The tumorigenic liver fluke Opisthorchis viverrini – multiple pathways to cancer

doi:10.1016/j.pt.2012.07.006

Trends in Parasitology

Volume 28, Issue 10, October 2012, Pages 395-407

https://doi.org/10.1016/j.pt.2012.07.006 Get rights and content

Liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Thailand and adjacent countries. In addition to infection-associated morbidity, infection with O. viverrini and the related Clonorchis sinensis are unarguable risk factors for cholangiocarcinoma (CAA, bile-duct cancer). Here we review the pathogenesis of opisthorchiasis and the association between O. viverrini infection and bile-duct cancer, focusing on the molecular parallels between wound healing, chronic inflammation, and cancer development. We review a schema for human disease progression from fluke infection, chronic opisthorchiasis, advanced periductal fibrosis, and cholangiocarcinogenesis, and present a rationale for biomarker discovery to facilitate early intervention. We conclude by addressing post-genomic advances with a view to developing new control strategies to combat this infectious cancer.

Section snippets

A liver fluke that causes cancer

Liver fluke infection with O. viverrini, Opisthorchis felineus and C. sinensis remains a major public health problem in many parts of Asia and Eastern Europe. For the purposes of this review we will restrict our focus to O. viverrini (for comprehensive reviews on C. sinensis see 1, 2, 3 and O. felineus see [4]). O. viverrini is a food-borne trematode that encysts as a metacercaria in the fins, skin, and musculature of cyprinoid fish. Infection occurs when individuals ingest raw or uncooked fish

The challenge: an infection-associated cancer in less developed countries

Approximately 750 million people are at risk of infection with fish-borne liver flukes [3]. An estimated 40 million people are currently infected with liver flukes in the Mekong Basin subregion alone (Figure 1) [6]. Whereas the infection can be resolved by chemotherapy (praziquantel), environmental, and socioeconomic factors in the Mekong Basin sub-region strongly favor rapid reinfection 6, 21. Hence, individuals resident in fluke endemic areas in the Mekong Basin subregion often remain

Opisthorchis-induced CCA – a ‘perfect storm’ of carcinogenic stimuli

Three main mechanisms are proposed to contribute to CCA through chronic infection with O. viverrini: (i) mechanical damage to the biliary epithelia caused by the feeding activities of the parasites, (ii) immunopathology due to infection-related inflammation, and (iii) toxic effects of parasite excretory/secretory (ES) molecules. The interplay of these mechanisms aligns with current knowledge of malignancies, suggesting that formation and progression relies on many interrelated factors that

Granulin: a parasite growth factor that causes proliferation of host cells

To identify parasite proteins central to liver fluke survival, the host-parasite relationship and the aetiology of CCA, proteomic approaches were employed to characterize 300 O. viverrini secreted and surface membrane proteins [35]. The ES products included a complex mixture of parasite proteins, some of which had homologs in the human host that were associated with cancers, including proteases, protease inhibitors, and orthologs of mammalian growth factors and anti-apoptotic proteins. Of note

Similarities between healing wounds and feeding liver flukes

Why O. viverrini secretes a potent growth factor that acts on host cells is unclear, but one potential role is apparent – wound healing. Mammalian inflammatory cells secrete peptides derived from PGRN [50], and PGRN mRNA is highly induced in dermal fibroblasts and epithelial cells following transcutaneous puncture wounds [51]. Furthermore, human recombinant PGRN increased the accumulation of inflammatory cells, blood vessels, and fibroblasts at puncture sites, implying a direct role as a

Disease progression from chronic O. viverrini infection to CCA: data from Thailand

The pathological consequences of chronic O. viverrini infection occur mainly in the liver, the intra- and extra-hepatic bile ducts, and the gall bladder, and have been described in human autopsy studies. The severity of the pathology is associated with both the intensity and the duration of infection (reviewed in [60]). During the decades of O. viverrini infection, a continuum of clearly defined, subclinical and clinical events, starting with bile-duct inflammation, proceeding through APF, and

Biomarkers of opisthorchiasis induced APF and CCA

IL-6 plays a role in systemic inflammation and is readily detected in plasma [76]. In community-based studies along the Chi River Basin in Khon Kaen Thailand we sought to determine if the concentration of IL-6 in the plasma of O. viverrini-infected individuals with APF and CCA was higher than in individuals infected with O. viverrini but without these advanced pathologies. Given the poor prognosis for CCA, especially in resource-poor settings such as Thailand, an early marker for the risk of

Proteomic biomarker discovery in O. viverrini-induced CCA

Outside Southeast Asia the risk factors for CCA are ill-defined and the rarity of the disease means that few samples are available for use in biomarker discovery. In Thailand, the existence of a clear risk factor and ample biobanked samples available for analysis make O. viverrini-induced CCA more amenable to the use of proteomic methods for protein-based biomarker discovery. Current tumor biomarkers for both O. viverrini and non-O. viverrini CCA are of little value [80] and, despite a great

The O. viverrini genome – functional genomics

As noted, the transcriptomes of O. viverrini and C. sinensis have been examined in depth 38, 39. Deep sequencing in tandem with integrated genomic–bioinformatic approaches identified more than 50 000 unique sequences being in each species. The genome of C. sinensis was described recently: it is predicted to have a haploid genome size of 516 Mb and to include ∼16 000 protein-coding genes [99]. It can be anticipated that the genome sizes of O. viverrini and C. sinensis would be similar based on

Opisthorchiasis vaccine – anti-parasite and anti-cancer?

Reliance on a sole drug, praziquantel, for the treatment of human opisthorchiasis is concerning, particularly given recent reports of diminished cure rates [105]. Moreover, repeated drug cure followed by repeated reinfection is associated with increased pathology in opisthorchiasis, potentially increasing the risk of CCA (next section). There is therefore a real need for alternative control methods for opisthorchiasis. The goal for development of a vaccine against O. viverrini infection is

Repeated infection and repeated treatment with praziquantel – a cautionary tale?

Opisthorchiasis-associated CCA follows several reasonably well-characterized pathological changes in the bile ducts, as described above. The changes include chronic inflammation and fibrosis, combined with nitrative stress from either endogenous and/or exogenous nitrosamines, leading to DNA damage and fixation of mutations [7]. A strong correlation between elevated immune responses to fluke antigens and hepatobiliary abnormalities has been described. IgG levels were most markedly elevated in

Concluding remarks

Despite the MDA programs throughout Thailand, oriental liver fluke infection is still a major public health concern, and its prevalence in some areas is increasing [21]. The association between the parasite and bile-duct cancer is undisputed; however, the mechanisms by which carcinogenesis occurs from chronic infection is less well understood. Moreover, despite its classification as a group I carcinogen, and the poor prognosis faced by the millions of people who either have or are at risk of

Acknowledgments

Research described here was partially supported by awards UO1AI065871 from the National Institute of Allergy and Infectious Disease (NIAID) and R01CA155297 from the National Cancer Institute (NCI) as well as project grant and fellowship support (A.L., J.M.) from the National Health and Medical Research Council of Australia (NHMRC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, NIAID, NCI, or

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Trends in Parasitology

ReviewFeature ReviewThe tumorigenic liver fluke Opisthorchis viverrini – multiple pathways to cancer

Section snippets

A liver fluke that causes cancer

The challenge: an infection-associated cancer in less developed countries

Opisthorchis-induced CCA – a ‘perfect storm’ of carcinogenic stimuli

Granulin: a parasite growth factor that causes proliferation of host cells

Similarities between healing wounds and feeding liver flukes

Disease progression from chronic O. viverrini infection to CCA: data from Thailand

Biomarkers of opisthorchiasis induced APF and CCA

Proteomic biomarker discovery in O. viverrini-induced CCA

The O. viverrini genome – functional genomics

Opisthorchiasis vaccine – anti-parasite and anti-cancer?

Repeated infection and repeated treatment with praziquantel – a cautionary tale?

Concluding remarks

Acknowledgments

Lancet Infect. Dis.

Parasitol. Int.

Parasitol. Int.

Parasitol. Int.

Cancer Lett.

Lancet

Lancet Infect. Dis.

Acta Trop.

Trends Parasitol.

Lancet Oncol.

Int. J. Parasitol.

Parasitol. Int.

Med. Hypotheses

Parasitol. Int.

Protein Expr. Purif.

Biochem. Biophys. Res. Commun.

Acta Trop.

Trans. R. Soc. Trop. Med. Hyg.

Trans. R. Soc. Trop. Med. Hyg.

Acta Trop.

Parasitol. Int.

Trans. R. Soc. Trop. Med. Hyg.

Cancer Cell

Trends Mol. Med.

Dig. Liver Dis.

Eur. J. Cancer

Am. J. Gastroenterol.

J. Hepatol.

Cancer Lett.

J. Clin. Exp. Hepatol.

Parasitol. Int.

Parasitol. Int.

Parasitol. Int.

Int. J. Parasitol.

Eur. J. Cancer

Parasitol. Int.

Food-borne trematodiases

Clin. Microbiol. Rev.

Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7–14 June 1994

IARC Monogr. Eval. Carcinog. Risks Hum.

Liver fluke induces cholangiocarcinoma

PLoS Med.

Liver flukes and liver cancer

Cancer Surv.

Effects of dimethylnitrosamine on induction of cholangiocarcinoma in Opisthorchis viverrini-infected Syrian golden hamsters

Cancer Res.

Opisthorchis viverrini infestation and endogenous nitrosamines as risk factors for cholangiocarcinoma in Thailand

Int. J. Cancer

Helminth and intestinal protozoa infections, multiparasitism and risk factors in Champasack province, Lao People's Democratic Republic

PLoS Negl. Trop. Dis.

Spatial distribution of, and risk factors for, Opisthorchis viverrini infection in southern Lao PDR

PLoS Negl. Trop. Dis.

Retention cyst of liver caused by opisthorchiasis associated with carcinoma; case report

Am. J. Gastroenterol.

Schistosomes and human cancer

Cancer Surv.

Infection with liver flukes (Opisthorchis viverrini, Opisthorchis felineus and Clonorchis sinensis)

IARC Monogr. Eval. Carcinog. Risks Hum.

Preliminary estimates of economic impact of liver fluke infection in Thailand and the feasibility of irradiation as a control measure

Southeast Asian J. Trop. Med. Public Health

Conquering cancer disparities: new opportunities for cancer epidemiology, biomarker, and prevention research

Cancer Epidemiol. Biomarkers Prev.

Genetics, epidemiology, and cancer disparities: is it black and white?

J. Clin. Oncol.

Review
Feature Review
The tumorigenic liver fluke Opisthorchis viverrini – multiple pathways to cancer