Altered metaplastic response of waved-2 EGF receptor mutant mice to acute oxyntic atrophy.
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.
Ogawa
Masako
M
Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Nomura
Sachiyo
S
Varro
Andrea
A
Wang
Timothy C
TC
Goldenring
James R
JR
D000818:Animals; D001384:Azetidines / Q000008:administration & dosage; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000172:deficiency*; D009124:Muscle Proteins / Q000172:deficiency*; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010455:Peptides / Q000172:deficiency*; D010879:Piperazines / Q000008:administration & dosage; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D000071164:Trefoil Factor-2
D001384:Azetidines; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; D010879:Piperazines; C481546:TFF2 protein, mouse; D000071164:Trefoil Factor-2; C105999:DMP 777; D066246:ErbB Receptors