ABSTRACT
Barrett's esophagus metaplasia is a pre-cancerous condition caused by chronic esophagitis. Chromosomal instability (CIN) is common in Barrett's cells: therefore, we investigated the possible presence of centrosomal aberrations (a main cause of CIN) by centrosomal protein immunostaining in paraffined esophageal samples of patients who developed a Barrett's adenocarcinoma. In most (55%) patients, alterations of the pericentriolar material (PCM) signals were evident and consistently marked the transition between normal epithelium to metaplasia. The alterations could even be found in adjacent native squamous epithelium, Barrett's mucosa and submucosal gland cells, as well as in the basal/epibasal layers of the mucosa and submucosal gland duct, which are the regions hosting esophageal stem and progenitor cells. These findings strongly support the hypothesis that the three esophageal histotypes (one being pathological) can have a common progenitor. Surprisingly, PCM defective signal eventually decreased with neoplastic progression, possibly to enhance the genome stability of advanced cancer cells. Importantly, PCM altered signals in Barrett's mucosa and their apparent evolution in successive histopathological steps were correlated to adenocarcinoma aggressiveness, suggesting PCM as a possible prognostic marker for tumor relapse. Extending our observations in a prospective study might help in the development of new prevention protocols for adenocarcinoma patients.
Subject(s)
Adenocarcinoma/metabolism , Barrett Esophagus/metabolism , Centrosome/metabolism , Esophageal Neoplasms/metabolism , Esophagus/metabolism , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Adult , Aged , Aged, 80 and over , Antigens/metabolism , Barrett Esophagus/genetics , Barrett Esophagus/pathology , Centrosome/pathology , Chromosomal Instability , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophagus/anatomy & histology , Esophagus/pathology , Female , Humans , Immunohistochemistry , Male , Metaplasia , Middle Aged , Models, Biological , Mucous Membrane/anatomy & histology , Mucous Membrane/metabolism , Mucous Membrane/pathology , Precancerous Conditions/genetics , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Prognosis , Tubulin/metabolismABSTRACT
BACKGROUND: Barrett's mucosa is the precursor of esophageal adenocarcinoma. The molecular mechanisms behind Barrett's carcinogenesis are largely unknown. Experimental models of longstanding esophageal reflux of duodenal-gastric contents may provide important information on the biological sequence of the Barrett's oncogenesis. METHODS: The expression of CDX2 hox-gene product was assessed in a rat model of Barrett's carcinogenesis. Seventy-four rats underwent esophago-jejunostomy with gastric preservation. Excluding perisurgical deaths, the animals were sacrificed at various times after the surgical treatment (Group A: <10 weeks; Group B: 10-30 weeks; Group C: >30 weeks). RESULTS: No Cdx2 expression was detected in either squamous epithelia of the proximal esophagus or squamous cell carcinomas. De novo Cdx2 expression was consistently documented in the proliferative zone of the squamous epithelium close to reflux ulcers (Group A: 68%; Group B: 64%; Group C: 80%), multilayered epithelium and intestinal metaplasia (Group A: 9%; Group B: 41%; Group C: 60%), and esophageal adenocarcinomas (Group B: 36%; Group C: 35%). A trend for increasing overall Cdx2 expression was documented during the course of the experiment (p = 0.001). CONCLUSION: De novo expression of Cdx2 is an early event in the spectrum of the lesions induced by experimental gastro-esophageal reflux and should be considered as a key step in the morphogenesis of esophageal adenocarcinoma.
Subject(s)
Esophageal Neoplasms/genetics , Homeodomain Proteins/genetics , Transcription Factors/genetics , Animals , Barrett Esophagus/pathology , CDX2 Transcription Factor , Disease Models, Animal , Esophageal Neoplasms/pathology , Esophagus/pathology , Gastroesophageal Reflux/pathology , Homeodomain Proteins/metabolism , Male , Rats , Rats, Wistar , Transcription Factors/metabolismABSTRACT
Skeletal muscle regeneration relies on satellite cells, a population of myogenic precursors. Inflammation also plays a determinant role in the process, as upon injury, macrophages are attracted by the damaged myofibers and the activated satellite cells and act as key elements of dynamic muscle supportive stroma. Yet, it is not known how macrophages interact with the more profound stem cells of the satellite cell niche. Here we show that in the presence of a murine macrophage conditioned medium (mMCM) a subpopulation of multipotent cells could be selected and expanded from adult rat muscle. These cells were small, round, poorly adhesive, slow-growing and showed mesenchymal differentiation plasticity. At the same time, mMCM showed clear myogenic capabilities, as experiments with satellite cells mechanically isolated from suspensions of single myofibers showed that the macrophagic factors inhibited their tendency to shift towards adipogenesis. In vivo, intramuscular administrations of concentrated mMCM in a rat model of extensive surgical ablation dramatically improved muscle regeneration. Altogether, these findings suggest that macrophagic factors could be of great help in developing therapeutic protocols with myogenic stem cells.
