Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update

Ishida, Kenji; Hsieh, Michael H.

doi:10.3389/fmed.2018.00223

Cited by 67 publications

(54 citation statements)

References 60 publications

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“…Infection with S. haematobium can result in a wide range of bladder pathogenesis, such as fibrosis, hyperplasia, dysplasia, squamous metaplasia, hematuria, and ultimately bladder cancer [29–32]. The link between S. haematobium infection and bladder cancer is so strong that the International Agency for Research on Cancer considers urogenital schistosomiasis as a class-1 carcinogen, “carcinogenic to humans” [33].…”

Section: Discussionmentioning

confidence: 99%

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%

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

Mbanefo

et al. 2019

Preprint

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“…Proteins at the interface between the host and the parasite are believed to play a key role in host immune system modulation and parasite survival [63] and so characterisation of these molecules is desirable to further our knowledge of parasite biology and pathogenesis and intervention targets. For example, the proteins secreted and located on/in the tegument of the blood-dwelling adult fluke are immune-accessible, and egg ES molecules are involved in the generation of a tumorigenic environment [13] and can be studied to gain insight into host pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…However, some eggs get trapped in the bladder wall causing a chronic local inflammation that will develop into a granuloma accompanied by relentless cell proliferation and ultimately in some patients, bladder cancer [16] as well as genital malignancy in women [17, 18]. The initial inflammatory response is thought to be a reaction to mechanical damage caused by passing of eggs through the urothelium (a multilayered epithelium that lines most of the urogenital tract) [13]; however, proteins secreted by parasite eggs have also been shown to increase cell proliferation and angiogenesis [13]. One of the most abundant proteins secreted by S .…”

Section: Introductionmentioning

confidence: 99%

In-depth proteomic characterization of Schistosoma haematobium: towards the development of new tools for elimination

Sotillo

Pearson

Becker

et al. 2018

Preprint

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BackgroundSchistosomiasis is a neglected disease affecting hundreds of millions worldwide. Of the three main species affecting humans, Schistosoma haematobium is the most common, and is the leading cause of urogenital schistosomiasis. S. haematobium infection can cause different urogential clinical complications, particularly in the bladder, and furthermore, this parasite has been strongly linked with squamous cell carcinoma. A comprehensive analysis of the molecular composition of its different proteomes will contribute to developing new tools against this devastating disease.Methods and FindingsBy combining a comprehensive protein fractionation approach consisting of OFFGEL electrophoresis with high-throughput mass spectrometry, we have performed the first in-depth characterisation of the different discrete proteomes of S. haematobium that are predicted to interact with human host tissues, including the secreted and tegumental proteomes of adult flukes and secreted and soluble egg proteomes. A total of 662, 239, 210 and 138 proteins were found in the adult tegument, adult secreted, soluble egg and secreted egg proteomes, respectively. In addition, we probed these distinct proteomes with urine to assess urinary antibody responses from naturally infected human subjects with different infection intensities, and identified adult fluke secreted and tegument extracts as being the best predictors of infection.ConclusionWe provide a comprehensive dataset of proteins from the adult and egg stages of S. haematobium and highlight their utility as diagnostic markers of infection intensity for the development of novel tools to control this important neglected tropical disease.Author SummarySchistosomiasis is a neglected tropical disease affecting millions of people worldwide. Of the main three species affecting humans, Schistosoma haematobium is the most common, and is the leading cause of urogenital schistosomiasis. This parasite can cause a range of clinical complications associated with bladder pathogenesis, including squamous cell carcinoma as well as genital malignancy in women. Herein, we have performed the first comprehensive characterisation of the proteins implicated in host-parasite interactions (secreted and surface proteins from the adult flukes and secreted and soluble egg proteins) in order to advance our understanding of the parasite’s biology. Furthermore, we have characterised the different antibody responses in urine from infected human subjects from an endemic area presenting different infection intensities. The data obtained in this study can be used as a first step towards the development of novel tools for the control of urogenital schistosomiasis.

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“…3 In North Africa, however, a predominance of squamous cell carcinoma (SCC) is seen, which is caused by Schistosoma haematobium infections. 4 While the evidence linking infection by Schistosoma infection to SCC of the bladder is convincing, 5,6 the association between common urinary tract infection (UTI) and bladder cancer remains unclear. [7][8][9][10][11][12] In 1984, Kantor et al found that a history of three or more UTIs was associated with a twofold increased risk of bladder cancer overall and a nearly fivefold increased risk of SCC.…”

Section: Introductionmentioning

confidence: 99%

Urinary tract infections and risk of squamous cell carcinoma bladder cancer: A Danish nationwide case–control study

Pottegård

Kristensen

Friis

et al. 2020

Intl Journal of Cancer

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Schistosoma haematobium infection can lead to squamous cell carcinomas (SCC) of the bladder. Whether this also applies to more common urinary tract infections (UTIs) is unclear. We therefore aimed to investigate the association between UTIs, reflected by the use of specific antibiotics and risk of SCC of the bladder. We conducted a Danish nationwide case-control study and identified histologically verified bladder cancer cases (2000-2015; n = 12,271) and age-and sex-matched cancerfree controls. We computed odds ratios (ORs) with 95% confidence intervals (CI) associating the use of UTI-specific antibiotics with SCC bladder cancer, using conditional logistic regression. We applied a 2-year lag-time to minimize reverse causation. To aid interpretation, similar analyses were performed for other bladder cancer types and other antibiotics. We identified 333 SCC cases (2.7% of all bladder cancers). Compared to no use (0-1 prescription), high-use (≥10 prescriptions) of UTI-specific antibiotics was associated with SCC with an OR of 11.4 (CI 7.6-17.2) and a clear dose-response pattern (p trend < 0.001). Use of phenoxymethylpenicillin, an antibiotic not used against UTIs, was not associated with SCC after adjustment for use of UTIspecific antibiotics (OR 0.5). Furthermore, UTI-specific antibiotic use was not associated with urothelial carcinomas (n = 11,029; OR 1.13; CI 0.97-1.32). Excluding patients with known urogenital disease did not influence the SCC estimates (overall OR 10.8; CI 6.2-18.9). Data on smoking were lacking, however, a quantitative bias analysis suggested this to be of limited importance. In conclusion, common UTIs are strong, dose-dependent and specifically associated with risk of SCC of the bladder.Additional Supporting Information may be found in the online version of this article.

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Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update

Cited by 67 publications

References 60 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

In-depth proteomic characterization of Schistosoma haematobium: towards the development of new tools for elimination

Urinary tract infections and risk of squamous cell carcinoma bladder cancer: A Danish nationwide case–control study

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