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Translational strategies for cancer prevention in liver

Nature Reviews Cancer volume 3, pages 321–329 (2003)Cite this article

Key Points

  • Liver cancer is the third most deadly cancer worldwide and is ranked fifth in terms of the number of cases.

  • Carcinogenic toxins produced by moulds (aflatoxins) interact synergistically with infection with hepatitis B virus (HBV) to amplify the risk of hepatocellular carcinoma (HCC) in humans — particularly in the developing world, where most of the disease burden lies.

  • Molecular-progression pathways have been difficult to elucidate for HCC. However, several genetic and epigenetic changes in targets that affect the fate and actions of the viral and chemical aetiological agents offer promise as aids for early diagnosis.

  • Primary prevention of HCC, in the form of universal vaccination programmes against HBV in newborns, is proving effective, but it remains beyond the reach of many at-risk populations.

  • Secondary prevention of HCC, in the form of chemoprevention directed at many targets, offers potential benefits. Early-stage interventions designed to intercept and enhance the detoxification of aflatoxins, and later-stage interventions to inhibit or reverse cirrhosis or block the occurrence of second primary HCCs, are important opportunities for clinical-trial development.

Abstract

Unlike many other types of human cancer, the aetiology of liver cancer is well understood. Infection with hepatitis viruses, coupled with dietary exposure to the fungal toxin aflatoxin, increases the risk of the disease. Although primary prevention, based on vaccination and avoiding exposure to these agents, is an appealing option, such strategies will require considerable investment of time and resources to be successful. In the developing world — where the burden of liver cancer is highest — immediate, practical and economical approaches are essential. So, targeted chemoprevention might be most appropriate for the present generation of individuals at risk.

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Figure 1: Pathogenesis of hepatocellular carcinoma.
Figure 2: HCC incidence in Jiangsu Province, China, by township, and incidence rates of HCC in Qidong from 1972–2001.
Figure 3
Figure 4: Age-specific incidence of HCC in Qidong and Beijing, China, compared with the United States.

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Acknowledgements

Our work is supported in part by United States Public Health Services grants from the National Cancer Institute and the National Institute of Environmental Health Sciences, as well as by the Science & Technology Commission of Shanghai Municipality, Shanghai Municipal Health Bureau and Jiangsu Province Department of Health.

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Authors and Affiliations

  1. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, 21205, Maryland, USA

    Thomas W. Kensler & John D. Groopman

  2. Department of Cancer Etiology, Shanghai Cancer Institute, Shanghai, 200032, People's Republic of China

    Geng-Sun Qian

  3. Department of Epidemiology, Qidong Liver Cancer Institute, Qidong, 226200, Jiangsu, People's Republic of China

    Jian-Guo Chen

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  1. Thomas W. Kensler
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DATABASES

Cancer.gov

hepatocellular carcinoma

Entrez

hepatitis B virus

hepatitis C virus

LocusLink

α-fetoprotein

CDKN2A

CDKN2B

CYP1A2

CYP3A4

GSTP1

GSTs

KEAP1

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p53

FURTHER INFORMATION

International Agency for Research on Cancer

Medline plus — hepatocellular carcinoma

World Health Organisation — hepatitis B

US Food & Drug Administration — aflatoxins

Environment, Health and Safety Online — aflatoxins

CancerBACUP — liver cancer

The United States Department of Agriculture — aflatoxin

Glossary

MYCOTOXINS

A group of chemically diverse secondary fungal metabolites that can induce various toxic responses in humans and animals when food containing these compounds is ingested. More than 100 structurally characterized mycotoxins are known.

SERUM TRANSAMINASES

These are used to detect liver injury, particularly to the parenchymal cells. Two commonly measured serum enzymes are aspartate aminotransferase (AST), which is somewhat nonspecific in that it can also indicate injury to non-hepatic tissues, and alanine aminotransferase (ALT), which is mainly found in the liver and is released during hepatotoxicity.

SCHISTOSOMIASIS

A severe, debilitating disease caused by infection with trematodes of the genus Schistosoma. Infection in humans is caused by cercaria, which are liberated from the invertebrate host (snails). They penetrate the skin and mainly affect the genitourinary and gastrointestinal systems.

ISOTHIOCYANATES

These exist in plants as relatively stable β-thioglucoside N-hydroxysulphate precursor conjugates (known as glucosinolates). The enzyme myrosinase promotes the hydrolysis of glucosinolates to isothiocyanates. Myrosinase is normally physically segregated from its glucosinolate substrates, but it is released when plant cells are injured (for example, by chewing, food preparation or insect predation). This reaction is responsible for the bitter taste of horseradish, mustard and wasabi.

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Kensler, T., Qian, GS., Chen, JG. et al. Translational strategies for cancer prevention in liver. Nat Rev Cancer 3, 321–329 (2003). https://doi.org/10.1038/nrc1076

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