Infection with Opisthorchis felineus induces intraepithelial neoplasia of the biliary tract in a rodent model

Abstract

The liver fluke Opisthorchis felineus is a member of the triad of epidemiologically relevant species of the trematode family Opisthorchiidae, and the causative agent of opisthorchiasis felinea over an extensive range that spans regions of Eurasia. The International Agency for Research on Cancer classifies the infection with the liver flukes Opisthorchis viverrini and Clonorchis sinensis as group 1 agents and a major risk factor for cholangiocarcinoma. However, the carcinogenic potential of the infection with O. felineus is less clear. Here, we present findings that support the inclusion of O. felineus in the Group 1 list of biological carcinogens. Two discrete lines of evidence support the notion that infection with this liver fluke is carcinogenic. First, novel oxysterol-like metabolites detected by liquid chromatography-mass spectroscopy in the egg and adult developmental stages of O. felineus, and in bile, sera, and urine of liver fluke-infected hamsters exhibited marked similarity to oxysterol-like molecules known from O. viverrini. Numerous oxysterols and related DNA-adducts detected in the liver fluke eggs and in bile from infected hamsters suggested that infection-associated oxysterols induced chromosomal lesions in host cells. Second, histological analysis of liver sections from hamsters infected with O. felineus confirmed portal area enlargement, inflammation with severe periductal fibrosis and changes in the epithelium of the biliary tract characterized as biliary intraepithelial neoplasia, BilIN. The consonance of these biochemical and histopathological changes revealed that O. felineus infection in this rodent model induced precancerous lesions conducive to malignancy.

Helminth infection-induced carcinogenesis: spectrometric insights from the liver flukes, Opisthorchis and Fasciola

“…It should be noted that the animals were processed as part of normal work of the slaughterhouse. O. viverrini and O. felineus were obtained as previously described [3,4]. In brief, metacercariae of Opisthorchis species were obtained from naturally infected cyprinoid fish in Khon Kaen province, Thailand or from naturally infected fish ( Leuciscus idus ) in the Ob River near the city of Novosibirsk, Siberia Russia, respectively.…”

“…In brief, metacercariae of Opisthorchis species were obtained from naturally infected cyprinoid fish in Khon Kaen province, Thailand or from naturally infected fish ( Leuciscus idus ) in the Ob River near the city of Novosibirsk, Siberia Russia, respectively. The fish were digested with pepsin-HCl [3]. Fifty metacercariae were used to infect hamsters ( Mesocricetus auratus ) and three months after infection, the animals were euthanized and adult O. viverrini or O. felineus flukes recovered from their bile ducts.…”

“…These group 1 agents include three helminth parasites, specifically the fish-borne trematodes (FZT) Opisthorchis viverrini and Clonorchis sinensis and the blood fluke, Schistosoma haematobium [2]. In addition, we reported findings from hamster infection that support the inclusion of Opisthorchis felineus , also an FZT, to this list of biological carcinogens and definitive cause of cholangiocarcinoma [3]. We hypothesised that these helminths produce and release derivatives of oestrogens and oxysterols that promote oxidation of host DNA, inducing lesions, adducts and mutations [1,3–6].…”

“…In addition, we reported findings from hamster infection that support the inclusion of Opisthorchis felineus , also an FZT, to this list of biological carcinogens and definitive cause of cholangiocarcinoma [3]. We hypothesised that these helminths produce and release derivatives of oestrogens and oxysterols that promote oxidation of host DNA, inducing lesions, adducts and mutations [1,3–6]. The findings supported the postulate that these infection-associated cancers originate from a biological and/ or chemical insult followed by chronic inflammation, fibrosis, and a change in the tissue microenvironment that leads to a pre-cancerous niche [7,8].…”

Parasites in Food: From a Neglected Position to an Emerging Issue

“…This is presumably because the domestic dog-livestock cycle associated with E. granulosus is relatively easier to interrupt (by worming dogs, preventing dogs from scavenging domestic animal remains at abattoirs and in the fields, and efforts at meat inspection), than the predominantly sylvatic E. multilocularis cycle (foxes-rodents). Not only is the prevalence of E. multilocularis apparently not decreasing, but the distribution of the parasite seems to be spreading in some areas of northern Europe and it seems to be emerging, becoming identified in some areas previously not considered particularly associated with the parasite, in other regions of the world (Conraths & Deplazes, 2015;Davidson, Romig, Jenkins, Tryland, & Robertson, 2012;Gottstein et al, 2015;Vuitton et al, 2015). For example, a case-finding study noted an increase in the prevalence of human AE in Switzerland over a 50-year period from 1956 to 2005, which could not be explained by improved diagnosis; the authors suggested that this change in prevalence may be associated with a rising fox population, which, in turn, is associated with a successful antirabies vaccination program (Schweiger et al, 2007).…”