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Methods in Cell Biology 2021Around 3% of new cancer diagnoses and 2% of all cancer deaths every year are caused by urinary bladder cancer (BC). This indicates a great need for intensive studying of...
Around 3% of new cancer diagnoses and 2% of all cancer deaths every year are caused by urinary bladder cancer (BC). This indicates a great need for intensive studying of BC by using different approaches including indispensable mice models. The most common preclinical mouse model of bladder carcinogenesis relies on the use of a nitrosamine compound, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) which causes high-grade, invasive tumors in the urinary bladder. BBN-induced bladder cancer in mice recapitulates the histology and manifests genetic alterations similar to human muscle-invasive bladder cancer. Here we present a detailed protocol for the induction of BC in mice which is based on the administration of 0.05%-0.1% BBN in drinking water. Six-to-eight-week-old mice are treated orally with BBN for 12weeks and tumors are expected 8weeks after the termination of BBN regimen. Histopathologic examination of the lesions should be routinely assessed after hematoxylin and eosin staining by an experienced pathologist and it can vary from urothelial dysplasia to invasive bladder cancer with glandular and squamous divergent differentiation, the incidence of which might depend on the mouse strain, gender, BBN concentration and the timeline of the protocol. Utilizing half of the urinary bladder tissue for the isolation and analysis of RNA, DNA and proteins provides a comprehensive insight into the biology of BC and reduces the number of mice per study. Finally, the successful use of the BC model can facilitate fundamental biomedical discoveries leading to novel diagnostic and therapeutic approaches with clinical benefits.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogenesis; Carcinogens; Mice; Mutation; Urinary Bladder Neoplasms
PubMed: 33785170
DOI: 10.1016/bs.mcb.2020.10.020 -
In Vivo (Athens, Greece) 2012Experimental urinary bladder tumours have been proposed as a useful model for the study of urinary bladder carcinogenesis, as well as for evaluating new therapeutic... (Review)
Review
Experimental urinary bladder tumours have been proposed as a useful model for the study of urinary bladder carcinogenesis, as well as for evaluating new therapeutic strategies. Consequently, the administration of chemical carcinogens is one of the most commonly used methods for inducing urinary bladder tumours. N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is, undoubtedly, the most-used urothelial chemical carcinogen. BBN belongs to the nitrosamine family, a wide group of alkylating agents that are able to induce bladder tumours in laboratory animals. Depending on the animal species, the spectrum of urothelial lesions induced by BBN varies, but is similar to those observed in humans. BBN has a high propensity to induce mutations affecting the expression of genes such as p53, RAS and H19 among others. The aim of this study was to review BBN as a urothelial tumour inducer, taking into consideration its chemical characteristics, properties and spectrum of lesions induced, as well as its possible applications.
Topics: Butylhydroxybutylnitrosamine; Carcinogens; Humans; Urinary Bladder Neoplasms
PubMed: 22773588
DOI: No ID Found -
Methods in Molecular Biology (Clifton,... 2018Urinary bladder cancer (UBC) is a common and complex malignancy, with a multifactorial etiology, like environmental factors, such as cigarette smoking, occupational... (Review)
Review
Urinary bladder cancer (UBC) is a common and complex malignancy, with a multifactorial etiology, like environmental factors, such as cigarette smoking, occupational exposure, and genetic factors.UBC exhibits considerable genotypic and phenotypic heterogeneity. Among all UBC lesions, urothelial carcinoma is the most frequently observed histological type. Despite all the developments made in urologic oncology field, therapeutic options remain inadequate. There is urgency for the identification and development of new antineoplastic drugs to replace or improve current protocols and in vivo models have been proven to be essential for this step. There are different animal models of UBC: Spontaneous and experimentally induced models (genetically engineered, transplantable-xenograft and syngeneic animals- and chemically induced models). N-butyl-N(4-hydroxybutil)nitrosamine (BBN) is the most suitable reagent to generate chemically induced in vivo models of UBC and to study bladder carcinogenesis. BBN has proven, over the years, to be very realistic and reliable. It is bladder specific, and induces high tumor incidence.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Cell Transformation, Neoplastic; Disease Models, Animal; FANFT; Humans; Mice; Mice, Transgenic; Urinary Bladder Neoplasms
PubMed: 28889385
DOI: 10.1007/978-1-4939-7234-0_13 -
Scientific Reports Nov 2021Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative...
Bladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Cell Line; Humans; Male; Metabolome; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Urinary Bladder Neoplasms; Urothelium
PubMed: 34764423
DOI: 10.1038/s41598-021-99746-3 -
Japanese Journal of Clinical Oncology Jul 2012Men are at a higher risk of developing bladder cancer than women. Since bladder cancer cell lines and tissues were found to express the androgen receptor, efforts have... (Review)
Review
Men are at a higher risk of developing bladder cancer than women. Since bladder cancer cell lines and tissues were found to express the androgen receptor, efforts have been made to inspect whether androgen-mediated androgen receptor signals are implicated in bladder carcinogenesis as well as cancer progression. Mounting evidence supports the view that bladder cancer is a member of the endocrine-related tumors and may clearly explain the gender-specific difference in the incidence. However, the underlying mechanisms of how androgen receptor signals regulate bladder cancer growth are still far from fully characterized. Moreover, it remains controversial whether the androgen receptor pathway always plays a dominant role in bladder cancer progression. In this review, we summarize the available data on the involvement of androgen receptor signaling in bladder cancer. In particular, current evidence demonstrating the stimulatory effects of androgens on tumor progression or, more convincingly, tumorigenesis via the androgen receptor pathway may offer great potential for androgen deprivation as a therapeutic or chemopreventive option in patients with bladder cancer.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Castration; Disease Models, Animal; Disease Progression; Evidence-Based Medicine; Female; Gene Expression Regulation, Neoplastic; Humans; Incidence; Male; Neoplasms, Hormone-Dependent; Receptors, Androgen; Risk Factors; Sex Factors; Signal Transduction; Urinary Bladder Neoplasms
PubMed: 22593639
DOI: 10.1093/jjco/hys072 -
Nutrition and Cancer 2022The present study was undertaken to evaluate the chemopreventive activity of myrtenal, a natural monoterpene, against bladder carcinoma in rats induced with...
The present study was undertaken to evaluate the chemopreventive activity of myrtenal, a natural monoterpene, against bladder carcinoma in rats induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and promoted with γ-ionizing radiation (γ-IRR) as well as to assess the involvement of inflammation, apoptosis and oxidative damage in tumor development. Histopathological examination of rat bladder revealed the presence of noninvasive papillary transitional cell carcinoma (Grade 2) in sections from BBN group indicating the credibility of the applied carcinogenesis model. Myrtenal treatment caused improvement in urinary bladder mucosa with cells more likely in Grade 1. Administration of myrtenal to BBN-treated rats exhibited downregulation in the expressions of COX-2, NF-kB and STAT-3 associated with suppression of inflammatory cytokines levels of TNF-α and IL-6 as well as biomarkers of oxidative damage (MDA & NO). In addition, myrtenal treatment caused a significant increase in caspase-3 activity and Bax/Bcl-2 ratio. Data obtained suggested that the anti-inflammatory effect and the induction of apoptosis contributed largely to the beneficial antitumor effects of myrtenal in rats with BBN/γ-IRR-induced bladder carcinoma. Present findings, in addition to benefits described in other pathologies, indicated myrtenal as a potential adjuvant natural compound for the prevention of tumor progression of bladder cancer.
Topics: Animals; Bicyclic Monoterpenes; Butylhydroxybutylnitrosamine; Carcinogenesis; Carcinogens; Nitrosamines; Rats; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 33511885
DOI: 10.1080/01635581.2021.1879881 -
Gan To Kagaku Ryoho. Cancer &... May 1997There are theoretical limits to the efficacy of intravesical chemotherapy for prevention of tumor recurrence after transurethral resection of a superficial bladder... (Review)
Review
There are theoretical limits to the efficacy of intravesical chemotherapy for prevention of tumor recurrence after transurethral resection of a superficial bladder cancer. Our multi-institutional studies revealed that the direct efficacy of BCG, intravesical instillation for treatment of an existing tumor is very promising. This efficacy persisted over a long period of time, and the subsequent recurrence rate was markedly reduced. Bladder cancer, sometimes earlier known as an occupational disease, might be related to unknown chemical carcinogens. Since enterobacterias are thought to produce carcinogens and mutagens, including nitroso-compounds in the intestinal tract, BLP (lactobacillus casei preparation), treatment may suppress the production of such compounds by altering the intestinal flora. Preclinical studies have demonstrated that BLP suppresses the development of bladder cancer induced by N-butyl-N-(4-hydroxy-butly)-nitrosamine in mice and rats. A double-blind clinical trial recently revealed that BLP was effective for preventing the recurrence of superficial bladder cancer. Bropirimine, a interferon inducer, is now an internationally developing agent for superficial bladder cancer, which is discussed on the basis of Japanese phase II trial data.
Topics: Administration, Intravesical; Animals; BCG Vaccine; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Cytosine; Humans; Interferon Inducers; Mice; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Rats; Urinary Bladder Neoplasms
PubMed: 9210905
DOI: No ID Found -
Scientific Reports Nov 2020Urinary incontinence of idiopathic nature is a common complication of bladder cancer, yet, the mechanisms underlying changes in bladder contractility associated with...
Urinary incontinence of idiopathic nature is a common complication of bladder cancer, yet, the mechanisms underlying changes in bladder contractility associated with cancer are not known. Here by using tensiometry on detrusor smooth muscle (DSM) strips from normal rats and rats with bladder cancer induced by known urothelial carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), we show that bladder cancer is associated with considerable changes in DSM contractility. These changes include: (1) decrease in the amplitude and frequency of spontaneous contractions, consistent with the decline of luminal pressures during filling, and detrusor underactivity; (2) diminution of parasympathetic DSM stimulation mainly at the expense of m-cholinergic excitatory transmission, suggestive of difficulty in bladder emptying and weakening of urine stream; (3) strengthening of TRPV1-dependent afferent limb of micturition reflex and TRPV1-mediated local contractility, promoting urge incontinence; (4) attenuation of stretch-dependent, TRPV4-mediated spontaneous contractility leading to overflow incontinence. These changes are consistent with the symptomatic of bladder dysfunction in bladder cancer patients. Considering that BBN-induced urothelial lesions in rodents largely resemble human urothelial lesions at least in their morphology, our studies establish for the first time underlying reasons for bladder dysfunction in bladder cancer.
Topics: Animals; Butylhydroxybutylnitrosamine; Disease Models, Animal; Male; Muscle Contraction; Rats; Rats, Wistar; TRPV Cation Channels; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Incontinence
PubMed: 33184390
DOI: 10.1038/s41598-020-76653-7 -
JCI Insight Jun 2021Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but...
Using genetically engineered mouse models, this work demonstrates that protein synthesis is essential for efficient urothelial cancer formation and growth but dispensable for bladder homeostasis. Through a candidate gene analysis for translation regulators implicated in this dependency, we discovered that phosphorylation of the translation initiation factor eIF4E at serine 209 is increased in both murine and human bladder cancer, and this phosphorylation corresponds with an increase in de novo protein synthesis. Employing an eIF4E serine 209 to alanine knock-in mutant mouse model, we show that this single posttranslational modification is critical for bladder cancer initiation and progression, despite having no impact on normal bladder tissue maintenance. Using murine and human models of advanced bladder cancer, we demonstrate that only tumors with high levels of eIF4E phosphorylation are therapeutically vulnerable to eFT508, the first clinical-grade inhibitor of MNK1 and MNK2, the upstream kinases of eIF4E. Our results show that phospho-eIF4E plays an important role in bladder cancer pathogenesis, and targeting its upstream kinases could be an effective therapeutic option for bladder cancer patients with high levels of eIF4E phosphorylation.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Cell Transformation, Neoplastic; Drug Screening Assays, Antitumor; Eukaryotic Initiation Factor-4E; Gene Knock-In Techniques; Homeostasis; Humans; Mice; Neoplasm Transplantation; Protein Biosynthesis; Protein Kinase Inhibitors; Pyridines; Pyrimidines; RNA, Messenger; Ribosomal Proteins; Urinary Bladder Neoplasms; Urothelium
PubMed: 34032633
DOI: 10.1172/jci.insight.144920 -
Toxicological Sciences : An Official... Aug 2022We investigated γ-H2AX formation, a biomarker of DNA damage, and expression of stem cell markers (SCMs), including cytokeratin 14, aldehyde dehydrogenase 1A1 (ALDH1A1),...
We investigated γ-H2AX formation, a biomarker of DNA damage, and expression of stem cell markers (SCMs), including cytokeratin 14, aldehyde dehydrogenase 1A1 (ALDH1A1), and CD44, in the development of rat bladder tumors induced by short-term administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Histopathological examination showed that diffuse simple hyperplasia of the bladder urothelium induced by BBN recovered to the normal-appearing urothelium after withdrawal, whereas focal proliferative lesions were newly developed and subsequently progressed to benign papilloma and carcinoma. Immunohistochemical analysis revealed that BBN-induced γ-H2AX formation and ALDH1A1 and CD44 expression persisted at higher levels in the normal-appearing urothelium than those in the control group for long periods after withdrawal. Since persistent chronic inflammation was observed even after withdrawal, targeted gene expression analysis of inflammation-related factors revealed 101 genes, including Stat3 and Myc, that showed persistent high expression. Pathway analysis suggested that Stat3 and/or Myc activation may be associated with SCM expression. We focused on hepatocyte growth factor (Hgf), one of the genes predicted in relation to Stat3/Myc, and confirmed that HGF-positive cells increased by BBN persisted in the normal-appearing urothelium after withdrawal and colocalized with γ-H2AX and SCMs. These results suggested that the long-term persistence of γ-H2AX formation and SCM expression, which occurred during the early stages of bladder tumorigenesis, is not a transient response to exposure and might contribute to bladder tumorigenesis. Although further studies are needed, BBN-induced rat bladder tumors may originate from focal hyperplasia arising from SCM-positive cells via activation of the STAT3/MYC pathway after DNA damage involving γ-H2AX formation.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogenesis; Histones; Hyperplasia; Inflammation; Nitrosamines; Phosphoproteins; Rats; Stem Cells; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 35771629
DOI: 10.1093/toxsci/kfac064