How a Liver Fluke Causes Cancer

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In Southeast Asia, an all-too-common parasite is known to increase the incidence of bile duct cancer in infected individuals. A paper just released in PLoS Pathogens shows how this happens. Knowing the molecular pathway that leads from parasite infection to cancer will almost certainly speed up the search for a cure for this cancer, and will probably add to our understanding of cancer in general.

Cancer is, of course, a category of diseases rather than a single disease. What holds cancer together as a coherent set of conditions is the inappropriate increase of cell proliferation in some tissue or another. Cell proliferation is, of course, normal and expected at some times and places. When an organism is growing there is quite a bit of proliferation. When a wound is healing, cell division must be sped up. Therefore, mechanisms have evolved to increase the rate of cell division, and many cancers are simply this mechanism operating in an inappropriate and sometimes out of control way.

The cause of inappropriate cell proliferation can be a genetic mutation, caused in turn by the chance mutation of an already susceptible gene, or by some kind of chemical or physical irritant.

Or it can be a fluke.

A fluke is a kind of worm in the class Trematoda. There are about 20,000 species of Trematoda, and many of them are parasites that live in mollusks and vertebrates. Commonly, Trematoda spend part of their life cycle in a mollusk, then move to a vertebrate host, and then move back to the mollusk host, as they reproduce alternatively using asexual and sexual mechanisms.

Opisthorchis viverrini, also known as the Southeast Asian or Oriental liver fluke, lives in a certain genus of freshwater snails and in humans, and when it lives in humans, it seems to predispose the humans to cholangiocarcinoma, which is cancer of the bile ducts.

The research reported yesterday identified a certain protein that is very similar to a human growth hormone, but that is found in and produced by the fluke.

Scientists knew that a particular protein of a type known as granulin was produced by the fluke, and it was known that other versions of granulin cause unchecked proliferation of cells. So they isolated the gene for the fluke version of the granulin, and placed the gene in bacteria which allows the production of sufficient quantities of the protein to use in experiments. This, in turn, allowed them to test the hypothesis that this fluke-produced protein acts like other granulin molecules in causing cancer-like growth of cells.

It turns out that fluke produced granulin is an effective cancer-causing agent.

The fluke appears to use the granulin to induce cell growth for its own nutrient supply. In addition, the fluke-produced granulin induces specific antibodies in the host that neutralize the granulin. So, there seems to be something of an arms race between parasite (fluke) and host (human).

Now that the protein is both characterized and linked to the cancer, it may be possible to produce a drug that will fight it, or to refocus efforts on the fluke infection itself to reduce the prevalence of this cancer. Also, the Opisthorchis viverrini system may now serve as a useful model for the study of growth hormone induced cancers.

Another reason that this research is very important is that there were two very strong hypotheses for the prevalence of this cancer in southeast Asia. The fluke could have caused the cancer by simply irritating the cells where the fluke lives. Alternatively, the people in regions where this fluke are common also have a diet high in a particular chemical compound called nitrosamines, abundant in the fermented fish eaten in the region, and thought to be possibly cancer-causing. While this research does not rule those ideas out, it does strongly suggest that fluke-excreted granulin is the culprit that should be addressed first.

This research is published in an OpenAccess journal, so you can read the original by clicking here.

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