Asunto(s)
Vacuna BCG , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Humanos , Vacuna BCG/administración & dosificación , Vacuna BCG/uso terapéutico , Administración Intravesical , Estudios de Seguimiento , Invasividad Neoplásica , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Resultado del TratamientoRESUMEN
Bacille Calmette-Guérin (BCG) vaccine has been used increasingly in immunotherapy, including treatment of non-muscle-invasive bladder cancer, as an adjuvant therapy in metastatic prostate cancer and metastatic melanoma. However, systemic infection from inadvertent intravenous (instead of intravesical) injection is uncommon and can have systemic ramifications. We encountered 3 patients with disseminated Mycobacterium bovis infection that ensued after intravenous BCG injection.
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Vacuna BCG , Mycobacterium bovis , Humanos , Vacuna BCG/efectos adversos , Vacuna BCG/administración & dosificación , Masculino , Mycobacterium bovis/aislamiento & purificación , Mycobacterium bovis/inmunología , Persona de Mediana Edad , Inyecciones Intravenosas , Tuberculosis/tratamiento farmacológico , Anciano , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Bladder cancer (BCa) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in BCa and elucidated the mechanisms in three-dimensional (3D) spheroid and organoid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49 respectively) and organoids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine)-induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. Intracellular ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids and organoids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition-induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 target cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of BCa with small-molecule inhibitors TTI-101 and SH5-07 via suppression of CSCs and STAT3 signaling.
Asunto(s)
Supervivencia Celular , Factor de Transcripción STAT3 , Esferoides Celulares , Neoplasias de la Vejiga Urinaria , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Humanos , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ratas , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patología , Esferoides Celulares/metabolismo , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Ratones , Transducción de Señal/efectos de los fármacos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Organoides/efectos de los fármacos , Organoides/metabolismo , Organoides/patologíaRESUMEN
Intravesical therapy (IT) is widely used to tackle various urological diseases. However, its clinical efficacy is decreased by the impermeability of various barriers presented on the bladder luminal surface, including the urinary mucus layer and the densely packed tissue barrier. In this study, we report a mucoadhesive-to-penetrating nanomotors-in-hydrogel system for urothelium-oriented intravesical drug delivery. Upon intravesical instillation, its poloxamer 407 (PLX) hydrogel gelated and adhered to the urothelium to prolong its intravesical retention. The urea afterwards diffused into the hydrogel, thus generating a concentration gradient. Urease-powered membrane nanomotors (UMN) without asymmetric surface engineering could catalyze the urea and migrate down this concentration gradient to deeply and unidirectionally penetrate the urothelial barrier. Moreover, the intravesical hybrid system-delivered gemcitabine could effectively inhibit the bladder tumor growth without inducing any side effect. Therefore, our mucoadhesive-to-penetrating nanomotors-in-hydrogel system could serve as an alternative to IT to meet the clinical need for more efficacious therapeutics for urological diseases.
Asunto(s)
Sistemas de Liberación de Medicamentos , Hidrogeles , Poloxámero , Neoplasias de la Vejiga Urinaria , Urotelio , Urotelio/metabolismo , Animales , Hidrogeles/química , Sistemas de Liberación de Medicamentos/métodos , Administración Intravesical , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Ratones , Poloxámero/química , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/administración & dosificación , Gemcitabina , Vejiga Urinaria/metabolismo , Humanos , Femenino , Línea Celular Tumoral , AdhesividadRESUMEN
The standard of care for advanced or metastatic urothelial carcinoma (mUC) was historically identified with platinum-based chemotherapy. Thanks to the advances in biological and genetic knowledge and technologies, new therapeutic agents have emerged in this setting recently: the immune checkpoint inhibitors and the fibroblast growth factor receptor inhibitors as the target therapy for patients harboring alterations in the fibroblast growth factor receptor (FGFR) pathway. However, chasing a tumor's tendency to recur and progress, a new class of agents has more recently entered the scene, with promising results. Antibody-drug conjugates (ADCs) are in fact the latest addition, with enfortumab vedotin being the first to receive accelerated approval by the U.S. Food and Drug Administration in December 2019, followed by sacituzumab govitecan. Many other ADCs are still under investigation. ADCs undoubtedly represent the new frontier, with the potential of transforming the management of mUC treatment in the future. Therefore, we reviewed the landscape of mUC treatment options, giving an insight into the molecular basis and mechanisms, and evaluating new therapeutic strategies in the perspective of more and more personalized treatments.
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Inmunoconjugados , Humanos , Inmunoconjugados/uso terapéutico , Metástasis de la Neoplasia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida/métodos , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Camptotecina/análogos & derivadosRESUMEN
PURPOSE: In high-risk non-muscle-invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy post-transurethral resection of bladder tumor (TURBT). Intravesical gemcitabine, used as an alternative or second-line therapy amid BCG shortages, lacks outcome studies in the Korean population. MATERIALS AND METHODS: Patients who received weekly intravesical gemcitabine for 6 weeks after TURBT from 2019 to 2022 were retrospectively investigated. Based on the American Urological Association risk classification, patients with high- or very high-risk NMIBC who refused cystectomy were included. Maintenance treatment was performed depending on their risk. Recurrence was defined as histologic confirmation on subsequent cystoscopic biopsies or TURBT. Disease free survival (DFS) was evaluated by the Kaplan-Meier method. RESULTS: The study included 60 patients, comprising 45 high-risk (group 1) patients with a median age of 76 years and 15 very high-risk (group 2) patients with a median age of 68 years. Among them, 28 patients had previously received intravesical BCG. Over a median follow-up of 22 months, recurrence occurred in 31 patients in group 1 and 11 in group 2. The DFS rates of the high-risk group and the very high-risk group were 57.8% versus 40% at 1 year, 20.7% versus 21.3% at 2 years and 20.7% versus 21.3% at 3 years, respectively (p=0.831). Tis stage (p=0.042) and prostatic urethra invasion (p=0.028) were significant predictors of DFS. Cancer-specific mortality rates were 2.2% in group 1 and 6.7% in group 2 (p=0.441). CONCLUSIONS: Similar DFS outcome between high-risk and very high-risk patients were observed based on short-term results in Korea. This finding is crucial for clinical practice; however, studies analyzing more patients and long-term outcomes are needed.
Asunto(s)
Antimetabolitos Antineoplásicos , Desoxicitidina , Gemcitabina , Invasividad Neoplásica , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/cirugía , Desoxicitidina/análogos & derivados , Desoxicitidina/administración & dosificación , Masculino , Administración Intravesical , Anciano , Femenino , República de Corea/epidemiología , Estudios Retrospectivos , Persona de Mediana Edad , Antimetabolitos Antineoplásicos/administración & dosificación , Resultado del Tratamiento , Factores de Tiempo , Anciano de 80 o más Años , Neoplasias Vesicales sin Invasión MuscularRESUMEN
BACKGROUND: The tumoricidal complex alpha1-oleate targets bladder cancer cells, triggering rapid, apoptosis-like tumor cell death. Clinical effects of alpha1-oleate were recently observed in patients with non-muscle invasive bladder cancer (NMIBC), using a randomized, placebo-controlled study protocol. AIMS: To investigate if there are dose-dependent effects of alpha1-oleate. MATERIALS AND METHODS: Here, patients with NMIBC were treated by intravesical instillation of increasing concentrations of alpha1-oleate (1.7, 8.5, or 17 mM) and the treatment response was defined relative to a placebo group. RESULTS: Strong, dose-dependent anti-tumor effects were detected in alpha1-oleate treated patients for a combination of molecular and clinical indicators; a complete or partial response was detected in 88% of tumors treated with 8.5 mM compared to 47% of tumors treated with 1.7 mM of alpha1-oleate. Uptake of alpha1-oleate by the tumor triggered rapid shedding of tumor cells into the urine and cell death by an apoptosis-like mechanism. RNA sequencing of tissue biopsies confirmed the activation of apoptotic cell death and strong inhibition of cancer gene networks, including bladder cancer related genes. Drug-related side effects were not recorded, except for local irritation at the site of instillation. DISCUSSION AND CONCLUSIONS: These dose-dependent anti-tumor effects of alpha1-oleate are promising and support the potential of alpha1-oleate treatment in patients with NMIBC.
Asunto(s)
Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Masculino , Femenino , Anciano , Persona de Mediana Edad , Apoptosis/efectos de los fármacos , Resultado del Tratamiento , Relación Dosis-Respuesta a Droga , Administración Intravesical , Antineoplásicos/uso terapéutico , Anciano de 80 o más AñosRESUMEN
PURPOSE: To report the oncological outcomes and the tolerance between 6 instillations and more than 6 cycles of hyperthermic intravesical chemotherapy(HIVEC) in patients with non-muscle invasive bladder cancer(NMIBC). METHODS: This is a multicenter retrospective study from a national database including 9 expert centers. All patients treated with HIVEC between 2016 and 2023 for NMIBC were included. Patients were classified into two groups according to the total number of HIVEC instillations, including induction plus maintenance. Kaplan-Meier curves were computed to present survival outcomes. RESULTS: 261 patients with a median follow-up of 25.5 months were included. 199(76.2%) and 62(23.8%) were treated by 6 and more than 6 cycles of HIVEC, respectively. The 2-years RFS(40.2% vs. 34.4%,p = 0.3) and the 2-years PFS(86% vs. 87%,p = 0.85) were similar between group treated with 6 and more than 6 instillations. 2-years CSS and OS were also similar between both groups. Univariate Cox regression showed no association between the number of bladder instillation and RFS (HR = 1.2 95%CI[0.8-1.84], p = 0.3) or PFS (HR = 0.8 95%CI[0.29-2.02], p = 0.2). In the group treated with more than 6 cycles, 2-years RFS and 2-years PFS were similar between patients who received induction plus maintenance compared to those treated with induction only. Finally, hematuria and urinary burning were significantly higher in the group treated by more than 6 cycles (21% vs. 8.5%(p < 0.01),and 29% vs. 17% (p = 0.03), respectively). Serious side effects(grade ≥ 3) are rare(3.1%) and similar in both groups. CONCLUSIONS: Results show no significant difference in two years RFS, PFS, CSS and OS according to number of instillations received, while toxicity profile seems better in the group receiving six instillations only.
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Hipertermia Inducida , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Estudios Retrospectivos , Femenino , Masculino , Administración Intravesical , Anciano , Persona de Mediana Edad , Hipertermia Inducida/métodos , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Alcaloides , Arsénico , Proliferación Celular , Transformación Celular Neoplásica , Matrinas , NADPH Oxidasa 2 , Quinolizinas , Especies Reactivas de Oxígeno , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Animales , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/inducido químicamente , Humanos , Arsénico/toxicidad , Arsénico/efectos adversos , Alcaloides/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratas , Quinolizinas/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Movimiento Celular/efectos de los fármacos , Línea Celular , MasculinoRESUMEN
Glutathione-S-transferases (GST) enzymes detoxify xenobiotics and are implicated in response to anticancer therapy. This study evaluated the association of GST theta 1 (GSTT1), GSTT2, and GSTT2B with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) response in non-muscle-invasive bladder cancer treatment. In vitro assessments of GSTT2 knockout (KO) effects were performed using cell lines and dendritic cells (DCs) from GSTT2KO mice. Deletion of GSTT2B, GSTT1, and single-nucleotide polymorphisms in the promoter region of GSTT2 was analysed in patients (n = 205) and healthy controls (n = 150). Silencing GSTT2 expression in MGH cells (GSTT2BFL/FL) resulted in increased BCG survival (p < 0.05) and decreased cellular reactive oxygen species. In our population, there are 24.2% with GSTT2BDel/Del and 24.5% with GSTT2BFL/FL. With ≤ 8 instillations of BCG therapy (n = 51), 12.5% of GSTT2BDel/Del and 53.8% of GSTT2BFL/FL patients had a recurrence (p = 0.041). With ≥9 instillations (n = 153), the disease recurred in 45.5% of GSTT2BDel/Del and 50% of GSTT2BFL/FL. GSTT2FL/FL patients had an increased likelihood of recurrence post-BCG therapy (HR 5.5 [1.87-16.69] p < 0.002). DCs from GSTT2KO mice produced three-fold more IL6 than wild-type DCs, indicating a robust inflammatory response. To summarise, GSTT2BDel/Del patients respond better to less BCG therapy and could be candidates for a reduced surveillance regimen.
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Vacuna BCG , Glutatión Transferasa , Inmunoterapia , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Humanos , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Animales , Ratones , Vacuna BCG/uso terapéutico , Inmunoterapia/métodos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Línea Celular Tumoral , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Ratones Noqueados , Mycobacterium bovisRESUMEN
Most recently, the antibody-drug conjugate, enfortumab vedotin, has been covered by insurance for the treatment of unresectable or metastatic urothelial carcinoma after chemotherapy and immune checkpoint inhibitors, and has significantly changed the pharmacotherapy for urothelial carcinoma in clinical practice. Recently, several reports demonstarated the efficacy and safety of enfortumab vedotin in real-world clinical practice, highlighting its current status and challenges. In addition, the combination of enfortumab vedotin and pembrolizumab for the treatment of untreated unresectable or metastatic urothelial carcinoma has received expedited approval by the FDA and is expected to become a key drug in urothelial carcinoma.
Asunto(s)
Inmunoconjugados , Humanos , Inmunoconjugados/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/inmunología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
The patient was a 35-year-old man who saw his first doctor with the chief complaint of painful urination. A contrast- enhanced CT scan of the abdomen revealed a diagnosis of abscess-forming appendicitis with inflammatory spread to the bladder, and conservative treatment was decided. Since antibiotic treatment failed to reduce the size of the abscess, he underwent surgery. The bladder wall was highly inflamed, only appendectomy was performed. Pathology revealed appendiceal mucinous carcinoma invading the bladder, so he was referred to our department. Because a total cystectomy was required for curative resection and there was concern about seeding associated with the initial surgery, he was judged to be unresectable, and received chemotherapy. After 6 courses of CAPOX+bevacizumab therapy, he was able to have a bladder- sparing curative resection because of the absence of distant metastasis and shrinkage of the tumor. He remains stable without recurrence 6 months after surgery. We herein report, with some discussion of the literature, this case of bladder-invading appendiceal mucinous carcinoma arising from abscess-forming appendicitis, for which a curative resection was possible after chemotherapy.
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Absceso , Adenocarcinoma Mucinoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Apéndice , Apendicitis , Invasividad Neoplásica , Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/tratamiento farmacológico , Neoplasias del Apéndice/cirugía , Adulto , Apendicitis/cirugía , Apendicitis/tratamiento farmacológico , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/cirugía , Adenocarcinoma Mucinoso/patología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugía , Absceso/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , ApendicectomíaRESUMEN
The addition of metastasis-directed radiotherapy (MDRT) to immunotherapy in patients with advanced urothelial carcinoma (aUC) has shown promising results. We report the real-world data from the ARON-2 study (NCT05290038) on the impact of conventional (CRT) or stereotactic body radiotherapy (SBRT) on the outcome of aUC patients receiving pembrolizumab after platinum-based-chemotherapy. Medical records of 837 patients were reviewed from 60 institutions in 20 countries. Two hundred and sixty-two patients (31%) received radiotherapy (cohort A), of whom 193 (23%) received CRT and 69 (8%) received SBRT. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. With a median follow-up of 22.7 months, the median OS was 10.2 months, 6.8 months and 16.0 months in no RT, CRT and SBRT subgroups (p = 0.005), with an 1y-OS rates of 47%, 34% and 61%, respectively (p < 0.001). The 1y-OS rate in the SBRT subgroup were significantly higher for both lower (63%) and upper tract UC (68%), for pure urothelial histology (63%) and variant histologies (58%), and for patients with bone (40%) and lymph-node metastases (61%). Median PFS was 4.8 months, 9.6 months and 5.8 months in the CRT, SBRT and no RT subgroups, respectively (p = 0.060). The 1y-PFS rate was significantly higher (48%) in the SBRT population and was confirmed in all patient subsets. The difference in terms of ORR was in favour of SBRT. Our real-world analysis showed that the use of SBRT/pembrolizumab combination may play a role in a subset of aUC patients to increase disease control and possibly overall survival.
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Anticuerpos Monoclonales Humanizados , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Urológicas/patología , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/terapia , Neoplasias Urológicas/tratamiento farmacológico , Radiocirugia/métodos , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Carcinoma de Células Transicionales/terapia , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/tratamiento farmacológico , Resultado del Tratamiento , Terapia Combinada , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are rapidly evolving in the management of bladder cancer (BLCA). Nevertheless, effective biomarkers for predicting immunotherapeutic outcomes in BLCA are still insufficient. Ferroptosis, a form of immunogenic cell death, has been found to enhance patient sensitivity to ICIs. However, the underlying mechanisms of ferroptosis in promoting immunotherapy efficacy in BLCA remain obscure. METHODS: Our analysis of The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) revealed two immunologically distinct subtypes. Based on these subtypes and various other public cohorts, we identified Apolipoprotein L6 (APOL6) as a biomarker predicting the efficacy of ICIs and explored its immunological correlation and predictive value for treatment. Furthermore, the role of APOL6 in promoting ferroptosis and its mechanism in regulating this process were experimentally validated. RESULTS: The results indicate that APOL6 has significant immunological relevance and is indicative of immunologically hot tumors in BLCA and many other cancers. APOL6, interacting with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), mediates immunotherapy efficacy by ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1). CONCLUSIONS: To conclude, our findings indicate APOL6 has potential as a predictive biomarker for immunotherapy treatment success estimation and reveal the STAT1/APOL6/GPX4 axis as a critical regulatory mechanism in BLCA.
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Biomarcadores de Tumor , Ferroptosis , Inmunoterapia , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/terapia , Ferroptosis/genética , Humanos , Inmunoterapia/métodos , Biomarcadores de Tumor/genética , Apolipoproteínas/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT1/genética , Animales , Pronóstico , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , RatonesRESUMEN
Muscle invasive bladder cancers (BCs) can be divided into 2 major subgroups-basal/squamous (BASQ) tumors and luminal tumors. Since Pparg has low or undetectable expression in BASQ tumors, we tested the effects of rosiglitazone, Pparg agonist, in a mouse model of BASQ BC. We find that rosiglitazone reduces proliferation while treatment with rosiglitazone plus trametinib, a MEK inhibitor, induces apoptosis and reduces tumor volume by 91% after 1 month. Rosiglitazone and trametinib also induce a shift from BASQ to luminal differentiation in tumors, which our analysis suggests is mediated by retinoid signaling, a pathway known to drive the luminal differentiation program. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients.
Asunto(s)
Apoptosis , Proliferación Celular , Modelos Animales de Enfermedad , Piridonas , Pirimidinonas , Rosiglitazona , Neoplasias de la Vejiga Urinaria , Animales , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/genética , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/uso terapéutico , Rosiglitazona/farmacología , Rosiglitazona/uso terapéutico , Ratones , Apoptosis/efectos de los fármacos , Humanos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Invasividad Neoplásica , Femenino , PPAR gamma/metabolismo , PPAR gamma/agonistas , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Diferenciación Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Retinoides/farmacología , Retinoides/uso terapéuticoRESUMEN
BACKGROUND: Urinary bladder cancer, is the 10th most common global cancer, diagnosed in over 600,000 people causing 200,000 deaths annually. Artemisinin and its derivatives are safe compounds that have recently been proven to possess potent anti-tumor effects in vivo, through inhibition of cancer cell growth. The aim of this study is to assess the efficiency of artemisinin as a cancer treatment alone and as a pre-treatment fore cisplatin therapy for high grade urothelial carcinoma. METHODS: Sixty male albino mice were divided into six groups, and BBN was used to induce urinary bladder cancer. Blood samples were tested for renal functions and complete blood counts, kidney and urinary bladder tissues were harvested for histopathological examination. Total RNAs from urinary bladder tissues was collected, and gene expression of FGFR3, HRAS, P53, and KDM6A was quantified using qRT-PCR. RESULTS: Compared to the induced cancer group, the results revealed that FGFR3 expression levels were down-regulated in the induced cancer group treated by artemisinin only and the induced cancer group pre-treated with artemisinin prior to cisplatin by ~ 0.86-fold and 0.4-folds, respectively, aligning with HRAS down-regulation by ~ 9.54-fold and 9.05-fold, respectively. Whereas, P53 expression levels were up-regulated by ~ 0.68-fold and 0.84-fold, respectively, in parallel with KDM6A expression, which is up-regulated by ~ 0.95-folds and 5.27-folds, respectively. Also, serum creatinine and urea levels decreased significantly in the induced cancer group treated by artemisinin alone and the induced cancer group pre-treated with artemisinin prior to cisplatin, whereas the induced cancer group treated by cisplatin their levels increased significantly. Moreover, Hb, PLT, RBC, and WBC counts improved in both cancer groups treated by artemisinin alone and pre-treated with artemisinin prior to cisplatin. Histologically, in kidney tissues, artemisinin pre-treatment significantly reduced renal injury caused by cisplatin. While Artemisinin treatment for cancer in bladder tissues reverted invasive urothelial carcinoma to moderate urothelial dysplasia. CONCLUSIONS: This study indicates that artemisinin demonstrated a significant effect in reversal of the multi-step carcinogenesis process of high grade urothelial carcinoma and could enhance the effect of cisplatin therapy using artemisinin pre-treatment.
Asunto(s)
Artemisininas , Cisplatino , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Proteína p53 Supresora de Tumor , Neoplasias de la Vejiga Urinaria , Animales , Cisplatino/farmacología , Cisplatino/uso terapéutico , Masculino , Artemisininas/farmacología , Artemisininas/uso terapéutico , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/metabolismo , Ratones , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Humanos , Modelos Animales de Enfermedad , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.
Asunto(s)
Estudio de Asociación del Genoma Completo , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Análisis de la Aleatorización Mendeliana , Simvastatina , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Animales , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Humanos , Simvastatina/efectos adversos , Transcriptoma/genética , Hidroximetilglutaril-CoA Reductasas/genética , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Polimorfismo de Nucleótido Simple/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , RatonesRESUMEN
The Bacillus Calmette-Guérin (BCG) vaccine is the oldest cancer immunotherapeutic agent in use. Despite its effectiveness, its initial mechanisms of action remain largely unknown. Here, we elucidate the earliest cellular mechanisms involved in BCG-induced tumor clearance. We developed a fast preclinical in vivo assay to visualize in real time and at single-cell resolution the initial interactions among bladder cancer cells, BCG and innate immunity using the zebrafish xenograft model. We show that BCG induced the recruitment and polarization of macrophages towards a pro-inflammatory phenotype, accompanied by induction of the inflammatory cytokines tnfa, il1b and il6 in the tumor microenvironment. Macrophages directly induced apoptosis of human cancer cells through zebrafish TNF signaling. Macrophages were crucial for this response as their depletion completely abrogated the BCG-induced phenotype. Contrary to the general concept that macrophage anti-tumoral activities mostly rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can induce tumor apoptosis and clearance. Thus, our results revealed an additional step to the BCG-induced tumor immunity model, while providing proof-of-concept experiments demonstrating the potential of this unique model to test innate immunomodulators.
Asunto(s)
Apoptosis , Vacuna BCG , Macrófagos , Transducción de Señal , Neoplasias de la Vejiga Urinaria , Pez Cebra , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Animales , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Vacuna BCG/farmacología , Vacuna BCG/uso terapéutico , Transducción de Señal/efectos de los fármacos , Humanos , Línea Celular Tumoral , Apoptosis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Microambiente TumoralRESUMEN
The team aimed to explore the possible functional significance of M6A regulation in Pan-programmed cell death (PCD) among patients with bladder cancer (BLCA). In BLCA patients, the analysis was conducted on the13 patterns of programmed cell death (PCD) and the regulation of M6A. Transcriptome, genomics, and clinical data were collected from TCGA-BLCA, GEO32548, and IMvigor210. Consensus clustering analysis, functional enrichment analysis, and other prognostic tools were used to validate the Pan-PCD. Finally, in vitro experiments and transcription sequencing were performed to understand the potential influence of the PI3K pathway on Pan-PCD in BLCA patients. Diverse PCD patterns were simultaneously activated, and M6A regulators exhibited significant variability in bladder malignant tissues. The machine learning algorithm established an 8-gene M6A-related Pan-PCD signature. This signature was validated in three independent datasets, and BLCA patients with higher risk scores had worse prognosis. An unsupervised clustering approach identified activated and suppressed Pan-PCD subgroups of BLCA patients, with distinct responses to immunotherapy and drug sensitivity. In addition, the PI3K pathway was identified as a key mechanism for various forms of programmed cell death, encompassing apoptosis, pyroptosis, autophagy, and cell death dependent on lysosomes. This research revealed that the Pan-PCD model was a more promising approach for BLCA patients under M6A regulation. A new signature from M6A-related Pan-PCD was proposed, with prognostic value for survival or drug sensitivity. The PI3K pathway was a key mechanism for multiple PCDs in BLCA patients.