Infection with the carcinogenic human liver fluke, Opisthorchis viverrini

Abstract

Summary Throughout Southeast Asia there is a strikingly high incidence of cholangiocarcinoma (CCA - hepatic cancer of the bile duct epithelium), particularly in people from rural settings in Laos and Northeast Thailand who are infected with the liver fluke, Opisthorchis viverrini, one of only three carcinogenic eukaryotic pathogens. More ubiquitous carcinogenic microbes, such as Helicobacter pylori, induce cancer in less than 1% of infected people, while as many as one-sixth of people with opisthorchiasis will develop CCA. The mechanisms by which O. viverrini causes cancer are multi-factorial, involving mechanical irritation from the activities and movements of the flukes, immunopathology, dietary nitrosamines and the secretion of parasite proteins that promote a tumourigenic environment. Genomic and proteomic studies of the liver fluke secretome have accelerated the discovery of parasite proteins with known/potential roles in pathogenesis and tumourigenesis, establishing a framework towards understanding, and ultimately preventing, the morbidity and mortality attributed to this highly carcinogenic parasite.

Proliferative activity of normal tissues and malignant tumors during infestation of the organism by a biotic ecopathogen

“…Literature analyses on the role of the natural environmental factor of the Tyumen region -opisthorchiasis infestation in the development of primary cholangiocellular liver cancer are numerous. They are confirmed by studies [1][2][3][4][5][6]. Based on the hyperendemicity of this territory for parasitization of the biotic pathogen -the helminth Opisthorchis felineus -in the hepatobiliary system of the human body, chronic opisthorchiasis is considered as a facultative precancer of the liver [4].…”

Proliferative activity of normal tissues and malignant tumors during infestation of the organism by a biotic ecopathogen

“…Literature analyses on the role of the natural environmental factor of the Tyumen region -opisthorchiasis infestation in the development of primary cholangiocellular liver cancer are numerous. They are confirmed by studies [1][2][3][4][5][6]. Based on the hyperendemicity of this territory for parasitization of the biotic pathogen -the helminth Opisthorchis felineus -in the hepatobiliary system of the human body, chronic opisthorchiasis is considered as a facultative precancer of the liver [4].…”

Granulin Secreted by the Food-Borne Liver Fluke Opisthorchis viverrini Promotes Angiogenesis in Human Endothelial Cells

“…Whereas the origin of helminth and host cell communication is unknown, the process likely evolved to facilitate parasitism ( 35 ). Metabolites participating in communication signaling may, however, contribute to carcinogenesis ( 1 , 35 ). The close homology between liver fluke and human granulins may enable secreted Ov -GRN-1 to activate signaling pathways that promote angiogenesis and wound repair of bile ducts damaged by the activities of the parasite ( 4 ).…”

Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype

“…While the mechanisms that drive chronic liver fluke infection toward cancer are multifactorial, a pivotal role for fluke ES products in promoting a tumorigenic phenotype has been demonstrated [ 7 ]. The intracellular localization of O. viverrini ES proteins in cholangiocytes of infected hosts has prompted speculation on the mechanisms underlying this process of parasite protein internalization and its potential pathologic and carcinogenic consequences [ 6 , 7 ].…”

“…While the mechanisms that drive chronic liver fluke infection toward cancer are multifactorial, a pivotal role for fluke ES products in promoting a tumorigenic phenotype has been demonstrated [ 7 ]. The intracellular localization of O. viverrini ES proteins in cholangiocytes of infected hosts has prompted speculation on the mechanisms underlying this process of parasite protein internalization and its potential pathologic and carcinogenic consequences [ 6 , 7 ]. Herein we show that O. viverrini secretes EVs that are internalized by human cholangiocytes in vitro and trigger a cascade of inflammatory and protumorigenic changes within the cell, thereby providing a plausible mechanism by which ES proteins are taken up by biliary cells of infected hosts and contribute to the development of CCA in infected individuals.…”

Proliferative activity of normal tissues and malignant tumors during infestation of the organism by a biotic ecopathogen

“…Literature analyses on the role of the natural environmental factor of the Tyumen region -opisthorchiasis infestation in the development of primary cholangiocellular liver cancer are numerous. They are confirmed by studies [1][2][3][4][5][6]. Based on the hyperendemicity of this territory for parasitization of the biotic pathogen -the helminth Opisthorchis felineus -in the hepatobiliary system of the human body, chronic opisthorchiasis is considered as a facultative precancer of the liver [4].…”

Granulin Secreted by the Food-Borne Liver Fluke Opisthorchis viverrini Promotes Angiogenesis in Human Endothelial Cells

“…Whereas the origin of helminth and host cell communication is unknown, the process likely evolved to facilitate parasitism ( 35 ). Metabolites participating in communication signaling may, however, contribute to carcinogenesis ( 1 , 35 ). The close homology between liver fluke and human granulins may enable secreted Ov -GRN-1 to activate signaling pathways that promote angiogenesis and wound repair of bile ducts damaged by the activities of the parasite ( 4 ).…”

Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype

“…While the mechanisms that drive chronic liver fluke infection toward cancer are multifactorial, a pivotal role for fluke ES products in promoting a tumorigenic phenotype has been demonstrated [ 7 ]. The intracellular localization of O. viverrini ES proteins in cholangiocytes of infected hosts has prompted speculation on the mechanisms underlying this process of parasite protein internalization and its potential pathologic and carcinogenic consequences [ 6 , 7 ].…”

“…While the mechanisms that drive chronic liver fluke infection toward cancer are multifactorial, a pivotal role for fluke ES products in promoting a tumorigenic phenotype has been demonstrated [ 7 ]. The intracellular localization of O. viverrini ES proteins in cholangiocytes of infected hosts has prompted speculation on the mechanisms underlying this process of parasite protein internalization and its potential pathologic and carcinogenic consequences [ 6 , 7 ]. Herein we show that O. viverrini secretes EVs that are internalized by human cholangiocytes in vitro and trigger a cascade of inflammatory and protumorigenic changes within the cell, thereby providing a plausible mechanism by which ES proteins are taken up by biliary cells of infected hosts and contribute to the development of CCA in infected individuals.…”

Proliferative activity of normal tissues and malignant tumors during infestation of the organism by a biotic ecopathogen

“…Literature analyses on the role of the natural environmental factor of the Tyumen region -opisthorchiasis infestation in the development of primary cholangiocellular liver cancer are numerous. They are confirmed by studies [1][2][3][4][5][6]. Based on the hyperendemicity of this territory for parasitization of the biotic pathogen -the helminth Opisthorchis felineus -in the hepatobiliary system of the human body, chronic opisthorchiasis is considered as a facultative precancer of the liver [4].…”

Granulin Secreted by the Food-Borne Liver Fluke Opisthorchis viverrini Promotes Angiogenesis in Human Endothelial Cells

“…Whereas the origin of helminth and host cell communication is unknown, the process likely evolved to facilitate parasitism ( 35 ). Metabolites participating in communication signaling may, however, contribute to carcinogenesis ( 1 , 35 ). The close homology between liver fluke and human granulins may enable secreted Ov -GRN-1 to activate signaling pathways that promote angiogenesis and wound repair of bile ducts damaged by the activities of the parasite ( 4 ).…”

Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype

“…While the mechanisms that drive chronic liver fluke infection toward cancer are multifactorial, a pivotal role for fluke ES products in promoting a tumorigenic phenotype has been demonstrated [ 7 ]. The intracellular localization of O. viverrini ES proteins in cholangiocytes of infected hosts has prompted speculation on the mechanisms underlying this process of parasite protein internalization and its potential pathologic and carcinogenic consequences [ 6 , 7 ].…”

“…While the mechanisms that drive chronic liver fluke infection toward cancer are multifactorial, a pivotal role for fluke ES products in promoting a tumorigenic phenotype has been demonstrated [ 7 ]. The intracellular localization of O. viverrini ES proteins in cholangiocytes of infected hosts has prompted speculation on the mechanisms underlying this process of parasite protein internalization and its potential pathologic and carcinogenic consequences [ 6 , 7 ]. Herein we show that O. viverrini secretes EVs that are internalized by human cholangiocytes in vitro and trigger a cascade of inflammatory and protumorigenic changes within the cell, thereby providing a plausible mechanism by which ES proteins are taken up by biliary cells of infected hosts and contribute to the development of CCA in infected individuals.…”