The role of estradiol metabolism in urogenital schistosomiasis-induced bladder cancer

Abstract

Urogenital schistosomiasis is a neglected tropical disease that can lead to bladder cancer. How urogenital schistosomiasis induces carcinogenesis remains unclear, although there is evidence that the human blood fluke Schistosoma haematobium, the infectious agent of urogenital schistosomiasis, releases estradiol-like metabolites. These kind of compounds have been implicated in other cancers. Aiming for enhanced understanding of the pathogenesis of the urogenital schistosomiasis-induced bladder cancer, here we review, interpret, and discuss findings of estradiol-like metabolites detected in both the parasite and in the human urine during urogenital schistosomiasis. Moreover, we predict pathways and enzymes that are involved in the production of these metabolites emphasizing their potential effects on the dysregulation of the tumor suppressor gene p53 expression during urogenital schistosomiasis. Enhanced understanding of these potential carcinogens may not only shed light on urogenital schistosomiasis-induced neoplasia of the bladder, but would also facilitate development of interventions and biomarkers for this and other infection-associated cancers at large.

Current and Novel Therapies Against Helminthic Infections: The Potential of Antioxidants Combined with Drugs

“…Although the infections with S. haematobium and O. viverrini are classified as a Group 1 biological carcinogen [5], much of the cellular and/or molecular mechanisms linking parasitic infections with carcinogenesis remains unclear [33]. Over recent years, our research group has undertaken studies aiming to clarify the role of these infections in helminth infection-associated carcinogenesis [23,[34][35][36].…”

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules

“…S. haematobium is considered a biological carcinogen and in fact, the most adverse pathology associated to infection is bladder cancer [ 12 ]. Recently, it has been hypothesized about the role of parasitic reactive electrophilic compounds, e.g., estrogen-like metabolites, on initiation of squamous cell carcinoma (SCC) [ 10 , 158 , 159 , 160 ]. Possibly, these metabolites are capable to react with host DNA leading to formation of DNA-adducts and liberation of ROS, triggering a cascade of events that ultimately leads to development of SCC.…”

Understanding Urogenital Schistosomiasis-Related Bladder Cancer: An Update

“…Parasite-derived estrogen-related compounds and metabolites, found during a study of hypogonadism in schistosomiasis patients ( 48 ), have been proposed to play a role in the development of schistosomal bladder cancer. Proteomic analysis of human urine containing S. haematobium eggs revealed the presence of several products not found in urine from uninfected individuals ( 49 ), including estrogen-like metabolites and guanine-derived oxidation products, which can both give rise to genetic mutation and carcinogenesis ( 27 , 50 ). Estrogen-like metabolites were also found in S. haematobium soluble egg antigen (SEA), which, when administered to urothelial cells, induced key cancer phenotypes, including increased cell proliferation and decreased apoptosis ( 28 ).…”

“…The concurrent inflammation and presence of possibly mutagenic parasite molecules could explain the observation of increased chromosomal damage found in urogenital schistosomiasis patients ( 55 ). As discussed earlier, estrogen-like metabolites of schistosome origin may also drive an increase in the rate of gene mutation by forming adducts with DNA ( 50 ). Accumulation of these potentially mutagenic events over many cell generations could eventually give rise to dysfunctional or even cancerous cells.…”