Urine Proteomics in Schistosoma haematobium-induced Bladder Cancer

Abstract

Schistosomiasis, or Bilharziasis, is a neglected tropical disease caused by Schistosoma parasites, which significantly impacts public health, particularly in Africa. Schistosoma haematobium, the primary species responsible for urogenital schistosomiasis (UGS), is associated with severe chronic conditions, including squamous cell carcinoma (SCC) of the bladder. This review explores the pathogenesis of UGS and its link to bladder cancer, highlighting the molecular mechanisms involved. The chronic inflammation caused by S. haematobium eggs leads to tissue damage, fibrosis, and granuloma formation, creating a pre-cancerous environment. Notably, the role of the p53 pathway in UGS-associated bladder cancer is emphasized, with mutations in the TP53 gene and overexpression of p53 contributing to genetic instability and malignant transformation. Additionally, the review discusses the presence of oestrogen-like metabolites in the urine of UGS patients, which are suspected to be involved in carcinogenesis through an oestrogen-DNA adduct-mediated pathway. Mass spectrometric analysis of urine samples from UGS patients revealed specific metabolites, including 8-oxodG, a marker of oxidative DNA damage, which could serve as potential biomarkers for early detection and progression of bladder cancer. The urine proteome profiling also identified distinct molecular pathways activated in UGS-related bladder cancer, including Th2-type immune responses, oxidative stress, and inflammation. These findings underscore the need for further research into the host-parasite interactions and the development of diagnostic biomarkers for schistosome-induced carcinogenesis. Understanding these mechanisms could enhance treatment strategies and improve prevention efforts for UGS-related bladder cancer, particularly in endemic regions where the disease burden remains high.

Full text

Salim et al., 2024 AJINAS, 4 (2)
Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria. 88
ABUAD INTERNATIONAL JOURNAL OF NATURAL AND APPLIED SCIENCES
ISSN: 2955-1021
AIJNAS Volume 4, Issue 2, 2024 pp 88-95
https://doi.org/10.53982/aijnas.2024.0402.11-j
Copyright ©2024
https://journals.abuad.edu.ng/index.php/aijnas
AIJNAS
Urine Proteomics in Schistosoma haematobium-induced Bladder Cancer
1,2*Aminu Salim, 1,3Obajuluwa Adejoke Olukayode, 2Madara Alhaji. Adamu, 1,3Okiki Pius Abimbola
1Department of Biological Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
2Department of Biology, Federal University of Health Sciences, Azare, Bauchi State, Nigeria
3ABUAD Biotechnology Centre, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
*Corresponding author: salim.aminu@fuhsa.edu.ng
Abstract
Schistosomiasis, or Bilharziasis, is a neglected tropical disease caused by Schistosoma parasites, which signicantly impacts public health,
particularly in Africa. Schistosoma haematobium, the primary species responsible for urogenital schistosomiasis (UGS), is associated with
severe chronic conditions, including squamous cell carcinoma (SCC) of the bladder. This review explores the pathogenesis of UGS and its
link to bladder cancer, highlighting the molecular mechanisms involved. The chronic inammation caused by S. haematobium eggs leads
to tissue damage, brosis, and granuloma formation, creating a pre-cancerous environment. Notably, the role of the p53 pathway in UGS-
associated bladder cancer is emphasized, with mutations in the TP53 gene and overexpression of p53 contributing to genetic instability
and malignant transformation. Additionally, the review discusses the presence of oestrogen-like metabolites in the urine of UGS patients,
which are suspected to be involved in carcinogenesis through an oestrogen-DNA adduct-mediated pathway. Mass spectrometric analysis
of urine samples from UGS patients revealed specic metabolites, including 8-oxodG, a marker of oxidative DNA damage, which could
serve as potential biomarkers for early detection and progression of bladder cancer. The urine proteome proling also identied distinct
molecular pathways activated in UGS-related bladder cancer, including Th2-type immune responses, oxidative stress, and inammation.
These ndings underscore the need for further research into the host-parasite interactions and the development of diagnostic biomarkers for
schistosome-induced carcinogenesis. Understanding these mechanisms could enhance treatment strategies and improve prevention eorts
for UGS-related bladder cancer, particularly in endemic regions where the disease burden remains high.
Keywords: Urogenital schistosomiasis, bladder cancer, molecular pathways, Squamous cell carcinoma, Urine proteomics
INTRODUCTION
Schistosomiasis, known as Bilharziasis, is a neglected
tropical disease caused by digenean parasites from
the genus Schistosoma. These multicellular parasites
are classied under the Phylum Platyhelminthes, Class
Trematoda, and the genus Schistosoma comprises ve
species that infect humans: Schistosoma haematobium,
Schistosoma mansoni, Schistosoma japonicum,
Schistosoma intercalatum, and Schistosoma mekongi
(Adell & Riutort, 2021). The German pathologist
Theodor Bilharz made the parasite’s rst description in
1851 (Bilharz, 1853) during post-mortem examinations
of Egyptian soldiers in Cairo. Initially, Bilharz referred
to the parasite as belonging to the genus Distomum, but
in 1858, Weinland proposed a new genus, Schistosoma,
to account for the substantial differences observed
(Machado-Silva et al., 1998). In 1859, Cobbold proposed
the amendment of the genus Schistosoma for Bilharzia
in honour of Theodor Bilharz, and nowadays, the name
Schistosomiasis is commonly used despite references
to the disease as bilharziasis in French and Portuguese
medical literature (Cobbold, 1959). During the same
year, Harley and Cobbold reported that human infection
occurred through the skin (Cobbold, 1959; Harley,
1964). In 1902, Manson suggested the presence of two
distinct species of Schistosoma, and a few years later,
schistosomiasis was rst identied in Brazil in 1908
(Manson, 1903). Pirajá da Silva’s contributions included
identifying two distinct species of S. haematobium and S.
mansoni (Katz, 2008). These two species’ infections were
ult i ma t ely con r med by Leip e r in 1915, who deter m i n e d
that the parasite’s life cycle involved a freshwater snail
as an intermediate host (Santos et al., 2021).
During the 1970s, Bayer developed Praziquantel (PZQ),
a pyrazinoisoquinoline derivative that demonstrated
potent activity against parasitic atworms, including
schistosomes (Sprague et al., 2023; Park et al., 2021). PZQ
remains the primary drug for combating schistosomiasis
despite being more than 40 years since its development.
Mass drug administration (MDA) programs relying on
PZQ were initiated in endemic regions in Africa, Latin
America, and the Middle East during the early 21st
century (Archer et al., 2020; Wang et al., 2021). In 2018,
approximately 235 million individuals received PZQ
tablets, reducing the global disease burden (Santos et
al., 2021). Howeve r, the long-term ee c t iveness of MDA
approaches for controlling morbidity or eliminating
transmission remains contentious, particularly in
regions with inadequate sanitation and continuous
parasite exposure. Additionally, the reliance on a limited
number of drugs and their widespread administration

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
89
may contribute to drug resistance development (Crellen
et al., 2016). More than 90% of schistosomiasis cases
are reported in Africa, with two-thirds caused by
Schistosoma haematobium (Lo et al., 2022). Urogenital
schistosomiasis (UGS) cases may be much higher than
previously estimated. Furthermore, female genital
schistosomiasis increases the risk of HIV transmission,
and a recent resurgence of urogenital schistosomiasis in
Corsica conrms its re-emergence in Europe (Sturt et al.,
2020). Chronic infection with S. haematobium impacts
infected populations’ development, health, and well-
being, leading to squamous cell carcinoma (SCC) of the
urinary bladder (Turner et al., 2023). Consequently, there
is limited understanding of the host-parasite interaction
that triggers carcinogenesis.
More than 20 % of cancers in the developing world
are caused by infections (Volesk y-Avel l ane d a et al.,
2023). The blood uke Schistosoma haematobium is of
particular concern; infection with this worm, urogenital
schistosomiasis (UGS), is carcinogenic and classied as
a group 1 carcinogen (Santos et al., 20 21). In addition
to directly damaging the development, health, and
prosperity of infected populations, infection with these
parasites leads to squamous cell carcinoma (SCC) of
the urinary bladder (Da Costa et al., 2 021). Squamous
cell carcinoma is the standard form of bladder cancer
in rural Africa, where S. haematobium is prevalent
(Osakunor et al., 2022) (Figure 1). In contrast, the
majority of bladder cancer in developing countries
and regions not endemic for UGS is transitional (or
urothelial) cell carcinoma (TCC) (Khizar et al., 2022).
The epidemiologic association between SCC of the
bladder and UGS is based on case-control studies and
the correlation of bladder cancer incidence with the
prevalence of infection with S. haematobium in di erent
geographic locations. UGS is usually a chronic disease;
the adult, egg-producing schistosomes live for many
years, re-infections occur frequently, and UGS-SCC of
the bladder appears relatively early, often by middle age
(Bernardo et al., 2016).
The exact cellular and molecular mechanisms that connect
S. haematobium infection with cancer development are
unknown. Nevertheless, recent evidence suggests that
S. haematobium antigens may directly cause changes
in the urothelium in mice (Zaghloul et al., 2020).
Furthermore, there is a possibility that the carcinogenesis
of the bladder linked to S. haematobium infection
involves an oestrogen-DNA adduct-mediated pathway
(Masamba & Kappo, 2021). These unique oestrogen-
like metabolites are present in the schistosome sera and
urine during UGS (Bernardo et al., 2021). The use of
Liquid Chromatography-Tandem Mass Spectrometry
(LC-MS/MS) analyses can provide deeper insights into
the development of UGS-induced bladder cancer. They
can highlight potential biomarkers for diagnosing and
predicting the outcomes of this neglected tropical disease-
associated malignancy (Gouveia et al., 2015). Previous
research involving animal studies and chemically
induced urothelial carcinoma has demonstrated the
potential of mass spectrometry-based urine proteomics
in identifying the biological processes underlying disease
pathogenesis (Macklin et al., 2020). This review takes a
new approach, focusing on the urine proteome, to better
understand cancer development due to S. haematobium
infection.
Figu re 1: Di st r ibut i on of th e blo o d uke Schistosoma haematobium
in sub-Sahara n Africa, Nile valley in Egypt and Sudan, t he Maghreb,
and the Arabian Peninsula (Da Costa et al., 20 21).
Urogenital Schistosomiasis: Pathogenesis and Cancer
Urogenital schistosomiasis (UGS) results from egg-laying
S. haematobium worms residing in the veins that drain
the pelvic organs such as the bladder, uterus, and cervix.
The parasite’s infectious larvae cercariae are transmitted
to humans through direct skin penetration in freshwater.
These worms travel through the bloodstream, mature,
and settle in the venous plexus of the bladder, where
female worms produce around 3000 eggs daily. While
half of these eggs are expelled in the urine to continue the
parasite’s life cycle, the rest get trapped in the capillary
beds of pelvic organs, particularly in the bladder, ureters,
and genital tract. UGS is characterized by a persistent
immune-mediated condition. The ongoing inammatory
response to the eggs results in damage to the parenchymal
tissue, inammation, brosis, granulomas, and ultimately

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
90
the formation of brotic nodules known as sandy patches
(Figure 2) (Santos et al., 20 21).
Figure 2: (A) displays the posterior bladder mucosa with UGS
lesions, granulomas, u lcers, and tumou rs as seen throug h cystoscopy.
(B)The bladder mass biopsy histology revealed the presence of S.
haematobium ova (depicted as black circles) and SCC of the bladder,
according to Santos et al. (20 21).
The lesions induced by the entrapped eggs lead to bladder
and ureteral inammation and haematuria in more than
50% of cases, in addition to organ deformities such as
narrowing of the ureters. Secondary urinary tract and
renal infections, hydronephrosis, and, ultimately, renal
failure was observed in millions of people (Parsegian
et al., 2021). Importantly, bladder cancer is a frequent
and dire complication of chronic UGS. The incidence of
SCC associated with UGS is estimated at 3-4 cases per
100,000 (Bernardo et al., 2020). Untreated patients often
develop schistosome-related bladder cancer. The tumours
are found in a relatively younger age group, commonly
present as well-dierentiated SCC locally advanced,
and have poor overall survival (Kaseb et al., 2024). The
severity and frequency of UGS sequelae are related to
the intensity and duration of the infection (Santos et al.,
2021). Genetic alterations, chromosomal aberrations, and
cytological changes have been described in carcinomas
associated with UGS (Mohebalizadeh and Rezaei, 2023).
N-nitroso compounds have been implicated as tentative
etiologic agents in the process of bladder carcinogenesis
(Santo et al., 2021). Elevated levels of DNA alkylation
damage in carcinomas associated with UGS and a high
frequency of G to A transitions in the H-ras gene and
the CpG sequences of the p53 tumour suppressor gene
have also been reported (Mohebalizadeh & Rezaei,
2023). These outcomes indicate that UGS-associated
SCC arises through a progressive accumulation of
genetic changes in epithelial cells. A positive correlation
between UGS and increased levels of oxidative stress
accompanied by continuous DNA damage and repair
in urothelial carcinomas has been observed by several
groups (Santos et al., 2021). More recently, Santos et al.
(2021) have shown that schistosome eggs co-cultured
with informative human cell lines promote proliferation
of the urothelial cells (HCV29 cell line) but inhibit
cholangiocytes (H69 cells).
Urine Proteome in Urogenital Schistosomiasis
The urine proteome proling of patients with UGS
alone, UGS-related bladder cancer, and bladder cancer
without infection highlighted the activation of distinct
molecular pathways. Successively Santos et al. (2021)
described that urine proteins are separated using
sodium dodecyl sulphate-precast polyacrylamide gel
electrophoresis (SDS-PAGE) and then analysed by mass
spectrometric (GeLC-MS/MS) after purication. The
subsequent protein-protein interaction analysis revealed
that Th2-type immune response and oxidative stress
were the most prevalent biological processes in UGS
samples. UGS-related bladder cancer is found to be
associated with proteins involved in inammation and
negative regulation of endopeptidase activity. In contrast,
bladder cancer without infection showed proteins mainly
associated with metabolism, cell adhesion, tumour
growth and metastasis, and immune response (Santos
et al., 2021).
The Schistosoma japonicum genome revealed shared
sequences with humans for mammalian-like receptors
for insulin, progesterone, cytokines, and neuropeptides,
suggesting that host hormones or endogenous parasite
analogues might coordinate parasite development
and maturation and that Schistosoma modulates host
immune responses through inhibitors, molecular
mimicry and other invasion strategies (Hambrook &
Hanington, 2021). Genome sequencing and analysis
of S. haematobium proteome also showed molecules
linked to immunomodulation, such as inhibition of
antigen processing and Th2 responses (Carson et al.,
2020). Similarly, quantitative photocytometry analysis of
tissue samples from UGS-related bladder cancer using T
cells specic ant ib o d ies showed an unbala nc e d Th1/ Th2
relation in which Th2 was upregulated and dominated
(Santos et al., 2021). Both inammation and alternative
complement pathway activation are upregulated in this
situation. A prolonged inammatory response might
lead to increased DNA mutation rates due to previous
alterations in suppressor genes such as TP53 (expressed
by the accumulation of p53 in the urothelium) and
overall genetic instability, characterized by high levels
of 8-nitroguanidine and 8-hydroxy-20 -deoxyguanosine
(8-oxodG) (Khatri et al., 2020).
The consistency of the data collected from the proteomic
and spectrometric studies suggests that most cancers
could stem from a biological or chemical injury that

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
91
initiates a series of events leading to developing a pre-
cancerous environment (Santos et al., 2021). Gaining a
deeper understanding of the mechanisms involved in
immunomodulation during chronic schistosomiasis and
UGS-related carcinogenesis will oer new perspectives
for optimizing schistosomiasis treatment strategies and
preventing or treating UGS-related bladder cancer.
Figure 3: Model of Protein alteration during S. haematobium
infections aicted to host pathology (Osakunor et al., 2022).
Proteomic alterations contribute to the complex dynamics
of urothelial pathology and characteristic bladder tissue
changes in urogenital schistosomiasis (Figure 3). This
model demonstrates how the dierential expression of
the observed proteins contributes to notable pathology
including, urothelial hyperplasia, carcinogenesis,
active protein translation and enhanced immune and
inammatory responses relevant for wound healing
and granuloma formation, induction of Th2 immune
responses, reduced structural integrity important for egg
shedding, all of which are characteristic of Schistosoma
infection (Hambrook and Hanington, 2021).
The p53 Pathway Associated with UGS-Associated
Bladder Cancer
P53 loss of function results in changes to cell proliferation,
cell lifespan, and resistance to cytotoxic drugs (Murray
& Mirzayans, 2020). The functional alterations of the
gene suppressor TP53, caused by mutations that decrease
MDM2 levels, promote the transcription and protein
phosphorylation of p53, leading to a loss of regulatory
capacity. Usually, p53 is rapidly degraded after synthesis,
but mutated p53 with increased half-life accumulates
intracellularly. Intense p53 expression is observed in
urothelial carcinomas, aecting malignant cell clones
and neighbouring seemingly normal urothelial mucosal
cells (Hasan et al., 20 23).
What role does p53 play in UGS-associated bladder
cancer? Studies on this topic have indicated that the
tumour suppressor protein p53 is elevated in bladder
urothelial mucosa in individuals with UGS or SCC related
to UGS. What is the signicance of this discovery? It
is crucial to rst compare these results with the most
common p53 expression pattern in normal bladder
urothelium. P53 is present in only 5% of urothelial cells,
occurring in 1 to 37% of cases and appearing scattered.
In summary, the protein’s expression in physiological
situations is rare and short-lived (Moulis et al., 2020;
Ali & Malik, 2021). TP53 is not just overexpressed in
the bladder urothelial mucosa of individuals with UGS-
bladder cancer but also in those with only UGS; could this
be regarded as a biomarker for malignant transformation
of the bladder tissue associated with S. haematobium
infection? The expression of p53 in cells of the urothelium
and the occurrence of mutations of the TP53 gene in
comparative studies suggest that the profuse expression
of p53 is associated with mutations in the TP53 gene
(Murray and Mirzayans, 2020). According to Moulis
et al. (2020), their research revealed that the expression
of p53 was signicantly higher in poorly dierentiated
tumours in the context of malignancies associated with
S. haematobium infection in urothelial and squamous
cells. Furthermore, they noted that the expression of
p53 prevailed in locally advanced tumours in the UGS.
The study by Santo et al. (2021) discovered that patients
with UGS exhibited a high frequency of DNA damage
caused by alkylating agents. These mutations occurred
alongside a disruption of DNA repair mechanisms. The
study indicated that mutations were induced by the
G-transitions of the H-ras gene and CpG sequences on
the TP53 gene. Additionally, in their research, Cancrini et
al. (2022) noted that p53 expression was more prevalent
in malignant tumours associated with UGS compared
to other bladder tumours. Similarly, Santos et al. (2021)
documented that cases of squamous metaplasia and
hyperplasia in bladders not linked to UGS displayed
elevated p53 expression. A recent study revealed elevated
p53 expression in a range of conditions, including cystitis
without tumour, malignant neoplasms, and squamous
cells, as well as in urothelial or mixed carcinoma and
normal mucosa adjacent to the tumour. This suggests
that increased p53 expression is not limited to tumour
tissues, but also occurs in adjacent non-tumour tissues.
The presence of p53 was high in UGS patients, whether
they had bladder cancer or not, and it aected a signicant
number of neighbouring cells, indicating an accumulation
of p53 at the nuclear level (Hasan et al., 2023). This
physiological process occurs due to mutations in the p53
gene, resulting in the lack of protein degradation. Under
these conditions, the function of p53 is disrupted, leading
to the accumulation of DNA changes and their transfer
to daughter cells. Without repair and apoptosis, new
mutations may arise, creating a conducive environment
for malignant transformation. Santos et al. (2021)

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
92
demonstrated a decrease in the p53 pathway in urothelial
cells exposed to live S. haematobium or S. mansoni eggs
(Figure 4). However, the specic genes responsible for
the pathway’s overall downregulation diered for each
Schistosoma species (Lu et al., 2022). In summary, the
sequence of these molecular events in UGS patients
further supports the signicant role of S. haematobium in
initiating bladder carcinogenesis, potentially facilitated
by oestrogen metabolites, chronic inammation, brosis,
and changes in the tissue microenvironment, including
mutations in crucial tumour suppressor genes and proto-
oncogenes. Furthermore, compelling evidence from
animal models of Schistosoma haematobium infection
reinforces the involvement of p53 in the development
of UGS-associated SCC. The animal model of the
infectious disease developed by Michael Hiseh is based
on the injection of S. haematobium eggs directly into the
bladder of the mouse. This led to urinary tract brosis,
bladder dysfunction and other alterations of morphology
consistent with human UGS (Santos et al., 2021).
Using this model in transgenic mice, Honeycutt and
colleagues found that alteration in the p53 signalling in
the urothelium might aect the normal tissue homeostasis
during UGS (Santos et al., 2021).
Figure 4: Signicant dysregulation of P53 pathway in urothelial
cells exposed to either S. haematobium or S. mansoni eggs for
24 hours. P53 pathway highlighting upregulated or downregulated
genes in red or green, respectively. Genes aected by S. mansoni or
S. haematobium are indicated by blue or red squares, respectively
(Nacif-Pimenta et al., 2019).
Biomarkers for the early detection and progression of
bladder cancer
Researchers have identied several biomarkers associated
with schistosomal bladder cancer, particularly focusing
on COX2, iNOS, EGFR, and TGFα (Ishida & Hsieh,
2018). These markers are crucial for understanding
the carcinogenic processes linked to Schistosoma
haematobium infection, which is recognized as a major
risk factor for bladder cancer, especially squamous cell
carcinoma in endemic regions.
COX2 (Cyclooxygenase-2) and iNOS (inducible Nitric
Oxide Synthase) are enzymes that play signicant roles in
inammation and tumor progression. Elevated levels of
COX2 have been associated with increased tumor growth
and poor prognosis in bladder cancer patients. Studies
have shown a strong correlation between the expression
of COX2 and iNOS in bladder lesions, suggesting that
these markers could serve as indicators of schistosomal-
related malignancies (Ishida & Hsieh, 2018; Zaghloul et
al., 2020).
EGFR (Epidermal Growth Factor Receptor) and
TGFα (Transforming Growth Factor Alpha) are also
implicated in the pathogenesis of bladder cancer. Their
expression is often upregulated in tumors associated with
schistosomiasis, reecting the aggressive nature of these
cancers. Research indicates that these markers may help
predict disease progression and response to therapies,
highlighting their potential as unique diagnostic and
prognostic tools for schistosomal bladder cancer (Ishida
& Hsieh, 2018; Madureira, 2022).
Inspired by the chemical carcinogenesis phenomenon
described for several types of cancer (Das et al.,
2020), it was hypothesized by Santos et al. (2021) that
reactive metabolites derived from schistosomes might
be involved in the SCC carcinogenesis associated with
UGS. Hydroxylation of oestrogens forms the 2- and
4-catechol oestrogens involved in further oxidation to
semiquinones and quinones, including the formation
of the catechol oestrogen-3,4-quinones, and the major
carcinogenic metabolite of oestrogen have been reported
(Roy et al., 2024). These electrophilic compounds can
react covalently with macromolecules, including DNA,
to form the depurinating adducts that eventually generate
mutations in proto-oncogenes and/or tumour suppressors,
consequently leading to carcinogenic progression. A
recent review has reported alterations in p53 in most
schistosome-associated bladder tumours, irrespective
of their histopathological nature (Santos et al., 20 21).
The urine of individuals with UGS was found to contain
oestrogen metabolite species as the main components,
according to Santos et al. (2021). In a study of 40 UGS
patients, the mass spectrometric analysis of urine samples
revealed the presence of seven specic metabolites.
However, these metabolites were more prominent in
individuals without non-malignant lesions than in UGS-
related cancer cases, as Santos et al. (2021) indicated.
Investigating these compounds provides insights into
the fundamental pathophysiology of cancer associated
with the infection and presents potential translational

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
93
opportunities, such as identifying the molecules as
potential biomarkers. The molecules originating from
8-oxodG or oestrogen derivatives (Figure 5) could
potentially serve as urine biomarkers for the early
detection and progression of bladder cancer, as stated by
Santos et al. (2021). 8-oxodG is a representative indicator
of DNA oxidative damage during oxidative stress. The
presence of 8-oxodG in urine samples suggests that
DNA damage occurs during UGS. These reactive oxygen
species induce oxidation, nitration, halogenation, and
deamination of biomolecules, including nucleic acids,
leading to the formation of toxic and mutagenic products,
according to Santos et al. (2021).
Figure 5: Metabolites identied in urine with UGS and UGS-
associated SCC that were not present in the urine of healthy
individuals (Santos et al., 20 21). The metabolites were divided into
three groups: catechol-oestrogen-like (green), catechol-oestrogen-
DNA adducts (red), and 8-oxodG derivatives (blue). The catechol
oestrogen-DNA adducts may result from the interaction of catechol
oestrogen derivatives with host DNA. On the other hand, 8-oxodG
derivatives may be a result of the liberation of nitrogenous bases
from DNA and/or its oxidation.
CONCLUSIONS
Despite all the eorts, schistosomiasis remains a great
concern for public health in developing countries. S.
haematobium is considered a carcinogenic biological
agent and bladder cancer is one of the direst complications
aecting individuals from a young age. What should be
the focus of research on schistosomiasis? We believe that
the research should focus on three main components: (1)
understanding the host-parasite interactions (e.g., the
immune response elicited by infection); (2) mechanisms
underlying the UGS-related carcinogenesis; and (3) novel
control strategies for both schistosomiasis and associated
carcinogenesis. Biomarkers for early detection and
prognosis of malignancy induced by UGS are needed.
Promising candidates, notably (1) oestrogen-like and (2)
8-oxodG-related metabolites highlighted in this review,
appear worthy of validation in larger population-based
studies. Mixed urothelial cancer with squamous features,
such as some cases in individuals with UGS and bladder
cancer (either SCC or urothelial cancer cell), may display
a distinct pathophysiology compared to UGS-related
‘pure’ SCC, and the literature indicates that UGS is a
risk factor for SCC but not UCC (Santos et al., 2021).
Accordingly, investigations of larger populations may
also facilitate the identification of metabolites that
characterize the discrete pathogenesis of SCC and UCC.
Further studies in vitro and in vivo using animal models
will shine a light on these components.
REFERENCES
Adell, T., & Riutort, M. (2021). Phylu m Platyhel m int h e s.
In Invertebrate Zoology (pp. 219-230). CRC Press.
Ali, Q., & Malik, A. (2021). Genetic response of growth
phases for abiotic environmental stress tolerance in
cereal crop plants. Genetika, 53(1) , 419- 456.
Archer, J., O’Halloran, L., Al-Shehri, H., Summers,
S., Bhattacharyya, T., Katherine, N. B., ... &
Stothard, J. R. (2020). Intestinal schistosomiasis
and giardiasis co-infection in sub-Saharan Africa:
can a one health approach improve control of each
waterborne parasite simultaneously? Tropical
medicine and infectious disease, 5(3), 137.
Bernardo, C., Cunha, M. C., Santos, J. H., da Costa,
J. M. C., Brindley, P. J., Lopes, C., ... & Santos,
L. L. (2016). Insight into the molecular basis of
Schistosoma haematobium-induced bladder cancer
through urine proteomics. Tumour Biology, 37,
112 79 -11287.
Bernardo, C., Santos, J., Costa, C., Tavares, A., Amaro,
T., Marques, I., ... & Santos, L. L. (2020). Oestrogen
receptors in urogenital schistosomiasis and bladder
cancer: Oestrogen receptor alpha-mediated cell
proliferation. In Urologic Oncology: Seminars
and Original Investigations (Vol. 38, No. 9, pp.
738-e23). Elsevier.
Bilharz, T. (1853). Fernere mittheilungen über Distomun
haematobium. Zeitschrift fur Wissenschaftliche
Zoologie, 4, 454-456.
Cancrini, F., Michel, F., Cussenot, O., Alshehhi, H.,
Comperat, E., & Phe, V. (2022). Bladder carcinomas
in patients with neurogenic bladder and urinary
schistosomiasis: are they the same tumours? World
Journal of Urology, 40(8), 1949-1959.
Ca rso n , J. P., Robinson, M. W., Hsie h , M. H., Cody, J., Le,
L., You , H., ... & Gober t , G. N. (20 20). A compa r ative
proteomics analysis of the egg secretions of
three major schistosome species. Molecular and
Biochemical Parasitology, 240, 111322 .
Cobbold, T. S. (1859). XXVII. On some new forms of
Entozoa. Transactions of the Linnean Society of
London, (4), 363-366.

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
94
Cook, G. C., & Zumla, A. I. (2009). Manson’s tropical
diseases. 22. Au.[Edinburgh]: Saunders.
Correia da Costa, J. M., Vale, N., Gouveia, M. J., Botelho,
M. C., Sripa, B., Santos, L. L., ... & Brindley, P.
J. (2014). Schistosome and liver fluke derived
catechol-oestrogens and helminth associated
cancers. Frontiers in Genetics, 5, 444.
Crellen, T., Walker, M., Lamberton, P. H., Kabatereine,
N. B., Tukahebwa, E. M., Cotton, J. A., & Webster,
J. P. (2016). Reduced ecacy of praziquantel against
Schistosoma mansoni is associated with multiple
rounds of mass drug administration. Clinical
Infectious Diseases, 63(9), 1151-1159.
Da Costa, J. M. C., Gouveia, M. J., Rinaldi, G.,
Brindley, P. J., Santos, J., & Santos, L. L. (2021).
Control strategies for carcinogenic-associated
helminthiases: an integrated overview. Frontiers
in Cellular and Infection Microbiology, 11, 626672.
Das, S., Kundu, M., Jena, B. C., & Mandal, M. (2020).
Causes of cancer: physical, chemical, biological
carcinogens, and viruses. Biomaterials for 3D
Tumour Modeling, 607–641.
Fujinami, K. (1909). The route of infection, the
development of the parasite of Katayama disease
and its infection in animals. Kyoto Medical
Journal, 6, 224-252.
Gouveia, M. J., Santos, J., Brindley, P. J., Rinaldi, G.,
Lopes, C., Santos, L. L., ... & Vale, N. (2015).
Oestrogen-like metabolites and DNA adducts in
urogenital schistosomiasis-associated bladder
cancer. Cancer Letters, 359(2), 226-232.
Hambrook, J. R., & Hanington, P. C. (2021). Immune
evasion strategies of schistosomes. Frontiers in
Immunology, 11, 624178.
Hambrook, J. R., & Hanington, P. C. (2021). Immune
evasion strategies of schistosomes. Frontiers in
Immunology, 11, 624178.
Harley, J. (1864). On the endemic haematuria of
the Cape of Good Hope. Medico-Chirurgical
Transactions, 47, 55.
Ha s a n, A., Moh a m me d , Y., Ba sion y, M., Ha n ba z a z h, M.,
Samman, A., Abdelaleem, M. F., ... & Mandour,
E. (2023). Clinico-pathological features and
immunohistochemical comparison of p16, p53,
and Ki-67 expression in muscle-invasive and non-
muscle-invasive conventional urothelial bladder
carcinoma. Clinics and Practice, 13(4), 806 - 819.
Ishida, K., & Hsieh, M. H. (2018). Understanding
urogenital schistosomiasis-related bladder cancer:
an update. Frontiers in medicine, 5, 223.
Kaseb, H., & Aeddula, N. (2022). Bladder Cancer.
StatPearls. Available at: https://www.statpearls.
com/point-of-care/18354
Katz, N. (2008). The discovery of Schistosomiasis
mansoni in Brazil. Acta tropica, 108(2-3), 69-71.
Khatri, V., Chauhan, N., & Kalyanasundaram, R. (2020).
Parasite cystatin: an immunomodulatory molecule
with therapeutic activity against immune-mediated
disorders. Pathogens, 9(6), 431.
Khizar, S., Mirza, Z. I., Ahmed, H., Murtaza, B., Yasrab,
M., & Shahzad, K. (2022). Efficacy of Voided
Urine Cytology Compared to Cystoscopic Findings
in the Detection of Bladder Cancer-A Pakistani
Perspective. Pakistan Armed Forces Medical
Journal, 72(4), 136 4 -68.
Lo, N. C., Bezerra, F. S. M., Colley, D. G., Fleming, F.
M., Homeida, M., Kabatereine, N., ... & Garba, A.
(2022). Review of 2022 WHO guidelines on the
control and elimination of schistosomiasis. The
Lancet Infectious Diseases, 22(11), e327-e335.
Lu, L., Bu, L., Zhang, S. M., Buddenborg, S. K., &
Loker, E. S. (2022). An overview of transcriptional
responses of schistosome-susceptible (M line) or-
resistant (BS-90) Biomphalaria glabrata exposed
or not to Schistosoma mansoni infection. Frontiers
in Immunology, 12, 805882.
Machado-Silva, J. R., Pelajo-Machado, M., Lenzi, H. L.,
& Gomes, D. C. (1998). Morphological study of adult
male worms of Schistosoma mansoni Sa mbon , 1907
by confocal laser scanning microscopy. Memórias
do Instituto Oswaldo Cruz, 93, 303-307.
Macklin, A., Khan, S., & Kislinger, T. (2020). Recent
advances in mass spectrometry-based clinical
proteomics: applications to cancer research. Clinical
proteomics, 17(1), 17.
Madureira, A. C. (2022). Programmed Cell Death-
Ligand-1 expression in Bladder Schistosomal
Squamous Cell Carcinoma–There’s room for
Immune Checkpoint Blockage?. Frontiers in
Immunology, 13, 955000.
Manson, P. (1903). Tropical diseases: a manual, new and
rev. London: Cassell.
Masamba, P., & Kappo, A. P. (2021). Immunological and
biochemical interplay between cytokines, oxidative
stress and schistosomiasis. International Journal of
molecular Sciences, 22(13), 7216.
Mohebalizadeh, M., & Rezaei, N. (2023). Biomarkers for
Monitoring the Immunotherapy Response to Cancer.
In Handbook of Cancer and Immunology (pp. 1-37).
Cham: Springer International Publishing.

Official Journal of College of Sciences, Afe Babalola Universit y, Ado-Ekiti, Nigeria.
Salim et al., 2024 AJINAS, 4 (2)
95
Moulis, J. M. (2020). Cellular dynamics of transition metal
exchange on proteins: a challenge but a bonanza for
coordination chemistry. Biomolecules, 10(11), 158 4.
Murray, D., & Mirzayans, R. (2020). Cellular
responses to platinum-based anticancer drugs
and UVC: Role of p53 and implications for cancer
therapy. International Journal of Molecular
Sciences, 21(16), 5766.
Nacif-Pimenta, R., da Silva Orfanó, A., Mosley, I.
A., Karinshak, S. E., Ishida, K., Mann, V. H., ...
& Rinaldi, G. (2019). Dierential responses of
epithelial cells from urinary and biliary tract to
eggs of Schistosoma haematobium and S. mansoni.
Scientic Reports, 9(1), 10731.
Nelwan, M. (2020). Clinical Manifestation of
Schistosomiasis. SSRN Electronic Journal. ht t ps://
doi.org/10.2139/ssrn.3722685.
Oleaga, A., Rey, O., Polack, B., Grech-Angelini,
S., Quilichini, Y., Pérez-Sánchez, R., ... &
Boissier, J. (2019). Epidemiological surveillance
of schistosomiasis outbreak in Corsica (France):
Are animal reservoir hosts implicated in
local transmission?. PLoS Neglected Tropical
Diseases, 13(6), e0007543.
Osakunor, D. N., Ishida, K., Lamanna, O. K., Rossi, M.,
Dwomoh, L., & Hsieh, M. H. (2022). Host tissue
proteomics reveals insights into the molecular
basis of Schistosoma haematobium-induced
bladder pathology. PLoS Neglected Tropical
Diseases, 16(2), e0010176.
Park, S.-K., Friedrich, L., Yahya, N. A., Rohr, C.
M., Chulkov, E. G., Maillard, D., Rippmann,
F., Spangenberg, T., & Marchant, J. S. (2021).
Mechanism of praziquantel action at a parasitic
flatworm ion channel. Science Translational
Medicine, 13(625).
Parsegian, K., Trivedi, R., & Ioannidou, E. (2021). Renal
Diseases. Burket’s Oral Medicine, 579-626.
Roy, P., Kandel, R., Sawant, N., & Singh, K. P. (2024).
Oestrogen-induced reactive oxygen species,
through epigenetic reprogramming, causes
increased growth in breast cancer cells. Molecular
and Cellular Endocrinology, 579, 112092.
Santos, L. L., Santos, J., Gouveia, M. J., Bernardo,
C., Lopes, C., Rinaldi, G., ... & Costa, J. M. C.
D. (2021). Urogenital schistosomiasis-history,
pathogenesis, and bladder cancer. Journal of
Clinical Medicine, 10(2), 205.
Sprague, D. J., Kaethner, M., Park, S. K., Rohr, C. M.,
Harris, J. L., Maillard, D., ... & Marchant, J. S.
(2023). The Anthelmintic Activity of Praziquantel
Analogs Correlates with Structure-Activity
Relationships at TRPMPZQ Orthologs. AC S
Medicinal Chemistry Letters, 14(11), 1537-1543.
Sturt, A. S., Webb, E. L., Francis, S. C., Hayes, R. J., &
Bustinduy, A. L. (2020). Beyond the barrier: female
genital schistosomiasis as a potential risk factor for
HIV-1 acquisition. Acta Tropica, 209, 105524.
Turner, M. C., Cogliano, V., Guyton, K., Madia, F.,
Straif, K., Ward, E. M., & Schubauer-Berigan,
M. K. (2023). Research recommendations
for selected IARC-classified agents: impact
and lessons learned. Environmental Health
Perspectives, 131(10), 1050 01.
Vieira, P., Miranda, H. P., Cerqueira, M., de Lurdes
Delgado, M., Coelho, H., Antunes, D., ... & da
Costa, J. M. C. (2007). Latent schistosomiasis in
Portuguese soldiers. Military Medicine, 172(2),
144-14 6.
Volesky-Avellaneda, K. D., Morais, S., Walter, S. D.,
O’Brien, T. R., Hildesheim, A., Engels, E. A., ...
& Franco, E. L. (2023). Cancers Attributable to
Infections in the US in 2017: A Meta-Analysis. JAMA
Oncology, 9(12), 1678-1687.
Wang , W., Bergquist , R., Ki n g, C. H., & Yang , K. (20 21).
Elimination of schistosomiasis in China: Current
status and prospects. PLOS Neglected Tropical
Diseases, 15(8), e0009578.
Webster, B. L., Diaw, O. T., Seye, M. M., Webster, J. P.,
& Rollinson, D. (2013). Introgressive hybridization
of Schistosoma haematobium group species in
Senegal: species barrier break down between
ruminant and human schistosomes. PLoS Neglected
Tropical Diseases, 7(4), e2110.
Zaghloul, M. S., Zaghloul, T. M., Bishr, M. K., &
Baumann, B. C. (2020). Urinary schistosomiasis
and the associated bladder cancer: update. Journal
of the Egyptian National Cancer Institute, 32, 1-10.
Zaghloul, M. S., Zaghloul, T. M., Bishr, M. K., &
Baumann, B. C. (2020). Urinary schistosomiasis
and the associated bladder cancer: update. Journal
of the Egyptian National Cancer Institute, 32, 1-10.