ABSTRACT
PURPOSE: We aimed to investigate the prevalence and prognostic impact of tumor mesenchymal epithelial transition factor (MET) expression in stage IV gastric cancers in a real-world clinical setting because existing evidence is sparse. METHODS: The study included archived cancer specimens from 103 stage IV gastric cancer patients (2003-2010). We analyzed MET-protein expression by immunohistochemistry (MET-positive if ≥25% of tumor cells showed MET expression). We calculated overall survival using the Kaplan-Meier method and hazard ratios comparing mortality among MET-positive and MET-negative patients using Cox regression adjusted for age, gender, and comorbidity. RESULTS: We found that 62.1% (95% confidence interval, 52.0-71.5) of patients had MET-positive tumors. Median survival was lower among patients with MET-positive tumors (3.5 months) than among patients with MET-negative tumors (9.6 months), corresponding to an adjusted hazard ratio of 2.2 (95% confidence interval, 1.3-3.7). CONCLUSIONS: Tumor MET expression is prevalent and has substantial prognostic impact in stage IV gastric cancer patients.
Subject(s)
Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Biomarkers, Tumor/metabolism , Proto-Oncogene Proteins c-met/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/mortality , Adenocarcinoma/pathology , Adult , Aged , Cohort Studies , Confidence Intervals , Databases, Factual , Denmark , Disease-Free Survival , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Invasiveness/pathology , Neoplasm Staging , Prognosis , Proportional Hazards Models , Proto-Oncogene Mas , Retrospective Studies , Risk Assessment , Stomach Neoplasms/pathology , Survival AnalysisABSTRACT
BACKGROUND: Reelin is an extracellular glycoprotein of crucial importance in the developmental organisation of neurons in the mammalian cerebral cortex and other laminated brain regions. The pig possesses a gyrencephalic brain that bears resemblance to the human brain. In order to establish an animal model for neuronal migration disorders in the pig, we have studied the expression pattern and structure of Reelin during pig brain development. RESULTS: We determined the sequence of pig Reelin mRNA and protein and identified a high degree of homology to human Reelin. A peak in Reelin mRNA and protein expression is present during the period of major neurogenesis and neuronal migration. This resembles observations for human brain development. Immunohistochemical analysis showed the highest expression of Reelin in the Cajal-Reztius cells of the marginal zone, in resemblance with observations for the developing brain in humans and other mammalian species. CONCLUSIONS: We conclude that the pig might serve as an alternative animal model to study Reelin functions and that manipulation of the pig Reelin could allow the establishment of an animal model for human neuronal migration disorders.
Subject(s)
Brain/embryology , Brain/metabolism , Cell Adhesion Molecules, Neuronal/metabolism , Extracellular Matrix Proteins/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Serine Endopeptidases/metabolism , Animals , Blotting, Western , Cell Adhesion Molecules, Neuronal/genetics , Cell Movement/physiology , Extracellular Matrix Proteins/genetics , Immunohistochemistry , Nerve Tissue Proteins/genetics , Neurogenesis/physiology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reelin Protein , Reverse Transcriptase Polymerase Chain Reaction , Serine Endopeptidases/genetics , SwineABSTRACT
BACKGROUND: Mammalian evolution is characterized by a progressive expansion of the surface area of the cerebral cortex, an increase that is accompanied by gyration of the cortical surface. The mechanisms controlling this gyration process are not well characterized but mutational analyses indicate that genes involved in neuronal migration play an important function. Due to the lack of gyration of the rodent brain it is important to establish alternative models to examine brain development during the gyration process. The pig brain is gyrated and accordingly is a candidate alternative model. FINDINGS: In this study we have identified genes differentially expressed in the pig cerebral cortex before and after appearance of gyration. Pig cortical tissue from two time points in development representing a non-folded, lissencephalic, brain (embryonic day 60) and primary-folded, gyrencephalic, brain (embryonic day 80) were examined by whole genome expression microarray studies. 91 differentially expressed transcripts (fold change >3) were identified. 84 transcripts were annotated and encoding proteins involved in for example neuronal migration, calcium binding, and cytoskeletal structuring. Quantitative real-time PCR was used to confirm the regulation of a subset of the identified genes. CONCLUSION: This study provides identification of genes which are differentially expressed in the pig cerebral cortex before and after appearance of brain gyration. The identified genes include novel candidate genes which could have functional importance for brain development.
