Abstract
Bladder cancers arise from transformed urothelial cells that line the bladder. These cancers are urothelial or squamous cell carcinomas or, more rarely, additional histologic variants such as adenocarcinoma. The most important bladder cancer risk factors worldwide are arguably smoking and urogenital schistosomiasis. The parasitic Schistosoma haematobium worm causes urogenital schistosomiasis in approximately 112 million people, primarily in sub-Saharan Africa and the Middle East [1]. During infection, S. haematobium worms lay highly inflammatory eggs in the bladder wall. This inflammation is thought to promote carcinogenesis through unclear mechanisms. People with chronic urogenital schistosomiasis exhibit increased risk and earlier onset of bladder cancer (up to two decades earlier), with a predominance of squamous cell carcinoma [2]. Consequently, S. haematobium has been categorized as a Group I carcinogen (“carcinogenic to humans”) by the International Agency on Research on Cancer of the World Health Organization [3].
Highlights
To address the need for tractable tools to study schistosomal cancer biology, we developed the first experimentally tractable mouse model of urogenital schistosomiasis [13]
To identify what bladder urothelial DNA methylation events occur in the preneoplastic period in our mouse model of urogenital schistosomiasis, we microinjected S. haematobium eggs into the bladder walls of mice and 2 weeks later microdissected the urothelium of each bladder from the remaining bladder tissue
Using thresholds of >10x coverage, >25% difference in methylation, and p < 0.05, we found that short-term exposure of the mammalian bladder to S. haematobium infection led to massive changes in DNA methylation of the urothelium
Summary
To address the need for tractable tools to study schistosomal cancer biology, we developed the first experimentally tractable mouse model of urogenital schistosomiasis [13] In this model, microinjection of S. haematobium parasite eggs into the bladder walls of mice leads to rapid urothelial hyperplasia [13] and squamous metaplasia. To identify what bladder urothelial DNA methylation events occur in the preneoplastic period in our mouse model of urogenital schistosomiasis, we microinjected S. haematobium eggs into the bladder walls of mice and 2 weeks later microdissected the urothelium of each bladder from the remaining bladder tissue. We gave the DNA methylation inhibitor 5-fluoro-20-deoxycytidine (FdCyd, 12.5 mg/kg) and tetrahydrouridine (THU, an inhibitor of FdCyd metabolism, 25 mg/kg) on an every other day basis (14 days total) intraperitoneally to S. haematobium egg-injected mice This drug combination suppressed S. haematobium egg-induced urothelial hyperplasia, a key preneoplastic change in the bladder (Fig 3).
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