RESUMEN
BACKGROUND & AIMS: Studies of the clonal architecture of gastric glands with intestinal metaplasia are important in our understanding of the progression from metaplasia to dysplasia. It is not clear if dysplasias are derived from intestinal metaplasia or how dysplasias expand. We investigated whether cells within a metaplastic gland share a common origin, whether glands clonally expand by fission, and determine if such metaplastic glands are genetically related to the associated dysplasia. We also examined the clonal architecture of entire dysplastic lesions and the genetic changes associated with progression within dysplasia. METHODS: Cytochrome c oxidase-deficient (CCOâ») metaplastic glands were identified using a dual enzyme histochemical assay. Clonality was assessed by laser capture of multiple cells throughout CCOâ» glands and polymerase chain reaction sequencing of the entire mitochondrial DNA (mtDNA) genome. Nuclear DNA abnormalities in individual glands were identified by laser capture microdissection polymerase chain reaction sequencing for mutation hot spots and microsatellite loss of heterozygosity analysis. RESULTS: Metaplastic glands were derived from the same clone-all lineages shared a common mtDNA mutation. Mutated glands were found in patches that had developed through gland fission. Metaplastic and dysplastic glands can be genetically related, indicating the clonal origin of dysplasia from metaplasia. Entire dysplastic fields contained a founder mutation from which multiple, distinct subclones developed. CONCLUSIONS: There is evidence for a distinct clonal evolution from metaplasia to dysplasia in the human stomach. By field cancerization, a single clone can expand to form an entire dysplastic lesion. Over time, this field appears to become genetically diverse, indicating that gastric cancer can arise from a subclone of the founder mutation.
Asunto(s)
Adenocarcinoma , Células Clonales/patología , Mucosa Gástrica/patología , Neoplasias Gástricas , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/fisiopatología , Anciano , División Celular/fisiología , Células Clonales/fisiología , ADN Mitocondrial/genética , Progresión de la Enfermedad , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Efecto Fundador , Mucosa Gástrica/fisiología , Regulación Neoplásica de la Expresión Génica , Variación Genética , Humanos , Pérdida de Heterocigocidad/genética , Metaplasia/genética , Metaplasia/patología , Metaplasia/fisiopatología , Persona de Mediana Edad , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/fisiopatologíaRESUMEN
Dextran sulfate sodium (DSS) is a strong negatively charged heparin-like polysaccharide and has anti-immunodeficiency virus, anti-carcinogenesis, or occasionally tumor-promotion effects. The biological metabolism of DSS, however, remains unclear. In a previous study, we reported a novel method for the separation and quantification of DSS, using fluorometric labeling with 2-aminopyridine and a combination of size-exclusion and reverse phase high-performance liquid chromatography. In the present study, we have applied this method for analyses of in vitro chemical or enzymatic depolymerization of pyridylamino-DSS (PA-DSS). PA-DSS was depolymerized by specific enzymes such as alpha-amylase and alpha-glycosidase, but not by dextranase or heparinase. Unknown enzymes derived from cultured intestinal cells also strongly depolymerized PA-DSS as did alkaline substances. On the other hand, we have established a novel detection system using a post-column reaction. This method utilizes the spectrophotometrically metachromatic reaction of toluidine blue solution with DSS. This novel detection system may be specific and may potentially provide useful information in the analyses of sulfated polysaccharides, which are present in environmental and biological materials.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Sulfato de Dextran/química , Polisacáridos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Glicósido Hidrolasas/química , Humanos , Enfermedades Inflamatorias del Intestino/patología , Modelos Químicos , Espectrofotometría , Factores de Tiempo , Cloruro de Tolonio/farmacología , alfa-Amilasas/químicaRESUMEN
Gastric inflammatory fibroid polyps (IFPs) are rare benign lesions that occur in the distal stomach. We describe a 70-year-old woman with Helicobacter pylon-positive gastric IFP treated with eradication. Gastroduodenal endoscopy revealed a pyramidal-shaped, broad-based tumor with an ulcerated apex at the antrum. Helicobacter pylori was positive by both histology and tissue culture, and eradication (a proton pump inhibitor, amoxicillin, and clarithromycin) was performed. After 3 months, the tumor morphologically changed and the apex ulcer was markedly enlarged. This case suggests that H. pylori may play a role in the pathophysiology of IFPs.