Metaplastic cell lineages are putative precursors for the development of gastric
adenocarcinoma. The loss of parietal cells (oxyntic
atrophy) is the initiating step in the evolution of gastric fundic mucosal lineage changes including
metaplasia and
hyperplasia. However, the intrinsic mucosal factors that promote and modulate the emergence of metaplastic phenotypes remain obscure. Over the past several years, we have studied pharmacologically induced, reversible oxyntic
atrophy in rodents treated with
DMP-777, a
drug that acts as a parietal cell secretory membrane protonophore.
DMP-777 elicits a rapid loss of parietal cells followed by the emergence of foveolar
hyperplasia and
spasmolytic polypeptide (SP)-expressing
metaplasia (SPEM). The objective of the present study was to provide further insights into the intrinsic mucosal factors regulating the emergence of SPEM in the setting of oxyntic
atrophy. We therefore studied the effects of
DMP-777 administration on both SP/
trefoil factor (TFF)2-deficient mice, which lack SP/TFF2, a marker of SPEM, and waved-2 mice, which harbor a point mutation in the
EGF receptor that attenuates its
tyrosine kinase activity. As in wild-type mice, treatment with
DMP-777 for 7 days did elicit SPEM in SP/TFF2-deficient mice. These results suggest that SP/TFF2 does not impact on the development of
metaplasia after the induction of parietal cell loss. In contrast, waved-2 homozygous mice displayed accelerated SPEM development by 3 days of treatment with
DMP-777. These findings indicate that attenuation of
EGF receptor signaling in waved-2 mice does elicit a more rapid emergence of SPEM. The results support a role for
EGF receptor ligands in the regulation of gastric
metaplasia.