RESUMEN
BACKGROUND: Preclinical studies have shown that norepinephrine can directly stimulate tumor cell migration and that this effect is mediated by the beta-adrenergic receptor. PATIENTS AND METHODS: We retrospectively reviewed 722 patients with non-small-cell lung cancer (NSCLC) who received definitive radiotherapy (RT). A Cox proportional hazard model was utilized to determine the association between beta-blocker intake and locoregional progression-free survival (LRPFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). RESULTS: In univariate analysis, patients taking beta-blockers (n = 155) had improved DMFS (P < 0.01), DFS (P < 0.01), and OS (P = 0.01), but not LRPFS (P = 0.33) compared with patients not taking beta-blockers (n = 567). In multivariate analysis, beta-blocker intake was associated with a significantly better DMFS [hazard ratio (HR), 0.67; P = 0.01], DFS (HR, 0.74; P = 0.02), and OS (HR, 0.78; P = 0.02) with adjustment for age, Karnofsky performance score, stage, histology type, concurrent chemotherapy, radiation dose, gross tumor volume, hypertension, chronic obstructive pulmonary disease and the use of aspirin. There was no association of beta-blocker use with LRPFS (HR = 0.91, P = 0.63). CONCLUSION: Beta-blocker use is associated with improved DMFS, DFS, and OS in this large cohort of NSCLC patients. Future prospective trials can validate these retrospective findings and determine whether the length and timing of beta-blocker use influence survival outcomes.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Supervivencia sin Enfermedad , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Receptores Adrenérgicos beta/efectos de los fármacos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
WISP-1 (Wnt-1 induced secreted protein 1) is a member of the CCN family of growth factors. This study identifies WISP-1 as a beta-catenin-regulated gene that can contribute to tumorigenesis. The promoter of WISP-1 was cloned and shown to be activated by both Wnt-1 and beta-catenin expression. TCF/LEF sites played a minor role, whereas the CREB site played an important role in this transcriptional activation. WISP-1 demonstrated oncogenic activities; overexpression of WISP-1 in normal rat kidney fibroblast cells (NRK-49F) induced morphological transformation, accelerated cell growth, and enhanced saturation density. Although these cells did not acquire anchorage-independent growth in soft agar, they readily formed tumors in nude mice, suggesting that appropriate cellular attachment is important for signaling oncogenic events downstream of WISP-1.
Asunto(s)
Proteínas del Citoesqueleto/metabolismo , Sustancias de Crecimiento/genética , Proteínas Oncogénicas/genética , Oncogenes , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores , Transcripción Genética , Proteínas de Pez Cebra , Secuencia de Aminoácidos , Animales , Sitios de Unión , Proteínas CCN de Señalización Intercelular , Línea Celular , Transformación Celular Neoplásica , Clonación Molecular , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas del Citoesqueleto/química , Proteínas del Citoesqueleto/genética , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Sustancias de Crecimiento/metabolismo , Riñón , Ratones , Ratones Desnudos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Proteínas Oncogénicas/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Ratas , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Eliminación de Secuencia , Activación Transcripcional , Transfección , Proteínas Wnt , Proteína Wnt1 , beta CateninaRESUMEN
Wnt family members are critical to many developmental processes, and components of the Wnt signaling pathway have been linked to tumorigenesis in familial and sporadic colon carcinomas. Here we report the identification of two genes, WISP-1 and WISP-2, that are up-regulated in the mouse mammary epithelial cell line C57MG transformed by Wnt-1, but not by Wnt-4. Together with a third related gene, WISP-3, these proteins define a subfamily of the connective tissue growth factor family. Two distinct systems demonstrated WISP induction to be associated with the expression of Wnt-1. These included (i) C57MG cells infected with a Wnt-1 retroviral vector or expressing Wnt-1 under the control of a tetracyline repressible promoter, and (ii) Wnt-1 transgenic mice. The WISP-1 gene was localized to human chromosome 8q24.1-8q24.3. WISP-1 genomic DNA was amplified in colon cancer cell lines and in human colon tumors and its RNA overexpressed (2- to >30-fold) in 84% of the tumors examined compared with patient-matched normal mucosa. WISP-3 mapped to chromosome 6q22-6q23 and also was overexpressed (4- to >40-fold) in 63% of the colon tumors analyzed. In contrast, WISP-2 mapped to human chromosome 20q12-20q13 and its DNA was amplified, but RNA expression was reduced (2- to >30-fold) in 79% of the tumors. These results suggest that the WISP genes may be downstream of Wnt-1 signaling and that aberrant levels of WISP expression in colon cancer may play a role in colon tumorigenesis.