RESUMEN
Members of the leucine zipper putative tumor suppressor (LZTS) family play crucial roles in transcription modulation and cell cycle control. We previously demonstrated that LZTS2 functions as a novel ß-catenin-interacting protein and represses ß-catenin-mediated transcription on T-cell factor/lymphoid enhancing factor. Here, we investigate the biological role of LZTS2 using newly established Lzts2 KO mice. Homozygosity for loss-of-function of the Lzts2-targeted allele resulted in severe kidney and urinary tract developmental defects, including renal/ureteral duplication, hydroureter, and hydronephrosis, which were visible prenatally. Altered ureteric bud outgrowth was identified in Lzts2 null embryos. Further analysis indicated that ß-catenin subcellular localization was altered in fibroblasts isolated from Lzts2 null embryos. In addition, Wnt growth factor-induced ß-catenin-mediated transcriptional activity was increased in Lzts2 null fibroblasts, suggesting a direct role for Lzts2 in the Wnt signaling pathway. These data demonstrate a critical role of LZTS2 in renal development and implicate LZTS2 as a critical regulator of ß-catenin-mediated nephrogenesis.
Asunto(s)
Embrión de Mamíferos/embriología , Riñón/embriología , Organogénesis/fisiología , Proteínas Represoras/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Vía de Señalización Wnt/fisiología , Animales , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Embrión de Mamíferos/anomalías , Riñón/anomalías , Ratones , Ratones Noqueados , Proteínas Represoras/genética , Proteínas Supresoras de Tumor/genética , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismoRESUMEN
The androgen receptor (AR) is a ligand-induced transcription factor and contains the polyglutamine (polyQ) tracts within its N-terminal transactivation domain. The length of polyQ tracts has been suggested to alter AR transcriptional activity in prostate cancer along with other endocrine and neurologic disorders. Here, we assessed the role of ZMIZ1, an AR co-activator, in regulating the activity of the AR with different lengths of polyQ tracts as ARQ9, ARQ24, and ARQ35 in prostate cancer cells. ZMIZ1, but not ZMIZ2 or ARA70, preferably augments ARQ9 induced androgen-dependent transcription on three different androgen-inducible promoter/reporter vectors. A strong protein-protein interaction between ZMIZ1 and ARQ9 proteins was shown by immunoprecipitation assays. In the presence of ZMIZ1, the N and C-terminal interaction of the ARQ9 was more pronounced than ARQ24 and ARQ35. Both Brg1 and BAF57, the components of SWI/SNF complexes, were shown to be involved in the enhancement of ZMIZ1 on AR activity. Using the chromatin immunoprecipitation assays (ChIP), we further demonstrated a strong recruitment of ZMIZ1 by ARQ9 on the promoter of the prostate specific antigen (PSA) gene. These results demonstrate a novel regulatory role of ZMIZ1 in modulating the polyQ tract length of AR in prostate cancer cells.
Asunto(s)
Péptidos/genética , Neoplasias de la Próstata/genética , Proteínas Inhibidoras de STAT Activados/metabolismo , Receptores Androgénicos/genética , Factores de Transcripción/metabolismo , Activación Transcripcional , Western Blotting , Inmunoprecipitación de Cromatina , Humanos , Inmunoprecipitación , Masculino , Regiones Promotoras Genéticas/genética , Antígeno Prostático Específico/genética , Neoplasias de la Próstata/metabolismo , Proteínas Inhibidoras de STAT Activados/genética , Receptores Androgénicos/metabolismo , Factores de Transcripción/genética , Células Tumorales CultivadasRESUMEN
Melanoma of the penis is an uncommon cancer. We present the case of a 73-year-old male with penile melanoma and non palpable lymph nodes. Lymphoscintigraphy was applied to locate the sentinel lymph nodes for dissection. His lymph nodes were negative for melanoma and he has been disease-free for 1 year with careful surveillance.
RESUMEN
BACKGROUND: Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. METHODS: We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. RESULTS: We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. CONCLUSIONS: The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Crizotinib , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/farmacología , Masculino , Ratones , Trasplante de Neoplasias , Fosforilación , Piperidinas/farmacología , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-met/química , Pirazoles , Piridinas/farmacología , Transducción de Señal , Sulfonas/farmacologíaRESUMEN
Asymptomatic, atraumatic hematuria is a worrisome clinical sign for a patient that usually prompts a visit to a urologist. Hematuria is classified as microscopic versus gross; the evaluation for gross hematuria differs from that for microscopic hematuria, and the most important differentiating factor is the patient's age. The major causes of hematuria differ between children and adults, and the evaluation should reflect this. Renal disease is more common in children and malignancy more common in adults. The application and utility of laboratory tests, radiological studies, and cystoscopy are well established in adults but are more variable in children. Follow-up of hematuria after a negative evaluation is becoming more limited in adults but should be routine for children.
Asunto(s)
Hematuria/diagnóstico , Hematuria/terapia , Adulto , Factores de Edad , Niño , Estudios de Seguimiento , Hematuria/orina , HumanosRESUMEN
BACKGROUND: A 76-year-old man who underwent cystoprostatectomy with ileal conduit urinary diversion for muscle-invasive bladder cancer presented to his urologist 4 years later with episodes of spontaneous gross hematuria filling his ostomy bag with fresh clots. INVESTIGATIONS: Physical examination, urine culture, urine cytology, peripheral smear, complete blood count, loopogram, CT-intravenous pyelogram, loop endoscopy, bilateral ureteroscopy, liver function tests, CT angiography, (99m)Tc-tagged red cell scan, hepatitis panel, measurement of transjugular wedge pressure, transjugular liver biopsy with pathologic analysis and re-evaluation of CT angiogram. DIAGNOSIS: Hematuria secondary to portal hypertension. MANAGEMENT: The patient initially underwent revision of the ureteroileal anastomosis on the basis of the results of the (99m)Tc-tagged red cell scan, but hematuria recurred 9 months later. Once the hepatology service identified portal hypertension, the patient was taken to the operating room for ligation of a large venous communication between the ileal conduit and a branch of the inferior epigastric vein. He recovered well and was asymptomatic for 8 months. He was followed up by the hepatology service for his newly diagnosed portal hypertension secondary to cirrhosis.
Asunto(s)
Hematuria/diagnóstico , Hipertensión Portal/diagnóstico , Derivación Urinaria/efectos adversos , Anciano , Diagnóstico Diferencial , Hematuria/etiología , Hematuria/cirugía , Humanos , Hipertensión Portal/etiología , Hipertensión Portal/cirugía , MasculinoRESUMEN
BACKGROUND: A 61-year-old man with a history of recurrent prostate cancer presented with obstructive urinary symptoms. He had been diagnosed with locally invasive adenocarcinoma of the prostate 10 years previously and treated with neoadjuvant hormonal and external beam radiation therapies. Because of the patient's rising PSA level, he had been started on goserelin 6 years after this diagnosis and bicalutamide 6 months before the current presentation. The patient presented to the urology clinic with worsening lower urinary tract symptoms consisting of nocturia, urgency, and weak stream. INVESTIGATIONS: Physical examination revealed a largely normal digital rectal examination, although there was slight asymmetry. The post-void residual urine volume was approximately 200 ml. Laboratory tests showed no evidence of urinary tract infection, but confirmed a rising PSA level despite low serum testosterone levels. Cystoscopic examination revealed hypervascular, large lateral prostatic lobes obstructing the bladder neck. The bladder was normal. DIAGNOSIS: The patient underwent transurethral resection of the prostate. Soon after the resection started, bilateral papillary tumors arising from the stroma of both prostatic lobes were uncovered. Owing to the diffuse nature of the papillary tumors, complete resection was not possible. Pathologic analysis confirmed the presence of ductal carcinoma of the prostate. MANAGEMENT: The patient had an uneventful postoperative course and reported improvement of voiding symptoms. Staging with bone scan and CT of the abdomen and pelvis demonstrated multi-focal bony metastasis. The patient was started on docetaxel-based chemotherapy for hormone refractory recurrence of prostate cancer as ductal carcinoma of the prostate. He remains under close surveillance for clinical response and progression of disease.
Asunto(s)
Carcinoma Ductal/diagnóstico , Recurrencia Local de Neoplasia , Neoplasias de la Próstata/diagnóstico , Carcinoma Ductal/terapia , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/terapiaRESUMEN
PURPOSE: Animal models that mimic this hormone refractory prostate cancer may be useful for developing and testing novel treatment strategies. MATERIALS AND METHODS: Using the prostate of the 12T-10 transgenic mouse an allograft model was established by transplantation into a nude mouse. To our knowledge we describe the first allograft model derived from the primary prostate tumor of a transgenic mouse. RESULTS: The primary tumor progressed from high grade prostatic intraepithelial neoplasm to invasive, undifferentiated and metastatic cancer with loss of androgen receptor expression. After 10 passages in nude mice the allograft retained the same histological and immunohistochemical features as the primary tumors, including neuroendocrine differentiation. The allograft demonstrated androgen independent growth and metastases to liver and lung, paralleling tumor behavior in the original transgenic line. Cytogenetic characterization of the allograft revealed consistent chromosomal abnormalities for multiple in vivo passages. CONCLUSIONS: This allograft model may give insight into the mechanism by which human prostate cancer progresses to an androgen independent state and provide a system for testing drugs that can inhibit this disease.
Asunto(s)
Proteína de Unión a Andrógenos/genética , Carcinoma Neuroendocrino/genética , Neoplasias de la Próstata/genética , Transglutaminasas/genética , Andrógenos , Animales , Animales Modificados Genéticamente , Antígenos Virales de Tumores , Carcinoma Neuroendocrino/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Inmunohistoquímica , Cariotipificación , Masculino , Ratones , Ratones Desnudos/genética , Trasplante de Neoplasias , Neoplasias de la Próstata/patologíaRESUMEN
In breast and colon cancers, transforming growth factor (TGF)-beta signaling initially has an antineoplastic effect, inhibiting tumor growth, but eventually exerts a proneoplastic effect, increasing motility and cancer spread. In prostate cancer, studies using human samples have correlated the loss of the TGF-beta type II receptor (T beta R II) with higher tumor grade. To determine the effect of an inhibited TGF-beta pathway on prostate cancer, we bred transgenic mice expressing the tumorigenic SV40 large T antigen in the prostate with transgenic mice expressing a dominant negative T beta R II mutant (DN II R) in the prostate. Transgene(s) and TGF-beta 1 expression were identified in the prostate and decreased protein levels of plasminogen activator inhibitor type I, as a marker for TGF-beta signaling, correlated with expression of the DN II R. Although the sizes of the neoplastic prostates were not enlarged, increased amounts of metastasis were observed in mice expressing both transgenes compared to age-matched control mice expressing only the large T antigen transgene. Our study demonstrates for the first time that a disruption of TGF-beta signaling in prostate cancer plays a causal role in promoting tumor metastasis.