title: Active matrix metalloproteases are expressed early on and are high during the Barrett's esophagus malignancy sequence.
abstract: OBJECTIVE
  Molecular processes underlying Barrett's malignant development are poorly understood. Matrix metalloproteases (MMPs) are enzymes involved in inflammation, tissue remodeling, and malignant development. Therefore, active MMPs may have a role in early metaplasia development and Barrett's esophagus' malignant progression. We desired to gain more insight into the role of MMPs during the Barrett's esophagus pathogenesis sequence.
  
  
  METHODS
  In a surgical Barrett's mouse model, and in nonmalignant Barrett's and malignant esophageal cell lines, the activity of MMPs was investigated using a MMP activatable probe. MMP activity was further validated in Barrett's esophagus and esophageal adenocarcinoma patient biopsies and was further differentiated by investigating MMP9 and MMP13 expressions.
  
  
  RESULTS
  The mouse model showed probe activation in stromal cells early on in the esophagitis and metaplasia stages. MMP probe activation was higher in the Barrett's and cancer cell lines and biopsies as compared to normal cells and tissues. Co-immunostainings confirmed that, at the tissue level, the probe activation was mostly confined to CD45-positive stromal cells. MMP13 expression was highest in Barrett's metaplasia, whereas MMP9 was highest in the esophageal adenocarcinomas.
  
  
  CONCLUSIONS
  During the Barrett's pathogenesis process, MMP activity is increased early on in the inflamed esophagus and remains high in metaplasia and esophageal adenocarcinoma. However, there is a switch of MMP13 to MMP9 expression once neoplasia develops. In the future, detecting specific MMP subtypes could be used for distinguishing nonmalignant from neoplastic Barrett's esophagus.
authors.affiliation: Department of Gastroenterology and Hepatology, Academic Medical Center , Amsterdam , The Netherlands.
authors.forename: Akueni L
authors.initials: AL
authors.lastname: Davelaar
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Straub
authors.forename: Navtej S
authors.initials: NS
authors.lastname: Buttar
authors.forename: Paul
authors.initials: P
authors.lastname: Fockens
authors.forename: Kausilia K
authors.initials: KK
authors.lastname: Krishnadath
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000368:Aged; D000818:Animals; D001471:Barrett Esophagus / Q000473:pathology*; D001706:Biopsy; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004938:Esophageal Neoplasms / Q000473:pathology*; D004941:Esophagitis / Q000473:pathology*; D004947:Esophagus / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008679:Metaplasia; D051379:Mice; D008875:Middle Aged
chemical_list: C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Barrett’s esophagus; inflammation; matrix metalloproteases