanobody-phage based real-time immuno-PCR for detection of hepatocarcinogen aflatoxin in grains and feedstuffs.

Aflatoxins are a group of extremely toxic small molecules that have been involved in human hepatic and extrahepatic carcinogenesis as causative agents. Herein, we developed a real-time immuno polymerase chain reaction (IPCR) assay for the accurately quantitative detection of aflatoxins in agri-products base on a M13 phage containing aflatoxin anti-idiotypic nanobody and its encoding DNA which was used to design the specific primers. The limit of detection (LOD) of the assay is 0.02 ng/mL, which exhibits a 4-fold improvement over traditional phage ELISA. The developed method was successfully validated with the samples of corn, rice, peanut, and feedstuff, which are major aflatoxin-contaminated agri-products. And the recoveries were from 77.05 to 122.16%. For further validation, the developed assay was also compared with a reference HPLC method for the analysis of aflatoxins in corn and peanuts, and concordant results (R(2) = 0.991) were obtained. In this context, this study provides a novel opportunity to analyze aflatoxins in agri-products.

Inhibition of aflatoxin B1, B2, G1 and G2 production by Aspergillus parasiticus in nuts using yellow and oriental mustard flours

Aflatoxins (AFs) are naturally occurring mycotoxin compounds produced by several species of Aspergillus, as Aspergillus flavus and Aspergillus parasiticus and are mutagenic, teratogenic, and carcinogenic compounds that have been implicated as causative agents in human hepatic and extra hepatic carcinogenesis. In this study, the reduction of the AFs present in dried fruits (peanut, cashew, walnut, almond, hazelnut and pistachio), produced by A. parasiticus CECT 2681, by isothiocyanates (ITCs) generated by the enzymatic hydrolysis of the glucosinolates (GLCs) present in oriental and yellow mustard flours was evaluated. The AFs reduction activity through ITCs application in dried fruits was carried out using a model and food system experiments. The quantification of the AFs in the food products analyzed was carried out employing the technique of the liquid chromatography (LC) coupled to the mass spectrometry detection in tandem (MS/MS). The ITCs produced through GLCs hydrolysis reduced the A. parasiticus growth in the food products tested and in particular in the model system experiments the AFs B1, B2, G1 and G2 reduction ranged meanly from 83.1 to 87.2% using the oriental mustard flour, whereas employing the yellow flour the mean reduction observed ranged from 27.0 to 32.5%. In the food system experiments carried out employing only the oriental mustard flour the mean AFs reduction observed ranged from 88 to 89%.

Assessment of Aflatoxin M1 Levels by Enzyme-linked Immunosorbent Assay in Yoghurt Consumed in Tehran, Iran

Aflatoxins are the best known and most intensively researched mycotoxins produced by different species of Aspergillus namely A. flavus, A. parasiticus, A. bombycis, A. ochraceoroseus, A. nomius and A. pseudotamari, which contaminate agricultural commodities and feeds, particularly at a critical temperature and humidity conditions. The main types of aflatoxins are B1, B2, G1, G2, M1 and M2 . Aflatoxins are highly toxic, mutagenic, immunosuppressive, teratogenic and carcinogenic compounds that have been implicated to be the causative agents in human hepatic and extrahepatic carcinogenesis. Aflatoxin M1 (AFM1) has been found in the milk of animals when lactating animals are fed with aflatoxin B1 (AFB1) contaminated feeds. The International Agency for Research on Cancer of World Health Organization included aflatoxin B1 as primary and aflatoxin M1 as secondary groups of carcinogenic compounds. Aflatoxin M1 is the monohydroxylated metabolite of aflatoxin B1 forming in liver by means of microsomial cytochrome P450associated enzymes. There was a linear relationship between the amount of aflatoxin M1 in milk and aflatoxin B1 in the feed, which is consumed by these animals. Monitoring studies reported that approximately 0.3-6.2 % of aflatoxin B1 ingested by livestock is transformed to aflatoxin M1 in milk. However, this Assessment of Aflatoxin M1 Levels by Enzyme-linked Immunosorbent Assay in Yoghurt Consumed in Tehran, Iran

Reactive oxygen species from the uncoupling of human cytochrome P450 1B1 may contribute to the carcinogenicity of dioxin-like polychlorinated biphenyls

Polychlorinated biphenyls (PCBs) are classified by the International Agency for Research on Cancer as probable human carcinogens. A subset of PCBs are described as 'dioxin like' because of similarities to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Dioxin-like PCBs have been shown to tightly bind the active site of cytochrome P450 (CYP) 1A isoforms, primarily CYP1A1, resulting in inhibition of CYP activity and the generation of reactive oxygen species (ROS) as a result of uncoupling of the catalytic cycle. Human CYP1B1 (hCYP1B1) is an extrahepatic CYP closely related to hCYP1A1 and is overexpressed in the lungs of smokers. Moreover, hCYP1B1 has been found to be overexpressed in cancers derived from a number of tissue types, as well as in pre-malignant prostate tumours, implicating overexpression of hCYP1B1 as a risk factor for extrahepatic carcinogenesis. It has been demonstrated previously that hCYP1B1 is inhibited by dioxin-like PCBs, but whether or not it is uncoupled has not been investigated. In the current study, the ability of three dioxin-like PCBs 3,3',4,4'-tetrachlorobiphenyl, 3,3',4,4',5-pentachlorobiphenyl and 3,3',4,4',5,5'-hexachlorobiphenyl (PCB169) to inhibit hCYP1B1 and stimulate the formation of ROS in V79MZ cells (which lack endogenous CYPs) expressing hCYP1B1 was demonstrated. Moreover, the generation of ROS was also associated with increases in parameters of oxidative stress related to genotoxicity (DNA oxidation and lipid peroxidation). For PCB169, these effects were time and concentration dependent. These data identify a novel mechanism of genotoxicity for dioxin-like PCBs, as well as providing further evidence that overexpression of hCYP1B1 is a risk factor for extrahepatic carcinogenesis.

Effect of melatonin on the production of microsomal hydrogen peroxide and cytochrome P-450 content in rat treated with aflatoxin B 1

Aflatoxin B 1 (AFB 1) is a food contaminant fungal toxin that has been implicated as a causative agent in human hepatic and extrahepatic carcinogenesis. In this study we went on to show the effect of melatonin as a free radical scavenger on the production of microsomal hydrogen peroxide (H 2O 2) during the metabolic activation AFB 1. The production of microsomal H 2O 2 in vitro during the metabolic activation of different chemical carcinogens has been reported previously. We also studied the effect of melatonin on the cytochrome P-450 content as a major microsomal monooxygenase isoenzymes system in rat liver responsible for the metabolic activation of AFB 1. The amounts of H 2O 2 and cytochrome P-450 contents in rat treated with melatonin (0.2 mg/kg BW) and/or AFB 1 (0.2 mg/kg BW) at various time intervals has been measured. Animals treated with melatonin exhibited markedly inhibition in the amounts of H 2O 2 after 1, 3, and 6 h. The highest level of inhibition (3.0 nmol H 2O 2/mg protein) was detected after 6 h. However, cytochrome P-450 contents were also decreased after the same period of time. The highest level of inhibition (2.1 nmol/mg protein) was detected after 3 h of injection. A pronounced augmentation of H 2O 2 production was observed in rat treated with AFB 1 only. The highest level of H 2O 2 (100 nmol/mg protein) was measured after 1 h. Cytochrome P-450 contents were also decreased in response to AFB 1 injection over the same time intervals. Contrary data was detected in animals received both AFB 1 and melatonin. The generation of H 2O 2 was inhibited by melatonin after 1, 3 and 6 h. The highest level of inhibition (44.2 nmol/mg protein) was observed after 6 h. Finally, these data suggested that melatonin as a free radical scavenger inhibited the microsomal production of H 2O 2 in rat treated with AFB 1.

Biochemical and molecular aspects of mammalian susceptibility to aflatoxin B1 carcinogenicity.

Aflatoxin B1 (AFB1) is a fungal toxin that has been implicated as a causative agent in human hepatic and extrahepatic carcinogenesis. In this review, the mechanisms involved in AFB1 toxicity are delineated, in order to describe the features that make a specific cell, tissue, or species susceptible to the mycotoxin. Important considerations include: (i) different mechanisms for bioactivation of AFB1 to its ultimate carcinogenic epoxide metabolite; (ii) the balance between bioactivation to and detoxification of the epoxide; (iii) the interaction of AFB1 epoxide with DNA and the mutational events leading to neoplastic transformation; (iv) the role of cytotoxicity in AFB1 carcinogenesis; (v) the significance of nonepoxide metabolites in toxicity; and (vi) the contribution of mycotoxin-unrelated disease processes. Although considerable controversy remains about the importance of specific events, a great deal has been learned about biochemical and molecular actions of AFB1.

Reduction of 2-acetylaminofluorene-induced unscheduled DNA synthesis in human and rat hepatocytes by butylated hydroxytoluene

Butylated hydroxytoluene (BHT) protected against DNA damage induced in rat hepatocytes by 2-acetylaminofluorene (2AAF) or N-hydroxy 2AAF as shown by a marked reduction of unscheduled DNA synthesis. BHT also inhibited 2AAF-induced DNA damage (as shown by reduced repair) in human hepatocytes. In addition, rats pre-treated with BHT in the diet (0.5% w/w for 10 days) provided hepatocytes which exhibited less unscheduled DNA synthesis than did hepatocytes from control rats when these cells were exposed to either 2AAF or N-hydroxy 2AAF. The results indicate both direct (in vitro) and indirect (by pre-treatment in vivo) inhibitory effects of BHT on the genotoxicity of 2AAF in liver cells, in accord with the reported anti-tumorigenicity in the liver. This effect contracts with a BHT-mediated increase in the efflux of 2AAF-derived mutagens from liver cells which may contribute to enhanced extrahepatic carcinogenesis.

Reduction of 2-acetylaminofluorene-induced unscheduled DNA synthesis in human and rat hepatocytes by butylated hydroxytoluene

Butylated hydroxytoluene (BHT) protected against DNA damage induced in rat hepatocytes by 2-acetylaminofluorene (2AAF) or N-hydroxy 2AAF as shown by a marked reduction of unscheduled DNA synthesis. BHT also inhibited 2AAF-induced DNA damage (as shown by reduced repair) in human hepatocytes. In addition, rats pre-treated with BHT in the diet (0.5% w/w for 10 days) provided hepatocytes which exhibited less unscheduled DNA synthesis than did hepatocytes from control rats when these cells were exposed to either 2AAF or N-hydroxy 2AAF. The results indicate both direct (in vitro) and indirect (by pre-treatment in vivo) inhibitory effects of BHT on the genotoxicity of 2AAF in liver cells, in accord with the reported anti-tumorigenicity in the liver. This effect contracts with a BHT-mediated increase in the efflux of 2AAF-derived mutagens from liver cells which may contribute to enhanced extrahepatic carcinogenesis.