Alterations in DNA Methylation May Be the Key to Early Detection and Treatment of Schistosomal Bladder Cancer

Conti, Simon; Honeycutt, Jared; Odegaard, Justin I.; Gonzalgo, Mark L.; Hsieh, Michael H.

doi:10.1371/journal.pntd.0003696

Cited by 16 publications

(20 citation statements)

References 19 publications

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“…Previously, we used p53 haplo-insufficient mice to demonstrate that loss of one allele of p53, in combination with S. haematobium egg injection, was sufficient to induce pre-carcinogenic lesions in the bladder [31]. We have also reported that massive shifts in DNA methylation occur in the mouse urothelium following bladder injection with S. haematobium eggs, and that these methylation changes drive urothelial proliferation, a necessary but not sufficient condition for bladder carcinogenesis [23]. Alterations in cell cycle regulation are associated with genomic instability, neoplasia and cancer progression, all of which are characteristic of urogenital schistosomiasis-associated bladder cancer [34].…”

Section: Discussionmentioning

confidence: 99%

“…This is mainly due to the lack of a tractable animal model and research reagents. We recently pioneered surgical introduction of eggs in the bladder walls as a model of urogenital schistosomiasis, reproducing most of the pathological changes associated with human S. haematobium infection in this intramural model [21–23]. Notwithstanding that urothelial cells have been shown to express IL-4 receptor [24, 25], there is paucity of studies on the role of IL-4 in urothelial changes in normal and disease states.…”

Section: Introductionmentioning

confidence: 99%

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Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Mbanefo

et al. 2019

Preprint

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19IL-4 is crucial in many helminth infections, but its role in urogenital schistosomiasis, infection with 20 Schistosoma haematobium worms, remains poorly understood due to a historical lack of animal models. 21The bladder pathology of urogenital schistosomiasis is caused by immune responses to eggs deposited in 22 the bladder wall. A range of pathology occurs, including urothelial hyperplasia and cancer, but 23 associated mechanisms and links to IL-4 are largely unknown. We modeled urogenital schistosomiasis 24 by injecting the bladder walls of IL-4 receptor-alpha knockout(Il4ra -/-) and wild type mice with S. 25 haematobium eggs. Readouts included bladder histology and ex vivo assessments of urothelial 26 proliferation, cell cycle and ploidy status. We also quantified the effects of exogenous IL-4 on urothelial 27 cell proliferation in vitro, including cell cycle status and phosphorylation patterns of major downstream 28 regulators in the IL-4 signaling pathway. There was a significant decrease in the intensity of 29 granulomatous responses to bladder-wall injected S. haematobium eggs in Il4ra -/versus wild type mice. 30 S. haematobium egg injection triggered significant urothelial proliferation, including evidence of 31 urothelial hyperdiploidy and cell cycle skewing in wild type but not Il4ra -/mice. Urothelial exposure to 32 IL-4 in vitro led to cell cycle polarization and increased phosphorylation of AKT. Our results show IL-4 33 signaling is required for key pathogenic features of urogenital schistosomiasis, and that particular 34 aspects of this signaling pathway may exert these effects directly on the urothelium. These findings 35 point to potential mechanisms by which urogenital schistosomiasis promotes bladder carcinogenesis. 36 37 unfortunately sets the stage for the characteristic fibrotic response. For intestinal schistosomiasis, 48 hepatosplenomegaly and portal hypertension may result, or bladder cancer in the case of urogenital 49 schistosomiasis. 50The exact underlying mechanism by which schistosome eggs induce IL-4 production/release is still 51 uncertain [2]. The major sources of IL-4 have also been shown to include other sources beyond the Th2 52 cells themselves [14]. Parasite egg crude extract has been shown to stimulate enormous IL-4 release 53 from basophils [2, 15], mast cells and other non-T-cell, non-B-cell populations [16], which may indeed 54 represent constitutive sources of IL-4, apart from the Th2 cells. Other Fcε receptor negative non-55 lymphocyte sources of IL-4 have also been reported [17, 18]. The most abundant IL-4 inducing egg 56 antigen has since been identified and characterized from S. mansoni and S. haematobium [2, 15, 19, 20]. 57The interleuking-4 inducing principle from Schistosoma eggs (IPSE) binds to IgE on the surface of these 58 non-T-cell sources, inducing massive IL-4 release that subsequently drive type-2 response [2, 15, 19, 59 20]. 60Although the role of IL-4 in driving schistosomiasis-induced pathogenesis is widely studied for hepato-61 splenic schistosomi...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Mbanefo

et al. 2019

Preprint

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“…As with modulation of transcript expression, epigenetic changes in the host genome may also play a part in schistosomal bladder cancer. Inspired by the observation that DNA from the urine of patients infected with S. haematobium features hypermethylation of several genes correlated to degree of bladder damage (as evaluated by ultrasound) ( 36 ), our group conducted a similar study in egg-injected bladders and found a significant increase in DNA methylation in urothelial cells from parasite egg-injected bladders relative to vehicle-injected controls ( 19 ). Furthermore, drug-induced inhibition of DNA methylation resulted in decreased hyperplasia in the urothelium of the egg-injected bladders when compared to control animals that underwent egg-injection ( 19 ).…”

Section: Changes In Host Biology During S Haematobium mentioning

confidence: 99%

Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update

Ishida

Hsieh

2018

Front. Med.

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Infection with Schistosoma haematobium leads to urogenital schistosomiasis, which has been correlated with the occurrence of bladder cancer. However, mechanisms responsible for this association have not yet been clearly identified. In this short review, we provide an update, highlighting the most recent studies on schistosome-associated bladder cancer, including those that focus on identifying changes in host biology during S. haematobium infection, as well as studies for the identification of potentially pro-carcinogenic parasite molecules, and we offer a discussion on some possible mechanisms driving schistosomal bladder cancer.

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“…Clinical studies have shown that modification of the host genome occurs following infection with S . haematobium [ 23 – 25 ], and deeper studies are much needed in this area. Similarly, the influence of the microbiome (both host and parasite) on schistosomiasis infection is only beginning to be explored.…”

Section: Complementary Resourcesmentioning

confidence: 99%

The NIH-NIAID Schistosomiasis Resource Center at the Biomedical Research Institute: Molecular Redux

Cody¹,

Ittiprasert²,

Miller³

et al. 2016

PLoS Negl Trop Dis

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Schistosomiasis remains a health burden in many parts of the world. The complex life cycle of Schistosoma parasites and the economic and societal conditions present in endemic areas make the prospect of eradication unlikely in the foreseeable future. Continued and vigorous research efforts must therefore be directed at this disease, particularly since only a single World Health Organization (WHO)-approved drug is available for treatment. The National Institutes of Health (NIH)–National Institute of Allergy and Infectious Diseases (NIAID) Schistosomiasis Resource Center (SRC) at the Biomedical Research Institute provides investigators with the critical raw materials needed to carry out this important research. The SRC makes available, free of charge (including international shipping costs), not only infected host organisms but also a wide array of molecular reagents derived from all life stages of each of the three main human schistosome parasites. As the field of schistosomiasis research rapidly advances, it is likely to become increasingly reliant on omics, transgenics, epigenetics, and microbiome-related research approaches. The SRC has and will continue to monitor and contribute to advances in the field in order to support these research efforts with an expanding array of molecular reagents. In addition to providing investigators with source materials, the SRC has expanded its educational mission by offering a molecular techniques training course and has recently organized an international schistosomiasis-focused meeting. This review provides an overview of the materials and services that are available at the SRC for schistosomiasis researchers, with a focus on updates that have occurred since the original overview in 2008.

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Alterations in DNA Methylation May Be the Key to Early Detection and Treatment of Schistosomal Bladder Cancer

Cited by 16 publications

References 19 publications

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Interleukin-4 signaling plays a major role in urogenital schistosomiasis-associated bladder pathogenesis

Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update

The NIH-NIAID Schistosomiasis Resource Center at the Biomedical Research Institute: Molecular Redux

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