RESUMEN
Urothelial carcinoma (UC) of the bladder is a common cause of cancer-related death worldwide. Vasculogenic mimicry (VM) is a process by which the malignant cells can generate vascular-like structures formed of periodic acid-Schiff (PAS) positive/CD31 negative extracellular matrix independent of angiogenesis and thus promotes tumor progression. N-myc downstream-regulated gene 1 (NDRG1) is a protein that can modulate tumor angiogenesis; however, its role in regulating tumor angiogenesis and VM formation has not been previously investigated in UC. This study aims to evaluate the role of intra-tumor microvessel density (MVD) (as a surrogate measure of angiogenesis), VM, and NDRG1 in UC and their correlation with different clinicopathologic features, then assess the correlation between them in UC. Sixty specimens of UC of the bladder were included. PAS-CD31 immunohistochemical double staining method was used to evaluate the intra-tumor MVD and VM. Immunohistochemical expression of NDRG1 was also examined. VM and NDRG1 expression were detected in 41.7% and 83.3% of UC specimens respectively. The mean of intra-tumor MVD, VM area, and NDRG1 was significantly higher in tumors with higher grade, lymphovascular invasion, and higher T stage. NDRG1 expression was positively correlated with MVD and VM. We can suggest that MVD, VM, and NDRG1 may serve as poor prognostic markers for UC. The positive correlation between NDRG1 and both MVD and VM may provide the first evidence that NDRG1 can induce tumor angiogenesis and VM in UC which may offer a novel pathway for further therapeutic strategies.
Asunto(s)
Proteínas de Ciclo Celular , Péptidos y Proteínas de Señalización Intracelular , Densidad Microvascular , Neovascularización Patológica , Neoplasias de la Vejiga Urinaria , Humanos , Neovascularización Patológica/patología , Neovascularización Patológica/metabolismo , Masculino , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/metabolismo , Persona de Mediana Edad , Femenino , Anciano , Proteínas de Ciclo Celular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Adulto , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/irrigación sanguínea , Anciano de 80 o más Años , Inmunohistoquímica , Urotelio/patología , AngiogénesisRESUMEN
Pyruvate kinase M2 (PKM2) has been shown to promote tumorigenesis by facilitating the Warburg effect and enhancing the activities of oncoproteins. However, this paradigm has recently been challenged by studies in which the absence of PKM2 failed to inhibit and instead accelerated tumorigenesis in mouse models. These results seem inconsistent with the fact that most human tumors overexpress PKM2. To further elucidate the role of PKM2 in tumorigenesis, we investigated the effect of PKM2 knockout in oncogenic HRAS-driven urothelial carcinoma. While PKM2 ablation in mouse urothelial cells did not affect tumor initiation, it impaired the growth and maintenance of HRAS-driven tumors. Chemical inhibition of PKM2 recapitulated these effects. Both conditions substantially reduced complex formation of PKM2 with STAT3, their nuclear translocation, and HIF1α- and VEGF-related angiogenesis. The reduction in nuclear STAT3 in the absence of PKM2 also correlated with decreased autophagy and increased apoptosis. Time-controlled, inducible PKM2 overexpression in simple urothelial hyperplasia did not trigger tumorigenesis, while overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis strongly accelerated tumorigenesis. Finally, in human patients, PKM2 was overexpressed in low-grade nonmuscle-invasive and high-grade muscle-invasive bladder cancer. Based on these data, PKM2 is not required for tumor initiation but is essential for tumor growth and maintenance by enhancing angiogenesis and metabolic addiction. The PKM2-STAT3-HIF1α/VEGF signaling axis may play a critical role in bladder cancer and may serve as an actionable therapeutic target. SIGNIFICANCE: Genetic manipulation and pharmacologic inhibition of PKM2 in mouse urothelial lesions highlight its essential role in promoting angiogenesis and metabolic addiction, events indispensable for tumor growth and maintenance.
Asunto(s)
Carcinoma de Células Transicionales/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Piruvato Quinasa/genética , Neoplasias de la Vejiga Urinaria/genética , Transporte Activo de Núcleo Celular/genética , Animales , Apoptosis/genética , Autofagia/genética , Carcinogénesis/genética , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/metabolismo , Línea Celular Tumoral , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratones Noqueados , Ratones Transgénicos , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Piruvato Quinasa/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: Perifocal edema of brain tumors is associated with survival and neurological symptoms. Our aim was to analyze associations between perifocal edema and immunohistochemical features including proliferation potential, microvessel density, neoangiogenesis and invasiveness in brain metastasis (BM). METHODS: 35 patients with BM were included into the retrospective study. The tumors were localized supratentorial in 25 lesions (71.4%) and infratentorial in 10 lesions (28.6%). The following immunohistochemical features were calculated on histopathological specimens: microvessel density, proliferation index Ki 67, matrix-metallopeptidase 9 (MMP9) extracellular matrix metalloproteinase inducer (EMMPRIN) and vascular endothelial growth factor (VEGF) expression. Tumor and edema volumes were estimated semiautomatically on magnetic resonance images. RESULTS: There were no correlations between tumor volume and edema volume. Moreover, no correlation was identified between the investigated immunohistochemical features and tumor/edema volume. In the non-small cell lung cancer subgroup, a positive correlation between tumor volume and VEGF expression was observed (r = 0.52, P = 0.02) and edema volume correlated inversely with MMP9 expression (r = -0.53, P = 0.02). CONCLUSION: In BM, no linear associations exist between tumor volumes, edema volumes and immunohistochemical features reflecting proliferation potential, neoangiogenesis, microvessel density and MMP9 expression. However, in the subgroup of non-small cell lung cancer, there might be associations between MMP9 expression and edema volume as well as between tumor volume and angiogenesis.
Asunto(s)
Edema Encefálico/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/patología , Neovascularización Patológica/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Basigina/metabolismo , Neoplasias de los Conductos Biliares/patología , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/patología , Carcinoma/irrigación sanguínea , Carcinoma/diagnóstico por imagen , Carcinoma/metabolismo , Carcinoma/secundario , Carcinoma de Pulmón de Células no Pequeñas/irrigación sanguínea , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/secundario , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/diagnóstico por imagen , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/secundario , Proliferación Celular , Colangiocarcinoma/irrigación sanguínea , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/metabolismo , Colangiocarcinoma/secundario , Neoplasias Colorrectales/patología , Neoplasias Endometriales/patología , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Imagen por Resonancia Magnética , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Melanoma/irrigación sanguínea , Melanoma/diagnóstico por imagen , Melanoma/metabolismo , Melanoma/secundario , Densidad Microvascular , Persona de Mediana Edad , Carcinoma Nasofaríngeo/irrigación sanguínea , Carcinoma Nasofaríngeo/diagnóstico por imagen , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/secundario , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica , Neoplasias Cutáneas/patología , Neoplasias Gástricas/patología , Carga Tumoral , Neoplasias Urológicas/patologíaRESUMEN
We studied the characteristics of contrast-enhanced ultrasound (CEUS) in renal pelvic urothelial carcinomas and explored its performance in assessing microvessel density (MVD) of tumor tissues. We retrospectively analyzed the characteristics of 125 cases, which were confirmed pathologically to be renal pelvic urothelial carcinomas using CEUS. We performed CEUS and found that most tumors presented with an enhanced mode of "slow-in (meanâ¯=â¯16.7 ± 2.6 s, range: 12-25 s), hypo-enhancement and fast-out (meanâ¯=â¯69.3 ± 16.2 s, range: 42-113 s)." However, the wash-in pattern, homogeneity and wash-out pattern observed with CEUS was not correlated with pT stage and grade (p > 0.05). But advanced-pT-stage and high-grade tumors had a higher peak enhancement than early-pT-stage and low-grade tumors (p < 0.01). Peak enhancement obtained with CEUS can be used to evaluate the pT stage and grade of renal pelvic urothelial carcinomas more effectively. The MVD of those tissues was observed using immunohistochemical staining of cluster of differentiation 34 (CD34). MVD in the advanced-pT-stage and high-grade groups was significantly higher than that in the early-pT-stage and low-grade groups (p < 0.01). As tumor pT stage and grade improved, CEUS peak enhancement intensity and MVD of tumors also exhibited an upward trend. CEUS peak enhancement intensity has the potential to determine MVD of renal pelvic urothelial carcinomas.
Asunto(s)
Carcinoma de Células Transicionales/diagnóstico por imagen , Neoplasias Renales/diagnóstico por imagen , Densidad Microvascular , Ultrasonografía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/patología , Medios de Contraste , Femenino , Humanos , Neoplasias Renales/irrigación sanguínea , Neoplasias Renales/patología , Pelvis Renal , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
PURPOSE: To investigate whether volumetric imaging of tumor vasculature can be used to phenotypically characterize advanced upper tract urothelial carcinoma, and if this technique can distinguish aggressive invasive tumors from non-aggressive superficial ones. METHODS: In a pilot study, two TaG1 and two T3G3 formalin-fixed paraffin-embedded (FFPE) tumor samples were examined using the DIPCO pipeline (Tanaka et al. in Nature Biomed Eng 1(10):796-806. https://doi.org/10.1038/s41551-017-0139-0 , 2017). Briefly, punch biopsies of FFPE tumors were deparaffinized, cleared, immunolabeled with the vessel marker CD34 and imaged with a light-sheet microscope. Thereafter, the three-dimensional (3D) vasculature of the tumors was analyzed and characterized using a specialized image processing software. RESULTS: We found that T3G3 tumors had increased CD34 density kurtosis and skewness compared to TaG1 tumors. This suggests that analysis of the 3D vasculature can distinguish between high-grade invasive and low-grade superficial tumors. CONCLUSIONS: Volumetric imaging of tumor samples may represent novel methodology that can complement conventional histopathology. Volumetric imaging enabled us to differentiate between invasive and non-invasive upper tract urothelial carcinoma. The method is of particular interest in diagnostic work-up of patients with upper tract urothelial carcinoma as previous findings indicate that volumetric imaging of vascular patterns could be used to differentiate superficial and invasive urothelial carcinoma, irrespective of if the tumor sample was deep or superficial. However, further and more extensive studies are required before this method can be applied clinically.
Asunto(s)
Carcinoma de Células Transicionales/diagnóstico por imagen , Carcinoma de Células Transicionales/patología , Imagenología Tridimensional , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/patología , Neoplasias Ureterales/diagnóstico por imagen , Neoplasias Ureterales/patología , Carcinoma de Células Transicionales/irrigación sanguínea , Humanos , Neoplasias Renales/irrigación sanguínea , Estadificación de Neoplasias , Proyectos Piloto , Carga Tumoral , Neoplasias Ureterales/irrigación sanguíneaRESUMEN
OBJECTIVE: To investigate the effectiveness of combination treatment of vascular targeted photodynamic therapy and anti-cytotoxic T-lymphocyte-associated antigen 4 immunotherapy in a mouse model of urothelial carcinoma. METHODS: We used C57BL/6 mice injected with murine bladder 49 cell line. Mice were randomly allocated into four treatment groups: vascular targeted photodynamic therapy only, anti-cytotoxic T-lymphocyte-associated antigen 4 only, combination therapy and control. We carried out three separate experiments that used distinct cohorts of mice: tumor growth and development of lung metastases monitored with bioluminescent imaging (n = 91); survival evaluated with Kaplan-Meier curves (n = 111); and tumor cell population studied with flow cytometry (n = 20). In a fourth experiment, we re-challenged tumors in previously treated mice and compared tumor growth with that of naïve mice. RESULTS: Combination therapy provided significant benefits over the other three treatment groups: prolonged survival (P < 0.0001), lower tumor signal (P < 0.0001) and decreased lung signal uptake (P ≤ 0.002). We also observed that mice previously treated with vascular targeted photodynamic therapy only or combination therapy did not present tumor growth after re-challenged tumors. CONCLUSIONS: Combination of vascular targeted photodynamic therapy with anti-cytotoxic T-lymphocyte-associated antigen 4 is an effective therapy in a urothelial carcinoma syngeneic mouse model. The present results suggest this therapy as a potential treatment option for both bladder and upper tract tumors in future clinical trials.
Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Carcinoma de Células Transicionales/terapia , Neoplasias Pulmonares/tratamiento farmacológico , Fotoquimioterapia/métodos , Neoplasias de la Vejiga Urinaria/terapia , Animales , Antígeno CTLA-4/inmunología , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/inmunología , Carcinoma de Células Transicionales/secundario , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Humanos , Mediciones Luminiscentes , Pulmón/irrigación sanguínea , Pulmón/diagnóstico por imagen , Pulmón/efectos de los fármacos , Pulmón/efectos de la radiación , Neoplasias Pulmonares/irrigación sanguínea , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Masculino , Ratones , Ratones Endogámicos C57BL , Vejiga Urinaria/irrigación sanguínea , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/inmunología , Vejiga Urinaria/efectos de la radiación , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
First-line platinum-based chemotherapy combinations are considered standard-of-care in locally advanced and metastatic urothelial cancer. However, long-term outcomes, including disease-specific and overall survival, remain poor. In addition, a number of patients with advanced urothelial carcinoma have co-existing medical issues that preclude the use of conventional chemotherapy. Improvements in our understanding over the molecular mechanisms of urothelial cancer have led to first-generation clinical trials evaluating novel agents targeting molecular pathways that may be relevant, at least in sub-populations. Emerging information regarding outcome with agents targeting novel molecular targets in advanced urothelial cancer is discussed in this review.
Asunto(s)
Carcinoma de Células Transicionales/tratamiento farmacológico , Terapia Molecular Dirigida , Urotelio/patología , Carcinoma de Células Transicionales/irrigación sanguínea , Humanos , Factores Inmunológicos/farmacología , Neovascularización Patológica/tratamiento farmacológico , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: Angiogenesis is a pivotal process on which solid tumor growth is substantially dependent. Pigment epithelium-derived factor (PEDF) is the most potent natural anti-angiogenic factor, which has seldom been studied in bladder tumor, and whose functioning pathway remains unclear. We have thus investigated PEDF expression in relation to tumor necrosis factor-α (TNF-α) and microvessel density (MVD) with immunohistochemistry. METHODS: Antibodies of PEDF and TNF-α were examined by Western blotting before immunohistochemistry. Sixty-four urothelial tumor sections and 23 normal controls were stained and expression of PEDF, TNF-α, and MVD were studied. RESULTS: Decreased PEDF expression and increased TNF-α expression was noticed in tumorous tissue compared with healthy urothelium. Lower PEDF expression was related to higher tumor grade but stage. Increased TNF-α expression was noticed in recurrent, larger tumors as well as in tumors with progression in grade and stage. Expression of PEDF and TNF-α was correlated in bladder tumor. PEDF or TNF-α was correlated with MVD negatively or positively, respectively, in cancerous tissue and tumorous grouping without correlation in papillary urothelial neoplasm of low malignant potential. CONCLUSION: Expressional change of PEDF and TNF-α is in relation to angiogenesis of bladder tumor, especially in bladder cancer development.
Asunto(s)
Carcinoma de Células Transicionales/metabolismo , Proteínas del Ojo/biosíntesis , Neovascularización Patológica/metabolismo , Factores de Crecimiento Nervioso/biosíntesis , Serpinas/biosíntesis , Factor de Necrosis Tumoral alfa/biosíntesis , Neoplasias de la Vejiga Urinaria/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Western Blotting , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/patología , Proteínas del Ojo/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neovascularización Patológica/patología , Factores de Crecimiento Nervioso/análisis , Serpinas/análisis , Factor de Necrosis Tumoral alfa/análisis , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/patología , Adulto JovenRESUMEN
Upper tract urothelial carcinoma (UTUC) associated with Balkan endemic nephropathy (BEN) is characterized by a number of aberrations in cell-cycle regulation and apoptosis. The aim of this study was to detect angiogenesis-related marker(s) specific for BEN UTUC, and to examine the influence of HIF 1α upon angiogenesis and apoptosis in UTUC. Present investigation included 110 patients with UTUC, 50 from BEN region and 60 control tumors. Altered expression of VEGFR1 was more often present in control UTUC than in BEN tumors (p<0.005). It was associated with high grade, low and high stage, solid growth, and metaplastic change of control UTUC. Microvessel density assessed by CD31 (MVD CD31) was significantly higher in UTUC with lymphovascular invasion (p<0.05), and in BEN tumors with papillary growth (p<0.05). Discriminant analysis indicated that BEN and control tumors do not differ significantly in expression of angiogenesis related markers. The most important discriminant variable that determined control UTUC was expression of VEGFR1 (p=0.002). HIF 1α in UTUC significantly correlated with the low stage, papillary growth and expression of Bcl-2, Caspase-3 index, and MVD CD34 (p<0.001; 0.0005; 0.01; 0.005; 0.01, respectively). HIF-1α may be helpful marker in evaluation of UTUC, especially when combined with angiogenesis and apoptosis.
Asunto(s)
Nefropatía de los Balcanes/diagnóstico , Carcinoma de Células Transicionales/irrigación sanguínea , Pelvis Renal/patología , Neovascularización Patológica/diagnóstico , Neoplasias Ureterales/irrigación sanguínea , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Nefropatía de los Balcanes/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Análisis Discriminante , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Microvasos/metabolismo , Microvasos/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Nefrectomía , Uréter/irrigación sanguínea , Uréter/cirugía , Neoplasias Ureterales/metabolismo , Neoplasias Ureterales/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Adulto JovenRESUMEN
PURPOSE: miRNAs are noncoding RNAs that posttranscriptionally regulate gene expression. Altered expression and function have been observed in bladder cancer. We analyzed the expression profile of a group of miRNAs involved in bladder cancer angiogenesis, tumor cell proliferation, tumor suppressor inhibition, epithelial-mesenchymal transition and metastasis activation. Prognostic and diagnostic value, and validated targets were further examined. MATERIALS AND METHODS: Using quantitative real-time polymerase chain reaction 77 bladder cancer cases and 77 matched tumor associated normal samples were investigated to determine the expression of miR-10b, 19a, 19b, 21, 126, 145, 205, 210, 221, 296-5p and 378. The relationship between miRNA expression, patient survival and tumor pathological features was also examined. RESULTS: miR-10b, 19a, 126, 145, 221, 296-5p and 378 were significantly down-regulated in bladder cancer compared to adjacent normal urothelium. miR-145 was the most down-regulated microRNA of this group. miR-19b, 21, 205 and 210 showed no significant difference between the 2 tissue types. High miR-21 expression correlated with worse overall patient survival (p = 0.0099). Multivariate analysis revealed that miR-21, 210 and 378 may serve as independent prognostic factors for overall patient survival (p = 0.005, 0.033 and 0.012, respectively). miR-21 and 378 may serve as independent prognostic factors for recurrence (p = 0.030 and 0.031, respectively). miR-145, 221, 296-5p and 378 showed the best combined ROC curves for specificity and sensitivity. miRWalk analysis was used to identify validated miRNA target genes. Further Gene Ontology enrichment revealed the main classes of biological functions of these validated targets. CONCLUSIONS: Most miRNAs analyzed are down-regulated in bladder cancer. They may serve as candidate biomarkers for diagnostic and prognostic purposes in the future.
Asunto(s)
Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/secundario , Proliferación Celular , Transformación Celular Neoplásica/genética , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Genes Supresores de Tumor , MicroARNs/genética , Neovascularización Patológica/genética , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Transformación Celular Neoplásica/patología , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neovascularización Patológica/patología , Pronóstico , Reacción en Cadena en Tiempo Real de la Polimerasa , Estadística como Asunto , Análisis de Supervivencia , Tasa de Supervivencia , Regiones no Traducidas/genética , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
PURPOSE: Patients with non-muscle invasive bladder cancer recurrence after 2 induction courses of BCG are eligible for radical cystectomy. So, in the last years research to discover new drugs for the management of non-muscle invasive bladder cancer recurrence after failure of first and second line therapy is ongoing. In accordance to the results obtained with BCG, whose mechanism depends on the induction of the T helper 1 (TH1) immune response, we investigated the activity of a Toll-like receptor (TLR) 2 ligand, named Helicobacter Pylori Neutrophil Activating Protein (HP-NAP), that we recently demonstrated being able of enhancing the differentiation of Th1 cells, both in vitro and in vivo, because of its ability to create an IL-12 enriched milieu. MATERIALS AND METHODS: We show here, in a mouse model of bladder neoplasm implants, that local administration of HP-NAP decreases tumor growth by inducing tumor necrosis. RESULTS: The result is joined up with a massive cluster of both CD4+ and CD8+ IFN-γ+ cells, within neoplasm and regional lymph nodes. It is of note that HP-NAP-treated tumors show also a reduced vascularization due to the anti-angiogenic activity of IFN-γ induced by HP-NAP. CONCLUSIONS: The present study suggests that the activity of HP-NAP against urothelial tumor burden warrants subsequent in vivo studies.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Inhibidores de la Angiogénesis/uso terapéutico , Proteínas Bacterianas/uso terapéutico , Carcinoma de Células Transicionales/terapia , Inmunoterapia , Neoplasias de la Vejiga Urinaria/terapia , Adyuvantes Inmunológicos/administración & dosificación , Administración Intravesical , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Proteínas Bacterianas/administración & dosificación , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/inmunología , Carcinoma de Células Transicionales/patología , Movimiento Celular/efectos de los fármacos , Helicobacter pylori/química , Humanos , Ganglios Linfáticos/inmunología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Invasividad Neoplásica , Proteínas de Neoplasias/agonistas , Neovascularización Patológica/tratamiento farmacológico , Receptor Toll-Like 2/agonistas , Carga Tumoral , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To evaluate the prognostic value of HER2 expression in non-muscle invasive bladder transitional cell carcinoma (TCC) with special emphasis in the high grade population. MATERIALS AND METHODS (PATIENTS): Tissue microarrays (TMA) were performed with representative TUR-B specimens from 84 patients with non-muscle invasive bladder TCC (40 pT1GII and 44 pT1GIII) treated in our institution. Depth of invasion and grade were uniformly assigned by the same pathologist who performed blind immunohistochemical analysis with Hercep test: 3+ was considered strong positive HER2 overexpression. Other clinico-pathological variables were also assessed. RESULTS: HER2 protein overexpression was detected in 30/44 (68.2%) pT1GIII lesions and predicted recurrence in this subgroup of bladder TCC (p<0.01). Negative HER2 expression was detected in 26/40 (65%) cases with pT1GII TCC, and this condition was more frequent in unifocal tumours, without angiogenesis, with low recurrence rate and without progression. Recurrence-free survival can also be anticipated by HER 2 expression within pT1GII tumours (p<0.01). CONCLUSION: HER2 expression using Hercep test may be useful to predict recurrence in non-muscle invasive bladder TCC. The potential application of this study, especially regarding prediction of response to BCG, should be prospectively confirmed in multi-institutional trials.
Asunto(s)
Carcinoma de Células Transicionales/química , Regulación Neoplásica de la Expresión Génica , Proteínas de Neoplasias/análisis , Receptor ErbB-2/análisis , Neoplasias de la Vejiga Urinaria/química , Anciano , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/mortalidad , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/cirugía , Cistectomía , Cistoscopía , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Análisis por Matrices de Proteínas , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/genética , Método Simple Ciego , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
BACKGROUND: A strong rationale supports the role of antiangiogenic drugs in urothelial cancer. This trial was designed to assess the activity of sunitinib as first-line treatment in patients with metastatic urothelial cancer ineligible for cisplatin and to explore molecular and imaging variables predictive of clinical benefit. PATIENTS AND METHODS: This was a multicenter phase II trial with sunitinib 50 mg daily in 4/2-week schedule. Eligibility criteria were as follows: creatinine clearance 30-60 ml/min, Eastern Cooperative Oncology Group Pperformance Sstatus of one or less, and adequate hepatic and hematologic function. Twelve circulating cytokines were evaluated at baseline and sequentially using Luminex xMAP(®) (Austin, TX). Baseline and treatment-related changes in perfusion were evaluated in a patient subgroup using contrast-enhanced computed tomography. RESULTS: On intention-to-treat analysis, 38 patients showed 3 (8%) partial responses (PRs) and 19 (50%) presented with stable disease (SD), 17 (45%) of them ≥3 months. Clinical benefit (PR + SD) was 58%. Median time to progression (TTP) was 4.8 months and median overall survival 8.1 months. Toxicity was consistent with previous reports for sunitinib. Low interleukin-8 (IL-8) baseline levels were significantly associated with increased TTP. Baseline tumor contrast enhancement with >40 Hounsfield units was associated with clinical benefit. CONCLUSIONS: This study highlights the potential role of the angiogenic pathway as a therapy target in urothelial cancer. Baseline IL-8 serum levels and contrast enhancement of lesions warrant further study.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Células Transicionales/tratamiento farmacológico , Cisplatino/uso terapéutico , Indoles/uso terapéutico , Interleucina-8/sangre , Pirroles/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/diagnóstico por imagen , Carcinoma de Células Transicionales/mortalidad , Medios de Contraste , Supervivencia sin Enfermedad , Femenino , Humanos , Indoles/efectos adversos , Estimación de Kaplan-Meier , Masculino , Pirroles/efectos adversos , Sunitinib , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Neoplasias Urológicas/irrigación sanguínea , Neoplasias Urológicas/diagnóstico por imagen , Neoplasias Urológicas/mortalidadRESUMEN
Standard treatment for upper urinary tract urothelial carcinoma (UUTUC) implies the radical removal of all urothelium-lined tissue, which requires nephroureterectomy with bladder cuff removal. We report on a patient with a rare coincidence of UUTUC and horseshoe kidney in whom a preoperative angiography helped to identify and subsequently embolize an abberant isthmic feeding artery, which was located in between both collecting systems. Ischemic discoloration of the isthmus area facilitated resection and no major blood loss occurred. Preoperative superselective embolization of the isthmus as the renal split area can be an effective tool to facilitate nephroureterectomy in the case of a horseshoe kidney.
Asunto(s)
Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/cirugía , Embolización Terapéutica , Riñón/anomalías , Neoplasias Primarias Múltiples/irrigación sanguínea , Neoplasias Primarias Múltiples/cirugía , Cuidados Preoperatorios , Arteria Renal/anomalías , Neoplasias Ureterales/irrigación sanguínea , Neoplasias Ureterales/cirugía , Aortografía , Carcinoma de Células Transicionales/diagnóstico , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/diagnóstico , Nefrectomía , Complicaciones Posoperatorias/diagnóstico , Tomografía Computarizada Espiral , Uréter/cirugía , Neoplasias Ureterales/diagnóstico , UrografíaRESUMEN
This study was designed to investigate the protein levels of cyclooxyogenase-2 (COX-2) and survivin in superficial urothelial carcinoma (UC) and their correlation with microvessel density (MVD). High-grade UC was positive for both COX-2 and survivin protein, and the proportion of tumours positive for both proteins increased with increasing tumour grade. The presence of COX-2 protein was significantly correlated with the presence of survivin protein. Both COX-2 and survivin positivity were significantly correlated with MVD in all patients regardless of tumour grade, but there was no correlation between MVD and COX-2 and survivin positivity by individual tumour grade. Although there was no significant difference in the proportion of COX-2-positive tumours when patients were stratified by tumour stage, a significantly higher proportion of patients with pT1 stage tumours were survivin-positive compared with patients with pTa stage tumours. COX-2 and survivin positivity were significantly correlated in all patients regardless of tumour grade or stage. COX-2 and survivin were significantly correlated in patients with pTa, but there was no correlation in pT1 tumours. These findings demonstrate that together, COX-2, survivin and MVD may play an important role in UC.
Asunto(s)
Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/metabolismo , Ciclooxigenasa 2/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neovascularización Patológica , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/metabolismo , Carcinoma de Células Transicionales/patología , Humanos , Técnicas para Inmunoenzimas , Proteínas Inhibidoras de la Apoptosis , Estadificación de Neoplasias , Survivin , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Actors of the angiogenesis pathways are targets for the new promising targeted therapies already used in several malignancies. In bladder cancer, antiangiogenic molecules could also add to already existing treatment options. OBJECTIVE: To evaluate the involvement of angiogenesis pathways in bladder carcinogenesis and identify new molecular markers having a clinical implication. DESIGN, SETTING, AND PARTICIPANTS: Expression levels of 40 genes involved in angiogenesis were assessed by quantitative real time RT-PCR in 157 urothelial tumour bladder samples obtained from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2005. Pathologic tumour staging showed: 73 non-muscle-invasive bladder tumours (30 low-grade pTa, 14 high-grade pTa, and 29 high-grade pT1), and 84 muscle-invasive tumours (> or = pT2), all of high grade. RT-PCR results were associated with a survival analysis. RESULTS AND LIMITATIONS: VEGFA, MET, CXCR4, and IL8 were significantly overexpressed in tumour samples as compared to normal bladder tissue. VEGFA overexpressions were found in 89% of non-muscle-invasive and 66% of muscle-invasive tumour samples. In univariate analysis, for invasive tumours, VEGFA overexpression was associated with a poorer outcome in both overall and disease-free survival (p=0.011 and 0.026 respectively) at a 13-mo median follow-up. Multivariate analysis retained T stage, N status, and VEGFA overexpression as independent prognostic factors in both overall and disease-free survival (p=0.02 and p=0.04, respectively, for VEGFA). CONCLUSIONS: This study shows that, in bladder cancer, VEGFA status could be used as a prognostic factor at the individual level. VEGFA overexpression could guide a rationalized use of the costly antiangiogenic therapies which could therefore become part of the treatment options in bladder cancer.
Asunto(s)
Carcinoma de Células Transicionales/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Vejiga Urinaria/genética , Factor A de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/mortalidad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica , Pronóstico , ARN Mensajero/genética , Estudios Retrospectivos , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/mortalidad , Factor A de Crecimiento Endotelial Vascular/análisisAsunto(s)
Carcinoma de Células Transicionales/genética , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neoplasias de la Vejiga Urinaria/genética , Factor A de Crecimiento Endotelial Vascular/genética , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/química , Carcinoma de Células Transicionales/mortalidad , Regulación Neoplásica de la Expresión Génica , Humanos , Neovascularización Patológica , Pronóstico , ARN Mensajero/genética , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/química , Neoplasias de la Vejiga Urinaria/mortalidad , Factor A de Crecimiento Endotelial Vascular/análisisRESUMEN
BACKGROUND: Cycloxygenase (COX)-2 has been associated with proliferation, apoptosis and angiogenesis in urothelial cancer. The prognostic significance of COX-2 in patients who received adjuvant chemotherapy for urothelial cancer was examined. PATIENTS AND METHODS: Expression of COX-2, p53, ki67, beta-catenin, vascular endothelial growth factor (VEGF) and microvessel density (MVD) were studied retrospectively in 59 patients with urothelial cancer (pT3, pT4, N+) who had undergone surgery. The patients had subsequently received adjuvant chemotherapy. RESULTS: Thirty-eight out of 59 cases (64%) were positive for COX-2. COX-2 was not associated either with progression-free survival (PFS) or overall survival (OS). MVD levels > or =47 were associated with longer median PFS compared with lower levels (not reached vs. 13 months [95% CI: 8-18], p=0.048). The median PFS for patients with beta-catenin nuclear accumulation and COX-2 expression was 6 months (95% CI: 4-7) compared with 19 months (95% CI: 14-23) for neither or only one of these factors (p=0.018). CONCLUSION: MVD may be a useful indicator of relapse in high-risk urothelial cancer treated with adjuvant chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/metabolismo , Ciclooxigenasa 2/biosíntesis , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/metabolismo , beta Catenina/biosíntesis , Adulto , Anciano , Carboplatino/administración & dosificación , Carcinoma de Células Transicionales/irrigación sanguínea , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Paclitaxel/administración & dosificación , Estudios Retrospectivos , Neoplasias Urológicas/irrigación sanguíneaRESUMEN
Mitochondria-encoded Cytochrome B (CYTB) gene mutations were reported in different cancers, but the effect of these mutations on cellular metabolism and growth is unknown. In a murine xenograft and human model of bladder cancer, we show the functional effect of overexpression of a 21-bp deletion mutation (mt) of CYTB. Overexpression of mtCYTB generated increased reactive oxygen species (ROS) accompanied by increased oxygen consumption and lactate production. MtCYTB overexpression induced significant tumor growth in vitro and in vivo by triggering rapid cell cycle progression through up-regulation of the nuclear factor-kappa B2 signaling pathway. Tumor-generated ROS induced in vitro lysis of normal splenocytes. Thus, we present physiologic and functional evidence for the role of a bona fide mitochondrial gene mutation in cancer.
Asunto(s)
Carcinoma de Células Transicionales/genética , Citocromos b/genética , Eliminación de Gen , Neoplasias de la Vejiga Urinaria/genética , Animales , Apoptosis/genética , Carcinoma de Células Transicionales/irrigación sanguínea , Carcinoma de Células Transicionales/metabolismo , Carcinoma de Células Transicionales/patología , Adhesión Celular/genética , Ciclo Celular/genética , Procesos de Crecimiento Celular/genética , Citocromos b/biosíntesis , ADN Mitocondrial/genética , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/genética , Mitocondrias/metabolismo , FN-kappa B/metabolismo , Invasividad Neoplásica , Neovascularización Patológica/genética , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-2/genética , Especies Reactivas de Oxígeno/metabolismo , Bazo/metabolismo , Bazo/patología , Transfección , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Proteína X Asociada a bcl-2/biosíntesis , Proteína X Asociada a bcl-2/genéticaRESUMEN
Angiogenesis and inflammation are two processes regulated by numerous common molecular mechanisms. Inflammation can stimulate angiogenesis, and angiogenesis can facilitate inflammation; both mechanisms have been shown to be involved in carcinogenesis. With this study we sought to gain an understanding of the molecular mechanisms involved in tumor angiogenesis and inflammation in urinary bladder tumors. Tumor specimens were collected at slaughter from Friesian cows chronically exposed to bracken fern. Bracken chronic toxicity is characterized by the presence of multiple mixed tumors in the bladder, being reported throughout the world under the designation of bovine enzootic hematuria. We conducted molecular analyses of angiogenic factors and chemokine production by real-time RT-PCR, and also assessed microvessel density (MVD), microvessel pericyte coverage index (MPI) to reveal mature vessels, the extent of tumor-infiltrating leukocytes (TILk) and tumor cell apoptosis and proliferation in both epithelial and endothelial-derived bovine urinary bladder tumors. We defined a profile of chemokines/chemokine receptors (Mip1beta, CCR1) and angiogenesis-related factors (VEGF, VEGFR2) that allow distinguishing between urothelial carcinomas (epithelial origin) and hemangiosarcomas (endothelial origin). Taken together, our data reveals previously unrecognized paracrine and autocrine chemo-angiogenic loops in the context of bovine urinary bladder tumorigenesis.