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1.
Gastroenterology ; 145(5): 1110-20, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23896173

RESUMEN

BACKGROUND & AIMS: Many patients with pancreatic ductal adenocarcinoma (PDAC) develop recurrent or metastatic diseases after surgery, so it is important to identify those most likely to benefit from aggressive therapy. Disruption of tissue microarchitecture is an early step in pancreatic tumorigenesis and a parameter used in pathology grading of glandular tumors. We investigated whether changes in gene expression during pancreatic epithelial morphogenesis were associated with outcomes of patients with PDAC after surgery. METHODS: We generated architectures of human pancreatic duct epithelial cells in a 3-dimensional basement membrane matrix. We identified gene expression profiles of the cells during different stages of tubular morphogenesis (tubulogenesis) and of PANC-1 cells during spheroid formation. Differential expression of genes was confirmed by immunoblot analysis. We compared the gene expression profile associated with pancreatic epithelial tubulogenesis with that of PDAC samples from 27 patients, as well as with their outcomes after surgery. RESULTS: We identified a gene expression profile associated with tubulogenesis that resembled the profile of human pancreatic tissue with differentiated morphology and exocrine function. Patients with PDACs with this profile fared well after surgery. Based on this profile, we established a 6-28 gene tubulogenesis-specific signature that accurately determined the prognosis of independent cohorts of patients with PDAC (total n = 128; accuracy = 81.2%-95.0%). One gene, ASPM, was down-regulated during tubulogenesis but up-regulated in human PDAC cell lines and tumor samples; up-regulation correlated with patient outcomes (Cox regression P = .0028). Bioinformatic, genetic, biochemical, functional, and clinical correlative studies showed that ASPM promotes aggressiveness of PDAC by maintaining Wnt-ß-catenin signaling and stem cell features of PDAC cells. CONCLUSIONS: We identified a gene expression profile associated with pancreatic epithelial tubulogenesis and a tissue architecture-specific signature of PDAC cells that is associated with patient outcomes after surgery.


Asunto(s)
Carcinoma Ductal Pancreático/patología , Diferenciación Celular/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Proteínas del Tejido Nervioso/fisiología , Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Transcriptoma/genética , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/fisiología , Carcinoma Ductal Pancreático/genética , Diferenciación Celular/fisiología , Movimiento Celular/genética , Movimiento Celular/fisiología , Modelos Animales de Enfermedad , Epitelio/patología , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica/fisiología , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas del Tejido Nervioso/genética , Neoplasias Pancreáticas/genética , Pronóstico , Estudios Retrospectivos , Transducción de Señal/genética , Transducción de Señal/fisiología , Transcriptoma/fisiología , Proteínas Wnt/fisiología , beta Catenina/fisiología
2.
Am J Pathol ; 182(2): 363-74, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23219426

RESUMEN

Histopathological classification of human prostate cancer (PCA) relies on the morphological assessment of tissue specimens but has limited prognostic value. To address this deficiency, we performed comparative transcriptome analysis of human prostatic acini generated in a three-dimensional basement membrane that recapitulates the differentiated morphological characteristics and gene expression profile of a human prostate glandular epithelial tissue. We then applied an acinar morphogenesis-specific gene profile to two independent cohorts of patients with PCA (total n = 79) and found that those with tumors expressing this profile, which we designated acini-like tumors, had a significantly lower risk of postoperative relapse compared with those tumors with a lower correlation (hazard ratio, 0.078; log-rank test P = 0.009). Multivariate analyses showed superior prognostic prediction performance using this classification system compared with clinical criteria and Gleason scores. We prioritized the genes in this profile and identified programmed cell death protein 4 (PDCD4) and Kruppel-like factor 6 (KLF6) as critical regulators and surrogate markers of prostatic tissue architectures, which form a gene signature that robustly predicts clinical prognosis with a remarkable accuracy in several large series of PCA tumors (total n = 161; concordance index, 0.913 to 0.951). Thus, by exploiting the genomic program associated with prostate glandular differentiation, we identified acini-like PCA and related molecular markers that significantly enhance prognostic prediction of human PCA.


Asunto(s)
Células Acinares/patología , Proteínas Reguladoras de la Apoptosis/metabolismo , Perfilación de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/metabolismo , Morfogénesis/genética , Próstata/patología , Neoplasias de la Próstata/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Unión al ARN/metabolismo , Células Acinares/metabolismo , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Células Epiteliales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Factor 6 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Persona de Mediana Edad , Especificidad de Órganos/genética , Pronóstico , Próstata/crecimiento & desarrollo , Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Proteínas Proto-Oncogénicas/genética , Proteínas de Unión al ARN/genética , Recurrencia
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