API

Relationship: 1517

Title

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Hepatocytotoxicity leads to Liver Cancer

Upstream event

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Hepatocytotoxicity

Downstream event

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Liver Cancer

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Cyp2E1 Activation Leading to Liver Cancer non-adjacent Moderate Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Cell death by necrosis and necroptosis produces DAMPs that trigger inflammation. Inflammation is widely considered to be an important risk factor that sets the stage for malignant transformation; however, mechanistically, it is unclear how it does so.

Evidence Supporting this KER

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Biological Plausibility

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Weak. 

Cell death by necrosis and necroptosis produces DAMPs that trigger inflammation. Inflammation is widely considered to be an important risk factor that sets the stage for malignant transformation; however, mechanistically, it is unclear how it does so.

Empirical Evidence

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Moderate. 

Empirical evidence broadly supports the notion that cytotoxicity occurs at doses lower than those that cause liver cancer, and at early time points. A few examples are shown below. 


F344 rats exposed for 13 weeks to furan (0-60 mkd, gavage) showed a dose dependent increase in degeneration and necrosis of hepatocytes beginning at 8 mkd and 15 mkd, in males and females, respectively. A second group of rats (exposed to 0-8 mkd furan) was studied at nine months, fifteen months, and two years. After nine months, degeneration and necrosis were observed in the hepatocytes of all animals in the 4 and 8 mkd groups. After fifteen months, these endpoints were significantly increased in all animals (male and female) of each dose group. After two years, rats developed hepatocellular adenomas and carcinomas beginning at 4 mkd in male and female rats (NTP 1993). Thus, cytotoxicity precedes cancer and occurs at similar doses and the empirical evidence is concordant with a relationship between cytotoxicity and cancer.

In a study conducted by the NTP (1993), B6C3F1 mice (male and female) were exposed for 13 weeks to the hepatocarcinogen furan (0, 4, 8, 15, 30,60 mkd, gavage; n=10 per group) (nine male and four female mice exposed to 60 mkd died before the end of the study). Toxic lesions were seen in the liver at all doses and severity increased with dose, bile duct hyperplasia and cholangiofibrosis were observed at 30 and 60 mkd (NTP 1993). A two year study was conducted using a lower dose range (0, 4, 8, 15 mkd). Kaplan Meier survival curves showed a dose-dependent decrease in survivorship with increasing dose of furan. There was a dose dependent increase in hepatocellular adenoma and carcinoma in male and female mice (NTP 1993). 

Empirical evidence supporting an underlying mechanism relating to inflammation as a mitigating factor in this relationship is less clear. Inflammation in response to furan exposure occurs in mice at around the same dose as cytotoxicity and increases in a dose and time dependent manner (Fransson-Steen, et al. 1997, Moser, et al. 2009, NTP 1993). Inflammation is accompanied by an increase of circulating inflammatory markers (Wang, et al. 2014), and changes in inflammation-associated gene expression (Jackson, et al. 2014). In Moser et al. (2009) mild inflammation arose at very low doses (0.5 mkd), was moderate at 1 mkd, and was marked at 4mkd; whereas hepatocellular adenomas and carcinomas were not observed until 4 and 8 mkd, respectively.

Most recently, the relationship between chemically induced hepatocellular carcinoma and inflammation was outlined in an award-winning article that was published in the journal Carcinogenesis: The 2016 Carcinogenesis Award Winners “Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2” (Karin and Dhar 2016). Studies in which diethylnitrosamine (DEN, a liver carcinogen) was given to male mice demonstrated that induction of hepatocellular carcinoma is dependent upon induction of inflammation. A liver myeloid cell-specific ablation of IKK-beta was sufficient to inhibit DEN-dependent carcinogenesis, whereas its deletion in hepatocytes enhanced carcinogenesis (Maeda, et al. 2005). The latter was due to an increase in cell death, which caused a subsequent increase of the cytokine and tumour protomtor interleukin 6 (IL-6) (Maeda, et al. 2009). IL-6 is known to be inhibited by estrogen, which could account for the higher prevalence of hepatocellular carcinoma in males (Naugler, et al. 2007). IL-6 has been described as a “wolf in sheep’s clothing” and is thought to be an important link between inflammation and cancer (Naugler and Karin 2008). IL1-alpha released from dying hepatocytes is another important promoter of hepatocellular carcinoma (Sakurai, et al. 2008). 

 

 

Uncertainties and Inconsistencies

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This relationship appears to be valid for toxicants that produce moderate levels of cytotoxicity. Acetaminophen is a Cyp2E1 substrate that produces extremely high levels of hepatotoxicity. Acetaminophen does not cause liver cancer because death by liver failure occurs before cancer can develop.

Quantitative Understanding of the Linkage

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Unable to determine.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Brenner, C., Galluzzi, L., Kepp, O., Kroemer, G., 2013. Decoding cell death signals in liver inflammation. J. Hepatol. 59, 583-594.

Elsharkawy, A.M., Mann, D.A., 2007. Nuclear factor-kappaB and the hepatic inflammation-fibrosis-cancer axis. Hepatology 46, 590-597.

Finkin, S., Pikarsky, E., 2011. NF-kappaB in liver cancer: the plot thickens. Curr. Top. Microbiol. Immunol. 349, 185-196.

Fransson-Steen, R., Goldsworthy, T.L., Kedderis, G.L., Maronpot, R.R., 1997. Furan-induced liver cell proliferation and apoptosis in female B6C3F1 mice. Toxicology 118, 195-204.

Jackson, A.F., Williams, A., Recio, L., Waters, M.D., Lambert, I.B., Yauk, C.L., 2014. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol. Appl. Pharmacol. 274, 63-77.

Kaczmarek, A., Vandenabeele, P., Krysko, D.V., 2013. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209-223.

Karin, M., 2009. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect. Biol. 1.

Karin, M., 2006. Nuclear factor-kappaB in cancer development and progression. Nature 441, 431-436.

Karin, M., Dhar, D., 2016. Liver carcinogenesis: from naughty chemicals to soothing fat and the surprising role of NRF2. Carcinogenesis 37, 541-546.

Luedde, T., Kaplowitz, N., Schwabe, R.F., 2014. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147, 765-783.e4.

Luedde, T., Schwabe, R.F., 2011. NF-κB in the liver-linking injury, fibrosis and hepatocellular carcinoma. Nature Reviews Gastroenterology and Hepatology 8, 108-118.

Maeda, S., Hikiba, Y., Sakamoto, K., Nakagawa, H., Hirata, Y., Hayakawa, Y., Yanai, A., Ogura, K., Karin, M., Omata, M., 2009. Ikappa B kinasebeta/nuclear factor-kappaB activation controls the development of liver metastasis by way of interleukin-6 expression. Hepatology 50, 1851-1860.

Maeda, S., Kamata, H., Luo, J.L., Leffert, H., Karin, M., 2005. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977-990.

Moser, G.J., Foley, J., Burnett, M., Goldsworthy, T.L., Maronpot, R., 2009. Furan-induced dose–response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Experimental and Toxicologic Pathology 61, 101-111.

Naugler, W.E., Karin, M., 2008. The wolf in sheep's clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol. Med. 14, 109-119.

Naugler, W.E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A.M., Karin, M., 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121-124.

Pikarsky, E., Ben-Neriah, Y., 2006. NF-kappaB inhibition: a double-edged sword in cancer? Eur. J. Cancer 42, 779-784.

Pikarsky, E., Porat, R.M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., Ben-Neriah, Y., 2004. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461-466.

Sakurai, T., He, G., Matsuzawa, A., Yu, G.Y., Maeda, S., Hardiman, G., Karin, M., 2008. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer. Cell. 14, 156-165.

Vainer, G.W., Pikarsky, E., Ben-Neriah, Y., 2008. Contradictory functions of NF-kappaB in liver physiology and cancer. Cancer Lett. 267, 182-188.

Vallabhapurapu, S., Karin, M., 2009. Regulation and function of NF-kappaB transcription factors in the immune system. Annu. Rev. Immunol. 27, 693-733.

Wang, E., Chen, F., Hu, X., Yuan, Y., 2014. Protective effects of apigenin against furan-induced toxicity in mice. Food Funct. 5, 1804-1812.

Wang, J., Huang, Q., Chen, M., 2003. The role of NF-kappaB in hepatocellular carcinoma cell. Chin. Med. J. (Engl) 116, 747-752.