I’m an immunologist, or a parasitologist, depending on whom you ask or who asks me. I investigate how parasites modulate the human innate immune system to cause diseases like leishmaniasis and lymphatic filariasis. I’m certainly not a cancer biologist, but maybe I’ll have to become one. There are several parasite species – namely the trematode parasite Schistosoma haematobium, and the liver flukes Opisthorchis viverrini and Clonorchis sinensis, which actually cause cancer.
Schistosomiasis in particular is one of the most devastating parasitic diseases, with at least 240 million people currently infected across 76 countries, and resulting in 300,000 deaths annually in Africa alone according to the World Health Organization. Infection is at first asymptomatic and diagnosis may not be made until long after infection, which occurs when water-borne cercariae enter the skin. Adult worms dwell in the blood vessels, and S. haematobium worms produce eggs that lodge in the bladder wall. Granulomatous inflammation and fibrosis in the bladder surrounding the eggs is a hallmark of urogenital schistosomiasis, and in many cases this leads to neoplastic transformation.
There is overwhelming, but almost exclusively epidemiological, evidence of oncogenesis, specifically squamous cell carcinoma (SSC) in the bladder, from S. haematobium infection. For example, upon the reduction of S. haematobium in Egypt over a 37-year period, the percentage of SSC (as opposed to transitional cell carcinoma, which is not associated with S. haematobium) among bladder cancer decreased significantly, suggesting that S. haematobium was a major cause of SSC bladder cancer.
As such, S. haematobium, is classified by the International Agency for Research on Cancer within the World Health Organization as a Group 1 Agent – carcinogenic to humans – and is recognized by the American Cancer Society as an infectious agent that increases cancer risk.
Strikingly, however, the cellular and molecular mechanisms linking S. haematobium infection with cancer have yet to be defined.
In their landmark 2011 review, Hallmarks of Cancer: The Next Generation, Douglas Hanahan and Robert Weinberg highlighted two emerging “enabling characteristics” of cancer pathogenesis: Genome Instability and Mutation, and Tumor-Promoting Inflammation, that may be especially relevant to S. haematobium induced oncogenesis.
The pathology associated with urogenital schistosomiasis is due to granulomatous inflammation in response to schistosome eggs in the bladder wall. Macrophages and other inflammatory cells infiltrate the tissues surrounding the eggs, creating a dense, but hostile, environment of immune cells, cytokines, and effector molecules including reactive oxygen species.
Cancer biologists and pathologists have recognized that many tumors are surrounded by cells of the innate and adaptive arms of the immune system. While, historically, this was thought to be an anti-tumor response, it is becoming clearer that inflammation may actually encourage tumor progression by applying selective pressures. Inflammation brings with it growth factors and survival factors that encourage cell proliferation, but inflammatory cells also release reactive oxygen species that are mutagenic. This idea of a tumor microenvironment is analogous to granuloma formation around schistosome eggs, and further characterization of granulomatous inflammation in the bladder epithelium will shed light on mechanisms contributing to inflammation-related neoplastic progression. Characterization of granulomas surrounding schistosome eggs in the mouse bladder epithelium has already revealed gene expression signatures associated with multiple carcinogenesis pathways.
Genome Instability and Mutation: Carcinogenic molecules in Schistosome extracts
Much of what we know about the immunobiology of schistosomiasis comes from the use of schistosome egg antigen or soluble extracts of adult worms in laboratory experiments. It has been demonstrated that parasite products directly induce neoplastic transformation. Just this year, another study was published showing that schistosome egg antigen stimulates cell proliferation, reduces apoptosis, increases oxidative stress, and most interestingly, induces genotoxicity in urothelial cells. One theory is that catechol-estrogens found in the schistosome antigen preparations act as DNA adducts, binding to and damaging stretches of DNA. Rather, the genotoxic effects of these estrogen metabolites might be attributed to the formation of reactive oxygen species, which then react with DNA.
Kind of cool to think that this worm may be secreting small molecules or metabolites that more directly cause DNA mutagenesis than previously anticipated!
Stay tuned…this story is about to get more interesting
The correlation between S. haematobium and bladder cancer was first noted over 100 years ago. Just in the last 3 years, there have been new developments that will undoubtedly increase our understanding of schistosomiasis and cancer over the next several years. For one, a group at Stanford University developed a schistosome egg microinjection model, in order to study inflammation due to schistosome eggs directly in the bladder wall. Previously, infection was initiated by allowing cercariae to invade the tails of mice, requiring progression through the adult worm stage before any eggs might happen to lodge in the bladder.
The S. haematobium genome was also recently completed, and along with new transgenic technologies for the manipulation of schistosomes, this will surely provide new insights into the pathogenesis of this global health burden.
As the mechanisms driving cancer progression in parasitic infection continue to be discovered, it is certainly an exciting time to be at the nexus of parasitology, immunology, and cancer biology. Intellectual curiosity aside, Schistosomiasis continues to constitute a huge disease burden worldwide, and the new developments and potential discoveries discussed only in brief here, stand to improve the lives of millions of people.
Rachel Cotton is a Senior Biological Sciences major in the Eck Institute for Global Health at the University of Notre Dame, where she conducts immunology and infectious disease research. She is Co-Editor in Chief of the undergraduate research journal, Scientia