Liver flukes and cancer

Liver fluke Scientists have found that the human liver fluke (Opisthorchis viverrini) contributes to the development of bile duct (liver) cancer by secreting granulin, a growth hormone that is known to cause uncontrolled growth of cells. It was known that O. viverrini secreted a protein that caused cell growth, but the identity of the protein was unknown. It was also known that the parasite secreted granulin but we did not know that it could affect the human cells around it. Scientists used E. coli bacteria to express the O. viverrini granulin, which was shown to induce proliferation in mouse fibroblast cells and human bile duct cancer cells in the absence of the parasite. Proliferation of the cells was halted by adding anti-granulin antibody, proving granulin’s role in producing a cancerous environment.

The International Agency for Research on Cancer classifies the human liver fluke as a Group I Carcinogen, meaning that O. viverrini is a proven cause of cancer. In northern Thailand, where the liver fluke is most common, more than 7 million people are infected at any given time. Previously, it was thought that the cancer was caused by the physical damage brought about by the fluke feeding on cells lining the bile ducts, as well as a diet high in nitrosamines from fermented fish (a native dish of Thailand). The paper suggests that the granulin secreted by the parasite is a major contributing factor to developing bile duct cancer. This discovery leads the way to a better understanding of how liver flukes cause such a devastating form of cancer.

A Granulin-Like Growth Factor Secreted by the Carcinogenic Liver Fluke, Opisthorchis viverrini, Promotes Proliferation of Host Cells. PLoS Pathog 5(10): e100061 doi:10.1371/journal.ppat.1000611
The human liver fluke, Opisthorchis viverrini, infects millions of people throughout south-east Asia and is a major cause of cholangiocarcinoma, or cancer of the bile ducts. The mechanisms by which chronic infection with O. viverrini results in cholangiocarcinogenesis are multi-factorial, but one such mechanism is the secretion of parasite proteins with mitogenic properties into the bile ducts, driving cell proliferation and creating a tumorigenic environment. Using a proteomic approach, we identified a homologue of human granulin, a potent growth factor involved in cell proliferation and wound healing, in the excretory/secretory (ES) products of the parasite. O. viverrini granulin, termed Ov-GRN-1, was expressed in most parasite tissues, particularly the gut and tegument. Furthermore, Ov-GRN-1 was detected in situ on the surface of biliary epithelial cells of hamsters experimentally infected with O. viverrini. Recombinant Ov-GRN-1 was expressed in E. coli and refolded from inclusion bodies. Refolded protein stimulated proliferation of murine fibroblasts at nanomolar concentrations, and proliferation was inhibited by the MAPK kinase inhibitor, U0126. Antibodies raised to recombinant Ov- GRN-1 inhibited the ability of O. viverrini ES products to induce proliferation of murine fibroblasts and a human cholangiocarcinoma cell line in vitro, indicating that Ov-GRN-1 is the major growth factor present in O. viverrini ES products. This is the first report of a secreted growth factor from a parasitic worm that induces proliferation of host cells, and supports a role for this fluke protein in establishment of a tumorigenic environment that may ultimately manifest as cholangiocarcinoma.

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