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Retinoic acid induced glandular differentiation of the oesophagus
  1. Chih-Long Chang (clc47{at}cam.ac.uk)
  1. MRC Cancer Cell Unit, United Kingdom
    1. Pierre Lao-Sirieix (pss{at}hutchison-mrc.cam.ac.uk)
    1. MRC Cancer Cell Unit, United Kingdom
      1. Vicki Save (ves21{at}cam.ac.uk)
      1. Department of Histopathology, Addenbrooke's Hospital, United Kingdom
        1. Guillermo De La Cueva Mendez (gd247{at}hutchison-mrc.cam.ac.uk)
        1. MRC Cancer Cell Unit, United Kingdom
          1. Ron Laskey (ral{at}hutchison-mrc.cam.ac.uk)
          1. MRC Cancer Cell Unit, United Kingdom
            1. Rebecca C Fitzgerald (rcf{at}hutchison-mrc.cam.ac.uk)
            1. MRC Cancer Cell Unit, United Kingdom

              Abstract

              Introduction: Retinoic acid (RA) is a powerful differentiation agent. Barrett’s oesophagus (BE) occurs when duodeno-gastro-oesophageal reflux causes squamous tissue (SE) to become columnar by an unknown mechanism. The bile acid, lithocholic acid (LCA) competes for the RXR retinoid binding site. Hence RA pathways may be implicated in BE.

              Methods: RA activity in tissues and cell-lines treated with All Trans retinoic acid (ATRA) +/- LCA was assessed using a reporter. P21 expression was determined by real-time PCR in BE cell-lines +/- LCA. SE and BE biopsies were exposed to 100 mM ATRA or 20mM of an RA inhibitor citral in organ culture over 72h. Characteristics of treated, compared with untreated controls, were analysed using immunohistochemistry (cytokeratins (CKs), vimentin) and RT-PCR (CKs). Confocal microscopy assessed temporal changes in co-localisation of CK8/18 and vimentin. Cell proliferation was assessed by BrdU incorporation and immunohistochemistry for Ki67 and p21.

              Results: RA biosynthesis was increased in BE compared with SE (p<0.0001). LCA and ATRA caused a synergistic increase in RA signalling as shown by increased p21 (p<0.01). Morphological and molecular analysis of ATRA treated SE demonstrated columnar differentiation independent of proliferation. Metaplasia could be induced from the stromal compartment alone and vimentin expression co-localised with CK8/18 at 24h which separated into CK8/18 positive glands and vimentin positive stroma by 48h. Citral treated BE led to phenotypic and immunohistochemical characteristics of SE which was proliferation independent.

              Conclusion: RA activity is increased in BE and induced by LCA. Under conditions of altered retinoic acid activity and an intact stroma, the oesophageal phenotype can be altered independent of proliferation.

              • Barrett's oesophagus
              • gastro-oesophageal reflux
              • mesenchymal-epithelial transition
              • submucosal glands
              • vitamin A

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