The research deals with cholangiocarcinoma (CCA), bile duct cancer, caused by infection with the liver fluke, Opisthorchis viverrini. CCA is a primary cancer originafing in the epithelium (cholangiocytes) ofthe bile ducts. It has long latency, is invasive, metastasizes and has a dismal prognosis. The mechanisms by which chronic infection with the flukes results in CCA are likely mulfi-factorial, but one mechanism is the secrefion of parasite proteins with mitogenic and anti-apoptotic properties, both features of a pre-cancerous cellular environment. We have characterised the excretory/secretory (ES) products of O. viverrini and identified two candidate ES proteins that are central to these processes - we showed that a homologue of the human secreted growth factor, granulin, binds to cholangiocytes and stimulates proliferation of fibroblasts and CCA cell lines. We also showed that secreted thioredoxin peroxidase blocks apoptosis of damaged cholangiocytes. Progression of chronic opisthorchiasis to CCA follows a multi-factorial route(s). We hypothesize that key processes along the route include (1) secrefion of parasite proteins which induce pathology in the biliary tract and establish an environment conducive to cancer development by promoting cell proliferation and DNA damage, accelerating wound healing and blocking apoptosis;and (2) repeated administrafion of the anthelminfic drug praziquantel, for treatment of O. viverrini (Ov) infection, causes increased inflammation in the bile ducts and thereby precipitates tumorigenesis. The research will invesfigate these phenomena by assessing the ability of Ov-ES to (1) facilitate wound repair in mammalian cells;(2) promote cell invasion and migration;(3) interfere with apoptosis. To further address the carcinogenic roles of these proteins, we will vaccinate hamsters with Ov-ES and its defined components to determine whether this intervenfion can protect against liver fluke infecfion and CCA, and assessment of impact of repeated PZQ therapy in accelerafing tumorigenesis.
Despite treatment and health education campaigns, the prevalence of O. viverrini infection remains high in Northeast Thailand;more problemafically, infecfion with O. viverrini often leads to a deadly form of liver cancer. The work proposed here invesfigates - at the molecular level - how liver fluke infection causes this liver cancer, and could offer new strategies to control this disease.
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