TY - JOUR
T1 - A Molecular Signature of Gastric Metaplasia Arising in Response to Acute Parietal Cell Loss
AU - Nozaki, Koji
AU - Ogawa, Masako
AU - Williams, Janice A.
AU - Lafleur, Bonnie J.
AU - Ng, Vivian
AU - Drapkin, Ronny I.
AU - Mills, Jason C.
AU - Konieczny, Stephen F.
AU - Nomura, Sachiyo
AU - Goldenring, James R.
N1 - Funding Information:
These studies were supported by grants from a Department of Veterans Affairs Merit Review Award, a pilot project grant from the Vanderbilt Specialized Program of Research Excellence in Gastrointestinal Cancer (1P 50 CA95103), the AGA Funderburg Award in Gastric Biology Related to Cancer, and a Discovery Grant from the Vanderbilt-Ingram Cancer Center (J.R.G.). Also supported by National Institutes of Health grant K08 DK066062 (J.C.M.) and by grant RO1 DK55489 (S.F.K.). Also supported by National Institutes of Health grant K08 CA108748, the Ovarian Cancer Research Fund, the Fannie E. Rippel Foundation, and the Dunkin Donuts Rising Stars Program (R.D.). Also supported by the Jon Isenberg Award from the Foundation for Digestive Health and Nutrition/American Gastroenterological Association (K.N.).
PY - 2008/2
Y1 - 2008/2
N2 - Background & Aims: Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM. Methods: Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts. Results: DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regulation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings. Conclusions: Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.
AB - Background & Aims: Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM. Methods: Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts. Results: DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regulation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings. Conclusions: Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.
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U2 - 10.1053/j.gastro.2007.11.058
DO - 10.1053/j.gastro.2007.11.058
M3 - Article
C2 - 18242217
AN - SCOPUS:38649116307
SN - 0016-5085
VL - 134
SP - 511
EP - 522
JO - Gastroenterology
JF - Gastroenterology
IS - 2
ER -