RESUMO
Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO2 exposure rat model and a long-term NaAsO2 exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.
Assuntos
Alcaloides , Arsênio , Proliferação de Células , Transformação Celular Neoplásica , Matrinas , NADPH Oxidase 2 , Quinolizinas , Espécies Reativas de Oxigênio , NADPH Oxidase 2/metabolismo , NADPH Oxidase 2/genética , Animais , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/induzido quimicamente , Humanos , Arsênio/toxicidade , Arsênio/efeitos adversos , Alcaloides/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ratos , Quinolizinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Movimento Celular/efeitos dos fármacos , Linhagem Celular , MasculinoRESUMO
Exposure to environmental pollutants and human microbiome composition are important predisposition factors for tumour development1,2. Similar to drug molecules, pollutants are typically metabolized in the body, which can change their carcinogenic potential and affect tissue distribution through altered toxicokinetics3. Although recent studies demonstrated that human-associated microorganisms can chemically convert a wide range of xenobiotics and influence the profile and tissue exposure of resulting metabolites4,5, the effect of microbial biotransformation on chemical-induced tumour development remains unclear. Here we show that the depletion of the gut microbiota affects the toxicokinetics of nitrosamines, which markedly reduces the development and severity of nitrosamine-induced urinary bladder cancer in mice6,7. We causally linked this carcinogen biotransformation to specific gut bacterial isolates in vitro and in vivo using individualized bacterial culture collections and gnotobiotic mouse models, respectively. We tested gut communities from different human donors to demonstrate that microbial carcinogen metabolism varies between individuals and we showed that this metabolic activity applies to structurally related nitrosamine carcinogens. Altogether, these results indicate that gut microbiota carcinogen metabolism may be a contributing factor for chemical-induced carcinogenesis, which could open avenues to target the microbiome for improved predisposition risk assessment and prevention of cancer.
Assuntos
Carcinogênese , Carcinógenos , Microbioma Gastrointestinal , Nitrosaminas , Neoplasias da Bexiga Urinária , Animais , Feminino , Humanos , Masculino , Camundongos , Biotransformação , Carcinogênese/induzido quimicamente , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinógenos/química , Carcinógenos/metabolismo , Carcinógenos/farmacocinética , Carcinógenos/toxicidade , Microbioma Gastrointestinal/fisiologia , Vida Livre de Germes , Camundongos Endogâmicos C57BL , Nitrosaminas/química , Nitrosaminas/metabolismo , Nitrosaminas/farmacocinética , Nitrosaminas/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/etiologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/prevenção & controle , Suscetibilidade a DoençasRESUMO
Ingested arsenic is carcinogenic to the human urinary tract, but uncertainties remain regarding the dose-response relationship. To assess dose-response relationships between arsenic ingestion and urinary cancers, we evaluated the associations between the arsenic level in drinking water and mortality of cancers of the bladder, kidney, and prostate in Taiwan. We utilized the 1971-2000 Taiwan death registry data and calculated the age-standardized mortality rates (ASMRs) using the 1976 world standard population as the reference group. We used the data from a 1974-1976 census survey of wells on the arsenic levels in drinking water conducted by the government to assess exposure levels, which had been divided into three categories: below 0.05 ppm, 0.05-0.35 ppm, and above 0.35 ppm. The data were analyzed using multiple linear regression models and geographical information system. We found no increase in ASMR for all, or any, of the urinary cancers at exposure levels of 0.05-0.35 ppm arsenic, but at exposure levels > 0.35 ppm arsenic was associated with increased ASMR in both males and females for bladder cancer, kidney cancer, and all urinary cancers combined. There was no increased ASMR associated with prostate cancer observed for either exposure category.
Assuntos
Arsênio , Relação Dose-Resposta a Droga , Água Potável , Neoplasias da Bexiga Urinária , Poluentes Químicos da Água , Humanos , Taiwan/epidemiologia , Masculino , Água Potável/química , Feminino , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Próstata/mortalidade , Exposição Ambiental , Neoplasias Renais/mortalidade , Neoplasias Renais/induzido quimicamente , Pessoa de Meia-Idade , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/induzido quimicamente , Idoso , AdultoRESUMO
Arsenic (As) is recognized as a potent environmental contaminant associated with bladder carcinogenesis. However, its molecular mechanism remains unclear. Metabolic reprogramming is one of the hallmarks of cancer and is as a central feature of malignancy. Here, we performed the study of cross-talk between the mammalian target of rapamycin complex 1 (mTORC1)/ Hypoxia-inducible factor 1 alpha (HIF-1α) pathway and aerobic glycolysis in promoting the proliferation and migration of bladder epithelial cells treated by arsenic in vivo and in vitro. We demonstrated that arsenite promoted N-methyl-N-nitrosourea (MNU)-induced tumor formation in the bladder of rats and the malignant behavior of human ureteral epithelial (SV-HUC-1) cell. We found that arsenite positively regulated the mTORC1/HIF-1α pathway through glucose transporter protein 1 (GLUT1), which involved in the malignant progression of bladder epithelial cells relying on glycolysis. In addition, pyruvate kinase M2 (PKM2) increased by arsenite reduced the protein expressions of succinate dehydrogenase (SDH) and fumarate hydratase (FH), leading to the accumulation of tumor metabolites of succinate and fumarate. Moreover, heat shock protein (HSP)90, functioning as a chaperone protein, stabilized PKM2 and thereby regulated the proliferation and aerobic glycolysis in arsenite treated SV-HUC-1 cells. Taken together, these results provide new insights into mTORC1/HIF-1α and PKM2 networks as critical molecular targets that contribute to the arsenic-induced malignant progression of bladder epithelial cells.
Assuntos
Arsênio , Movimento Celular , Proliferação de Células , Células Epiteliais , Transportador de Glucose Tipo 1 , Subunidade alfa do Fator 1 Induzível por Hipóxia , Alvo Mecanístico do Complexo 1 de Rapamicina , Transportador de Glucose Tipo 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ratos , Arsênio/toxicidade , Movimento Celular/efeitos dos fármacos , Animais , Bexiga Urinária/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas de Ligação a Hormônio da Tireoide , Humanos , Proteínas de Transporte/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Glicólise/efeitos dos fármacosRESUMO
BACKGROUND: The carcinogenicity of air pollution and its impact on the risk of lung cancer is well known; however, there are still knowledge gaps and mixed results for other sites of cancer. METHODS: The current study aimed to evaluate the associations between ambient air pollution [fine particulate matter (PM2.5) and nitrogen oxides (NOx)] and cancer incidence. Exposure assessment was based on historical addresses of >900â000 participants. Cancer incidence included primary cancer cases diagnosed from 2007 to 2015 (n = 30â979). Cox regression was used to evaluate the associations between ambient air pollution and cancer incidence [hazard ratio (HR), 95% CI]. RESULTS: In the single-pollutant models, an increase of one interquartile range (IQR) (2.11 µg/m3) of PM2.5 was associated with an increased risk of all cancer sites (HR = 1.51, 95% CI: 1.47-1.54), lung cancer (HR = 1.73, 95% CI: 1.60-1.87), bladder cancer (HR = 1.50, 95% CI: 1.37-1.65), breast cancer (HR = 1.50, 95% CI: 1.42-1.58) and prostate cancer (HR = 1.41, 95% CI: 1.31-1.52). In the single-pollutant and the co-pollutant models, the estimates for PM2.5 were stronger compared with NOx for all the investigated cancer sites. CONCLUSIONS: Our findings confirm the carcinogenicity of ambient air pollution on lung cancer and provide additional evidence for bladder, breast and prostate cancers. Further studies are needed to confirm our observation regarding prostate cancer. However, the need for more research should not be a barrier to implementing policies to limit the population's exposure to air pollution.
Assuntos
Poluição do Ar , Neoplasias da Mama , Exposição Ambiental , Neoplasias Pulmonares , Material Particulado , Neoplasias da Próstata , Neoplasias da Bexiga Urinária , Humanos , Masculino , Incidência , Feminino , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/etiologia , Poluição do Ar/efeitos adversos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/induzido quimicamente , Material Particulado/efeitos adversos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/etiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/etiologia , Pessoa de Meia-Idade , Idoso , Exposição Ambiental/efeitos adversos , Exposição Ambiental/estatística & dados numéricos , Adulto , Óxidos de Nitrogênio/efeitos adversos , Poluentes Atmosféricos/efeitos adversos , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.
Assuntos
Receptores Androgênicos , Receptores de Peptídeos , Neoplasias da Bexiga Urinária , Urotélio , Humanos , Receptores Androgênicos/metabolismo , Receptores Androgênicos/genética , Animais , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , Urotélio/patologia , Urotélio/metabolismo , Camundongos , Receptores de Peptídeos/metabolismo , Receptores de Peptídeos/genética , Masculino , Carcinogênese/genética , Carcinogênese/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Feminino , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/genética , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
BACKGROUND/AIM: The efficacy of melatonin and its biological significance in human bladder cancer remain poorly understood. This study aimed to investigate the functional role of melatonin in urothelial carcinogenesis. MATERIALS AND METHODS: In human normal urothelial SVHUC cells with exposure to the chemical carcinogen 3-methylcholanthrene, we assessed the effects of melatonin on the neoplastic/malignant transformation. RESULTS: In the in vitro system with carcinogen challenge, melatonin significantly prevented the neoplastic transformation of SV-HUC-1 cells. In addition, melatonin treatment resulted in increased expression of SIRT1, Rb1, and E-cadherin, and decreased expression of N-cadherin and FGFR3 in SV-HUC-1 cells. Furthermore, publicly available datasets from GSE3167 revealed that the expression of melatonin receptor 1 and melatonin receptor 2 was significantly down-regulated in bladder urothelial carcinoma tissues, compared with adjacent normal urothelial tissues. CONCLUSION: These findings indicate that melatonin serves as a suppressor for urothelial tumorigenesis. To the best of our knowledge, this is the first preclinical study demonstrating the impact of melatonin on the development of urothelial cancer.
Assuntos
Carcinógenos , Transformação Celular Neoplásica , Melatonina , Neoplasias da Bexiga Urinária , Urotélio , Melatonina/farmacologia , Humanos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/metabolismo , Carcinógenos/toxicidade , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Urotélio/patologia , Urotélio/metabolismo , Urotélio/efeitos dos fármacos , Metilcolantreno/toxicidadeRESUMO
Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.
Assuntos
Carcinógenos , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Neoplasias da Bexiga Urinária , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Povo Asiático/genética , Carcinógenos/toxicidade , Carcinógenos/metabolismo , Estudos de Casos e Controles , China/epidemiologia , Fumar Cigarros/efeitos adversos , Fumar Cigarros/genética , População Europeia , Hidroxiesteroide Desidrogenases , Nicotiana , Nitrosaminas/toxicidade , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , População Branca/genéticaRESUMO
Environmental and occupational exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health effects in humans. Uncertainty exists regarding the causation of urinary bladder cancer by benzo[a]pyrene (B[a]P) due to a lack of sufficient data. In this work, we focused on in-vitro DNA damage and the formation of micronuclei and chromosomal aberrations as predictors of cancer risk, applying a wide range of dosages and time periods to quantify the onset, intensity, and duration of the response. We chose two urothelial cell types to compare susceptibility and the ability to increase the malignity of a pre-existing bladder cancer: a cancer cell line (T24) and a pooled sample of primary urinary bladder epithelia cells (PUBEC) from pigs. The highest level of DNA damage assessed by comet assay was observed following 24-h treatment in both cell types, whereas PUBEC cells were clearly more susceptible. Even 4-h treatment induced DNA damage in PUBEC cells with benchmark doses of 0.0027⯵M B[a]P and 0.00023⯵M after 4-h and 24-h exposure, respectively. Nearly no effect was observed for periods of 48â¯h. The frequency of micronucleus formation increased more markedly in T24 cells, particularly with 24-h treatment. In PUBEC cells, 48-h exposure notably induced the formation of nucleoplasmic bridges and nuclear buds. Even though only one biological replicate was studied due to the sophisticated study design, our results give a strong indication of the potential of B[a]P to induce and increase malignity in human-relevant cell types.
Assuntos
Benzo(a)pireno , Instabilidade Cromossômica , Dano ao DNA , Urotélio , Benzo(a)pireno/toxicidade , Dano ao DNA/efeitos dos fármacos , Projetos Piloto , Animais , Urotélio/efeitos dos fármacos , Urotélio/patologia , Instabilidade Cromossômica/efeitos dos fármacos , Humanos , Suínos , Testes para Micronúcleos , Relação Dose-Resposta a Droga , Aberrações Cromossômicas , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Fatores de Tempo , Ensaio Cometa , Linhagem Celular Tumoral , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologiaRESUMO
The etiology of bladder cancer among never smokers without occupational or environmental exposure to established urothelial carcinogens remains unclear. Urinary mutagenicity is an integrative measure that reflects recent exposure to genotoxic agents. Here, we investigated its potential association with bladder cancer in rural northern New England. We analyzed 156 bladder cancer cases and 247 cancer-free controls from a large population-based case-control study conducted in Maine, New Hampshire, and Vermont. Overnight urine samples were deconjugated enzymatically and the extracted organics were assessed for mutagenicity using the plate-incorporation Ames assay with the Salmonella frameshift strain YG1041 + S9. Logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer in relation to having mutagenic versus nonmutagenic urine, adjusted for age, sex, and state, and stratified by smoking status (never, former, and current). We found evidence for an association between having mutagenic urine and increased bladder cancer risk among never smokers (OR = 3.8, 95% CI: 1.3-11.2) but not among former or current smokers. Risk could not be estimated among current smokers because nearly all cases and controls had mutagenic urine. Urinary mutagenicity among never-smoking controls could not be explained by recent exposure to established occupational and environmental mutagenic bladder carcinogens evaluated in our study. Our findings suggest that among never smokers, urinary mutagenicity potentially reflects genotoxic exposure profiles relevant to bladder carcinogenesis. Future studies are needed to replicate our findings and identify compounds and their sources that influence bladder cancer risk.
Assuntos
Mutagênicos , Neoplasias da Bexiga Urinária , Humanos , Mutagênicos/toxicidade , Bexiga Urinária , Estudos de Casos e Controles , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/genética , New England/epidemiologia , Carcinógenos , Testes de MutagenicidadeRESUMO
Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens.
Assuntos
Fibroblastos Associados a Câncer , Transição Epitelial-Mesenquimal , Microambiente Tumoral , Neoplasias da Bexiga Urinária , Humanos , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/efeitos dos fármacos , Carcinógenos/toxicidade , Regulação Neoplásica da Expressão Gênica , Evasão da Resposta Imune , Multiômica , Prognóstico , Análise de Célula Única , Fumar/efeitos adversos , Microambiente Tumoral/imunologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
This study aimed to assess the global spatiotemporal variations of trihalomethanes (THMs) in drinking water, evaluate their cancer and non-cancer risks, and THM-attributable bladder cancer burden. THM concentrations in drinking water around fifty years on a global scale were integrated. Health risks were assessed using Monte Carlo simulations and attributable bladder cancer burden was estimated by comparative risk assessment methodology. The results showed that global mean THM concentrations in drinking water significantly decreased from 78.37 µg/L (1973-1983) to 51.99 µg/L (1984-2004) and to 21.90 µg/L (after 2004). The lifestage-integrative cancer risk and hazard index of THMs through all exposure pathways were acceptable with the average level of 6.45 × 10-5 and 7.63 × 10-2, respectively. The global attributable disability adjusted of life years (DALYs) and the age-standardized DALYs rate (ASDR) dropped by 16% and 56% from 1990-1994 to 2015-2019, respectively. A big decline in the attributable ASDR was observed in the United Kingdom (62%) and the United States (27%), while China experienced a nearly 3-fold increase due to the expanded water supply coverage and increased life expectancy. However, China also benefited from the spread of chlorination, which helped reduce nearly 90% of unsafe-water-caused mortality from 1998 to 2018.
Assuntos
Água Potável , Neoplasias da Bexiga Urinária , Poluentes Químicos da Água , Humanos , Trialometanos/toxicidade , Trialometanos/análise , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia , Efeitos Psicossociais da Doença , Medição de Risco , Poluentes Químicos da Água/toxicidade , Poluentes Químicos da Água/análiseRESUMO
Urothelial cell carcinoma (UCC) has been linked to environmental chemical exposures in people, but these risk factors are not well understood in dogs with UCC. We hypothesised that household chemical exposures contribute to the risk of UCC in pet dogs. This prospective cross-sectional case-control study included 37 dogs with UCC and 37 unaffected breed-, sex-, and age-matched controls. Dog owners completed an environmental questionnaire and household samples were collected and analysed for arsenic (in tap water and room dust) and acrolein (in room air). Urine samples from UCC dogs, control dogs, and consenting owners were analysed for inorganic arsenic species, the acrolein metabolite 3-HPMA, and the phenoxy herbicide 2,4-D. Public data on chlorination byproducts (total trihalomethanes) in municipal drinking water were also compared between case and control households. Dogs with UCC were more likely to swim in a pool (15.2%) compared with control dogs (0%) (OR 1.69, 95% CI = 1.69-∞; p = .02). Dogs with UCC also had more than 4-fold higher reported municipal water concentrations of chlorination byproducts (median 28.0 ppb) compared with controls (median 6.9 ppb; p < .0001). Dust arsenic concentrations were unexpectedly lower in case households (median 0.277 ng/cm2) compared with control households (median 0.401 ng/cm2; p = .0002). Other outcomes were not significantly different between groups. These data suggest that dog owners, especially those of breeds known to be at higher risk for UCC, consider limiting access to swimming pools and installing water filtration units that remove total trihalomethanes.
Assuntos
Doenças do Cão , Exposição Ambiental , Neoplasias da Bexiga Urinária , Cães , Animais , Estudos de Casos e Controles , Doenças do Cão/induzido quimicamente , Doenças do Cão/urina , Masculino , Feminino , Exposição Ambiental/efeitos adversos , Estudos Transversais , Neoplasias da Bexiga Urinária/veterinária , Neoplasias da Bexiga Urinária/induzido quimicamente , Estudos Prospectivos , Arsênio/urina , Carcinoma de Células de Transição/veterinária , Animais de EstimaçãoRESUMO
BACKGROUND: Bladder cancer has been linked to several occupations that involve the use of solvents, including those used in the dry-cleaning industry. OBJECTIVES: We evaluated exposure to solvents and risk of bladder cancer in 1182 incident cases and 1408 controls from a population-based study. METHODS: Exposure to solvents was quantitatively assessed using a job-exposure matrix (CANJEM). Exposure to benzene, toluene and xylene often co-occur. Therefore, we created two additional sets of metrics for combined benzene, toluene and xylene (BTX) exposure: (1) CANJEM-based BTX metrics and (2) hybrid BTX metrics, using an approach that integrates the CANJEM-based BTX metrics together with lifetime occupational histories and exposure-oriented modules that captured within-job, respondent-specific details about tasks and chemicals. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated using logistic regression. RESULTS: Bladder cancer risks were increased among those ever exposed to benzene (OR = 1.63, 95% CI: 1.14-2.32), toluene (OR = 1.60, 95% CI: 1.06-2.43), and xylene (OR = 1.67, 95% CI: 1.13-2.48) individually. We further observed a statistically significant exposure-response relationship for cumulative BTX exposure, with a stronger association using the hybrid BTX metrics (ORQ1vsUnexposed = 1.26, 95% CI: 0.83-1.90; ORQ2vsUnexposed = 1.52, 95% CI: 1.00-2.31; ORQ3vsUnexposed = 1.88, 95% CI: 1.24-2.85; and ORQ4vsUnexposed = 2.23, 95% CI: 1.35-3.69) (p-trend=0.001) than using CANJEM-based metrics (p-trend=0.02). IMPACT: There is limited evidence about the role of exposure to specific organic solvents, alone or in combination on the risk of developing bladder cancer. In this study, workers with increasing exposure to benzene, toluene, and xylene as a group (BTX) had a statistically significant exposure-response relationship with bladder cancer. Future evaluation of the carcinogenicity of BTX and other organic solvents, particularly concurrent exposure, on bladder cancer development is needed.
Assuntos
Benzeno , Exposição Ocupacional , Solventes , Tolueno , Neoplasias da Bexiga Urinária , Xilenos , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia , Exposição Ocupacional/efeitos adversos , Humanos , Solventes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Tolueno/efeitos adversos , Feminino , Adulto , Estudos de Casos e Controles , Idoso , Fatores de Risco , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/epidemiologia , Razão de Chances , Modelos LogísticosRESUMO
BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with several health outcomes, though few occupationally-exposed populations have been studied. We evaluated mortality and cancer incidence in a cohort of perfluorooctanesulfonyl fluoride-based specialty chemical manufacturing workers. METHODS: The cohort included any employee who ever worked at the facility from 1961 to 2010 (N = 4045), with a primary interest in those who had 365 cumulative days of employment (N = 2659). Vital status and mortality records were obtained through 2014 and the cohort was linked to state cancer registries to obtain incident cancer cases from 1995 to 2014. Cumulative exposure was derived from a comprehensive exposure reconstruction that estimated job-specific perfluorooctanesulfonate (PFOS)-equivalents (mg/m3 ) exposure. Overall and exposure-specific standardized mortality ratios (SMR) were estimated in reference to the US population. Hazard ratios (HRs) and 95% confidence interval (CI) for cumulative PFOS-equivalent exposure (log2 transformed) were estimated within the cohort for specific causes of death and incident cancers using a time-dependent Cox model. RESULTS: Death rates were lower than expected except for cerebrovascular disease (SMR = 2.42, 95% CI = 1.25-4.22) and bladder cancer (SMR = 3.91, 95% CI = 1.07-10.02) in the highest exposure quartile. Within the cohort, the incidence of bladder, colorectal, and pancreatic cancer were positively associated with exposure, however except for lung cancer (HR = 1.05, 95% CI = 1.00-1.11) the CIs did not exclude an HR of 1. CONCLUSIONS: This study provides some evidence that occupational exposure to PFOS is associated with bladder and lung cancers and with cerebrovascular disease.
Assuntos
Ácidos Alcanossulfônicos , Transtornos Cerebrovasculares , Fluorocarbonos , Neoplasias Pulmonares , Doenças Profissionais , Exposição Ocupacional , Neoplasias da Bexiga Urinária , Humanos , Fluoretos , Estudos de Coortes , Exposição Ocupacional/efeitos adversos , Incidência , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias Pulmonares/epidemiologia , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/epidemiologiaRESUMO
BACKGROUND: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN's downregulation have remained elusive. METHODS: We established targeted genes' knockdown or overexpressed cell lines to explore the mechanism how it drove the malignant transformation of urothelial cells or promoted anchorageindependent growth of human basal muscle invasive BC (BMIBC) cells. The mice model was used to validate the conclusion in vivo. The important findings were also extended to human studies. RESULTS: In this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary BMIBC accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN polyubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorageindependent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice. CONCLUSIONS: Our findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation.
Assuntos
RNA Longo não Codificante , Neoplasias da Bexiga Urinária , Animais , Humanos , Camundongos , Carcinogênese/genética , Proliferação de Células , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Camundongos Nus , Músculos/metabolismo , Músculos/patologia , Proteólise , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Longo não Codificante/genética , RNA Mensageiro/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismoRESUMO
BACKGROUND: Our aimed to conduct a meta-analysis of cohort studies on risk of genitourinary (GU) cancers in workers exposed to welding fumes (WF). METHODS: We performed a systematic review of studies published on Pubmed, Scopus and Embase following PRISMA criteria. Two researchers selected cohort studies on WF exposure. From 2582 articles, 7 non-overlapping studies were included. Quality of studies was scored according to CASP. We run a random effects meta-analysis to calculate the relative risk (RR) and 95% confidence intervals (CI) of GU cancer, overall and stratified by cancer, country, and quality score. RESULTS: We included seven studies reporting results on GU cancers, including prostate, bladder and kidney cancer (PC, BC, and KC). The RR was 1.19 (95% CI = 1.07-1.32, 16 risk estimates) for GU cancer; 1.13 (95% CI = 0.90-1.42, 4 risk estimates) for PC; 1.26 (95% CI = 0.98-1.60, 7 risk estimates) for BC and 1.28 (95% CI = 1.12-1.47, 5 risk estimates) for KC. Heterogeneity was present in all meta-analyses (p < 0.001). The increased risk was more pronounced in North American than in European studies (respectively, OR = 1.35, 95% CI = 1.18-1.55; OR = 1.13, 95% CI = 1.01-1.27 p heterogeneity = 0.03). There was no heterogeneity according to quality score (p = 0.4). Data were insufficient to investigate associations by industry or welding type. Publication bias for each cancer was excluded. CONCLUSION: This meta-analysis suggests increased risk of KC and BC, but not of PC, in workers exposed to WF. Confounding by other occupational and non-occupational risk factors could not be excluded. Data were not adequate to address the risk of specific exposure circumstances.
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Neoplasias Renais , Doenças Profissionais , Exposição Ocupacional , Neoplasias da Próstata , Neoplasias da Bexiga Urinária , Soldagem , Humanos , Exposição Ocupacional/efeitos adversos , Neoplasias da Próstata/epidemiologia , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/etiologia , Masculino , Neoplasias Renais/epidemiologia , Neoplasias Renais/etiologia , Doenças Profissionais/epidemiologia , Poluentes Ocupacionais do Ar/efeitos adversos , Fatores de RiscoRESUMO
Urinary bladder cancer is the tenth most common cancer worldwide with high morbidity and mortality. The majority of bladder cancers are urothelial carcinomas. More than half are papillomas or the papillary urothelial carcinomas (stages Ta and T1), which have a relatively good prognosis. Squamous cell carcinomas have a variable survival rate, while carcinomas in situ (Tis) can progress to muscle-invasive urothelial carcinomas (T2) with a poor prognosis. The most challenging feature of bladder cancer is its high recurrence rate, ranging from 50% to 90% of cases. The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) model is an invaluable experimental tool for bladder cancer research, as BBN-induced bladder cancer in rodents resembles human bladder cancer in its morphological, biological, and molecular features. We present here a detailed protocol for the treatment of mice and the main expected results.
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Carcinoma de Células Escamosas , Nitrosaminas , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/induzido quimicamente , Bexiga Urinária , MúsculosRESUMO
INTRODUCTION: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. MATERIALS AND METHODS: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. RESULTS: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. CONCLUSION: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.
Assuntos
Antineoplásicos Imunológicos , Carcinoma de Células de Transição , Neoplasias da Bexiga Urinária , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Interrupção do Tratamento , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos RetrospectivosRESUMO
INTRODUCTION: Urinary bladder cancer is a frequent neoplasia in the urogenital system. Ageing and smoking are the two main risk factors, however, some chemical agents such as artificial sweeteners could act as initiators or promoters. EVIDENCE ACQUISITION: After identifying trends in scientific literature, we conducted a wide search in PubMed database and a meta-analysis was performed on extracted data to determine the role of artificial sweeteners in the development of urinary bladder cancer. EVIDENCE SYNTHESIS: Twenty-one full reports were enrolled from screening of PubMed database into final analysis involving 116,568 subjects in comparisons. Overall, 13,682 and 102,886 cases were identified for bladder cancer patients and healthy controls, respectively. Among artificial sweetener users, 12.5% was the incidence of bladder cancer. In the control group, 11.2% of cases suffered from urothelial carcinoma of the bladder. About 40.7% of the patients suffering from urinary neoplasms and 37.8% of the healthy cases were artificial sweetener users, respectively. There were only minor differences in overall descriptive data. The incidence of urinary bladder cancer among artificial sweetener users and control cases showed no risk difference (RD: 0.00, CI: -0.06 to 0.06). The frequency of artificial sweetener use among patients suffering from urinary bladder neoplasms and healthy subjects was compared which showed equal occurrences (OR: 0.96, CI: 0.79 to 1.17). CONCLUSIONS: According to our results, the carcinogenic risk of artificial sweeteners is not proven. Saccharin should not be kept as a promoter in urothelial malignant transformation.