Barrett's metaplasia describes a condition in which the stratified squamous epithelium of the oesophagus switches to intestinal type columnar epithelium. The molecular mechanisms underlying the switch to intestinal epithelium is poorly understood but the transcription factor CDX2 has been implicated in the pathogenesis of Barrett's metaplasia and is sufficient to provoke an intestinal metaplasia in the stomach of transgenic mice. To address the molecular basis of Barrett’s, I developed an innovative explant system for adult mouse oesophageal epithelium in which the full repertoire of stratified squamous cell types is maintained for prolonged culture periods. In adult oesophageal cultures, cells expressing p63, K14, K4 and loricrin were detected. The ability of Cdx2 to induce intestinal genes in this model as well as in a human oesophageal cell line and foetal mouse oesophageal cultures was assessed.
Cdx2 was sufficient to induce intestinal markers in Het-1A cells and foetal oesophageal epithelium but not in adult oesophageal explants. Following infection with Cdx2, Het-1A cells expressed four intestinal genes, Cdx1, Muc2, villin and K20. Embryonic oesophagus responds similarly and Muc2 and villin mRNA and Muc2 protein were detected. In contrast, infection of adult oesophageal explants did not provoke the expression of intestinal genes. These data suggest that additional factor(s) to Cdx2 are required in the conversion of adult oesophagus towards an intestinal phenotype as seen in Barrett's metaplasia.
HNF4α is a candidate factor to cooperate with Cdx2 in intestinal development and therefore Barrett's metaplasia. Herein I demonstrate that HNF4α is sufficient to induce a
columnar phenotype and the expression of intestinal genes within adult squamous oesophageal cells. The resultant phenotype is consistent with that seen in Barrett's metaplasia. Furthermore HNF4α and Cdx2 synergise to further enhance intestinalisation. This data suggests a hitherto unknown potential role for HNF4a in Barrett’s metaplasia.
|Date of Award
|1 Jun 2010
|Jonathan Slack (Supervisor) & David Tosh (Supervisor)
- Oesophageal adenocarcinoma
- Barrett's Metaplasia