Relevance of iNOS expression in tumor growth and maintenance of cancer stem cells in a bladder cancer model.

The expression of inducible nitric oxide (NO) synthase (iNOS) in human bladder cancer (BC) is a poor prognostic factor associated with invasion and tumor recurrence. Here, we evaluated the relevance of iNOS expression in BC progression and in cancer stem cell (CSC) maintenance in a murine BC model. Also, iNOS expression and CSC markers were analyzed in human BC samples. iNOS inhibitors (L-NAME or 1400W) or shRNA were used on murine BC model with different iNOS expressions and invasiveness grades: MB49 (iNOS+, non-muscle invasive (NMI)) and MB49-I (iNOS++, muscle invasive (MI)), in order to analyzed cell proliferation, tumor growth, angiogenesis, number of CSC, and pluripotential marker expression. iNOS, SOX2, Oct4, and Nanog expressions were also analyzed in human BC samples by qPCR and immunohistochemistry. iNOS inhibtion reduced parameters associated with tumor progression and reduced the number of CSC, wich resulted higher in MB49-I than in MB49, in concordance with the higher expression of SOX2, Oct4, and Nanog. The expression of SOX2 was notoriously diminished, when iNOS was inhibited only in the MI cell line. Similar results were observed in human samples, where MI tumors expressed higher levels of iNOS and pluripotential genes, in comparison to NMI tumors with a positive correlation between those and iNOS, suggesting that iNOS expression is associated with CSC. iNOS plays an important role in BC progression and CSC maintenance. Its inhibition could be a potential therapeutic target to eradicate CSC, responsible for tumor recurrences. KEY MESSAGES: • iNOS expression is involved in bladder tumor development, growth, and angiogenesis. • iNOS expression is involved in bladder cancer stem cell generation and maintenance, playing an important role regulating their self-renewal capacity, especially in muscle invasive murine bladder cancer cells. • iNOS expression is higher in human muscle invasive tumors, in association with a high expression of pluripotential genes, especially of SOX2.

Nitric oxide in patients with transitional bladder cancer.

BACKGROUND AND OBJECTIVES: One of the current challenges in clinical oncology is the identification of patients with superficial transitional bladder carcinoma (TBC) at high risk of recurrence or myoinvasive disease. Recently, inducible nitric oxide synthase (iNOS) expression was detected in urinary bladder cancers. Because iNOS produces a high concentration of nitric oxide (NO), we thought it possible that urine from TBC patients produces high levels of NO. The aim of this study was to determine urine NO levels in TBC compared with healthy controls and with patients bearing other nonrelated tumors, as well as to examine iNOS expression in bladder cancer tissue. METHODS: This study evaluated patients with TBC (n = 33), with gynecological tumors (GT) (n = 19), TBC patients with no evidence of tumor (no evidence of disease [NED]) (n = 19), and healthy subjects (n = 39). Urine NO levels were determined by Griess reagent, expressed as microM NO(2) (-)/100 mg creatinine. RESULTS: TBC patients produced significantly higher urine NO median values (4.2 microM; range, 2.1-91.6) than were produced by healthy individuals (2.1 microM; range, 0.4-4.9), by the NED group (1.7 microM; range 1.2-5.4), and by GT patients (2.0 microM; range, 0.8-58.1) (P = 0.000, Kruskal-Wallis test). iNOS was detected by Western blot in 52% (13/25) of bladder tumors examined. CONCLUSIONS: Although a wider study is necessary, our results suggest that the enhanced NO levels could perhaps be considered as a putative marker in TBC patients.

Técnica del ganglio centinela dinámico en pacientes con cáncer de pene. Evaluación de la experiencia inicial del Instituto de Oncología Angel H. Roffo. U.B.A / Dinamic sentinel limph node technique in patients with penis cancer. Evaluation of initial experience. Instituto de Oncología Angel H. Roffo. U.B.A

Introducción: El manejo de los ganglios linfáticos ha sido durante mucho tiempo, motivo de controversia en el tratamiento del cáncer de pene. Su influencia en el factor pronóstico ha marcado la importancia de realizar un estudio detallado del mismo y tratar de encontrar un indicador que permita determinar un mayor riesgo de diseminación linfática o compromiso ganglionar con baja morbilidad. Objetivo: El propósito de este trabajo, es efectuar una descripción pormenorizada de la técnica dinámica del ganglio centinela (TDGC) y describir nuestra experiencia inicial con la misma, demostrando la franca disminución de la morbilidad que frecuentemente se asocia con la linfadenectomía clásica frente a la TDGC y estableciendo las pautas para que sea una técnica reproducible. Materiales y métodos: Durante el periodo 2000-2004, 20 pacientes con diagnóstico de cáncer de pene han sido sometidos a la aplicación de TDGC. Fueron incluidos pacientes en estadios T1-T3. Resultados: Un grupo de 10 pacientes presentaba adenopatías no palpables y otro grupo, también de 10 pacientes, adenopatías palpables, pequeñas, móviles y no adherentes. En total de 20 pacientes se identificaron 8 casos de metástasis con ganglio centinela positivo (40 porciento) y 12 casos con ganglio centinela negativo (60 porciento). A 6 de los 8 pacientes con ganglio centinela positivo, se les efectuó linfadenectomía iliofemoral, evidenciándose 2 pacientes con metástasis y 4 sin metástasis. En los otros dos pacientes no se realizo linfadenectomía: uno por presencia de metástasis a distancia y el otro por abandono voluntario del tratamiento. El seguimiento mínimo fue de un año y el máximo de 5 años, con una media de 3 años. Ninguno de los pacientes desarrollo recidivas en ganglios linfáticos. Los 4 casos de óbito fueron por recidiva local del tumor primario, sepsis e hipercalcemia. Conclusión: La utilización de TDGC puede ser de gran utilidad en la detección de metástasis ganglionares. Es un buen indicador prec...