Augmented intestinal trefoil factor (TFF3) and loss of pS2 (TFF1) expression precedes metaplastic differentiation of gastric epithelium

The trefoil peptides spasmolytic polypeptide (SP), intestinal trefoil facto r (ITF), and pS2 show lineage-specific expression in the normal gut and are strongly induced after mucosal injury. We assessed the relationship betwee n this induction and the development of the regenerative epithelial lineage over time in the rat stomach and verified these observations in the metapl astic and dysplastic human stomach. Antral or colonic ulcers were induced i n Wistar rats by application of serosal acetic acid and tissues harvested 2 hours to 125 days later. Human endoscopic biopsies or gastric resection sp ecimens were also assessed. Tissues were examined by radioimmunoassay, immu noblotting, or immunohistochemistry for ITF, SP, and transforming growth fa ctor a (rat) or ITF and pS2 (human) expression. ITF acid SP mRNA in antral ulcer margins was localized by in situ hybridization. ITF and SP peptide ex pression rose steadily in ulcer margins after 4 days, with the rise in ITF being more pronounced. By 40 days, several hundred-fold elevations in ITF l evels were present, with a field effect in uninvolved mucosa. Hyperprolifer ative, elongated glands of undifferentiated cells expressing abundant trefo il peptides and acid sulfomucins were present after day 12 and persisted af ter ulcer healing. ITF mRNA was aberrantly expressed in basal and mid-regio ns of these regenerative glands. In contrast, transforming growth factor al pha peptide expression rose promptly after injury then fell to baseline lev els with healing. Seven months after injury, gastric atrophy, intestinal me taplasia, and severe dysplasia with conserved ITF expression were seen. ITF was also induced in human intestinal metaplasia and conserved in all gastr ic cancers, whereas expression of the gastric peptide pS2 was progressively reduced in the progression from metaplasia to dysplasia. Persistent, selec tive overexpression of ITF, possibly acting in an autocrine fashion, is a f eature of regeneration after antral ulceration, and may provide insight int o the nature of metaplastic phenotypes arising from chronic gastric injury. The loss of pS2 expression in metaplasia and cancer supports a role for th is protein in gastric tumor suppression.