RESUMEN
BACKGROUND: Most prostate cancers (CaPs) grow slowly and remain indolent, yet some become aggressive and metastasize. Clinical decision-making requires prognostic markers that can be utilized at the time of diagnosis to identify aggressive tumors. Previous studies have shown a correlation between genomic alterations on the long arm of chromosome 18 (18q) and metastatic CaP. OBJECTIVE: The goal of this study was to comprehensively profile copy number alterations found on 18q in prostate tumors with varying outcomes to identify putative biomarkers associated with more aggressive disease METHODS: A custom comparative genomic hybridization array was created composed of high-density tiling of 18q sequences. Primary prostate tumor tissues were gathered from men who underwent radical prostatectomy and were categorized based on the patient's long-term clinical outcome as either metastatic disease (MET) or no evidence of disease (NED). DNA was isolated from formalin-fixed, paraffin-embedded prostatectomy tumor tissues, and analyzed for copy number variations (CNVs). Protein levels of genes found within the region of CNVs were analyzed using immunohistochemistry. RESULTS: Thirty-Four primary prostate tumors were analyzed: 17 NEDs and 17 METs. Two significant regions of copy number gains were found on 18q associated with outcome. One gain located at 18q11.2 was found exclusively in NED outcome tumors while another gain, located at 18q21.31, was found exclusively in MET outcome tumors (P -value< 0.0076). Immunohistochemistry analysis of protein levels showed more protein associated with copy number gain in the MET samples vs. those without the gain as indicated by H-scores of 184.7 and 121.0 respectively. CONCLUSIONS: The latter of these CNVs represent a putative biomarker for aggressive disease and highlights a putative metastasis promoting gene. Further study of known connections to CaP suggests that the paracaspase MALT1 is the most likely target of the copy number gain and represents a potential therapeutic target. Future studies would be of interest to determine MALT1's role in aggressive CaP and the ability of this CNV region to differentiate CaP that will eventually metastasize.
Asunto(s)
Variaciones en el Número de Copia de ADN , Metástasis de la Neoplasia/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Prostatectomía , Neoplasias de la Próstata/cirugíaRESUMEN
Nuclear NADPH oxidase-4 (Nox4) is a key component of metabolic reprogramming and is often overexpressed in renal cell carcinoma (RCC). However, its prognostic role in RCC remains unclear. Here we examined the significance of nuclear Nox4 on disease progression and development of drug resistance in advanced RCC. We analyzed human RCC tissue from multiple regions in the primary index tumor, cancer-associated normal adjacent parenchyma, intravascular tumor in locally advanced cancer patients. We found that the higher nuclear Nox4 expression was significantly associated with progression and death. These findings were consistent after controlling for other competing clinical variables. In contrast, patients with lower nuclear Nox4, even in higher stage RCC had better prognosis. We identified a subset of patients with high nuclear Nox4 who had rapid disease progression or died within 6 months of surgery. In addition, higher nuclear Nox4 level correlated with resistance to targeted therapy and immunotherapy. Western blotting performed on fresh human RCC tissue as well as cell-lines revealed increased nuclear Nox4 expression. Our data support an important prognostic role of Nox4 mediated regulation of RCC independent of other competing variables. Nox4 localizes to the nucleus in high-grade, high-stage RCC. Higher nuclear Nox4 has prognostic significance for disease progression, poor survival, and development of drug resistance in RCC.
Asunto(s)
Carcinoma de Células Renales/enzimología , Carcinoma de Células Renales/patología , Núcleo Celular/enzimología , Progresión de la Enfermedad , Neoplasias Renales/enzimología , Neoplasias Renales/patología , NADPH Oxidasa 4/metabolismo , Línea Celular Tumoral , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Supervivencia sin ProgresiónRESUMEN
Background: Obesity is associated with an increased risk of bladder cancer recurrence. This study investigated the role of adipose tissue in bladder cancer progression. Methods: Gene expression profiling was performed on adipose tissues collected from normal weight (n=5), overweight (n=11), and obese (n=10) patients with invasive bladder cancer, and adipose stromal cells (ASCs) were obtained from two normal weight, two overweight, and two obese patients. Conditioned media (CM) was characterized and evaluated for its effects on the proliferation, migration, and invasive potential of T24 bladder cancer cells. Results: Expression profiling demonstrated depot-specific or body mass index-specific differences. Increased T24 cell migration was observed using CM harvested from all ASCs. ASC CM from an obese patient significantly increased T24 cell migration and invasion compared to ASC CM collected from normal weight and overweight patients. We identified abundant expression of CXCL1, PAI1, IL6, CX3CL1, and CCL2 in all CM. Exogenous treatment of T24 cells with PAI1, IL6, and CXCL1 enhanced migration. Depletion of CXCL1, PAI1, and IL6 in an obese patient ASC CM abrogated T24 migration. Conclusion: Factors secreted by adipose tissue influence the migration of bladder tumor cells and could play an active role in tumor progression.