ABSTRACT
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.
Subject(s)
Adrenergic beta-Antagonists/therapeutic use , Carcinoma, Non-Small-Cell Lung/mortality , Coronary Artery Disease/drug therapy , Hypertension/drug therapy , Lung Neoplasms/mortality , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Disease-Free Survival , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Male , Middle Aged , Neoplasm Metastasis , Proportional Hazards Models , Receptors, Adrenergic, beta/drug effects , Retrospective Studies , Treatment OutcomeABSTRACT
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.
Subject(s)
Cytoskeletal Proteins/metabolism , Growth Substances/genetics , Oncogene Proteins/genetics , Oncogenes , Proto-Oncogene Proteins/metabolism , Trans-Activators , Transcription, Genetic , Zebrafish Proteins , Amino Acid Sequence , Animals , Binding Sites , CCN Intercellular Signaling Proteins , Cell Line , Cell Transformation, Neoplastic , Cloning, Molecular , Cyclic AMP Response Element-Binding Protein/metabolism , Cytoskeletal Proteins/chemistry , Cytoskeletal Proteins/genetics , Female , Fibroblasts/metabolism , Gene Expression Regulation , Growth Substances/metabolism , Kidney , Mice , Mice, Nude , Molecular Sequence Data , Mutagenesis, Site-Directed , Neoplasms, Experimental/genetics , Neoplasms, Experimental/pathology , Oncogene Proteins/metabolism , Promoter Regions, Genetic , Proto-Oncogene Proteins/genetics , Rats , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Sequence Deletion , Transcriptional Activation , Transfection , Wnt Proteins , Wnt1 Protein , beta CateninABSTRACT
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.
