A molecular signature of gastric metaplasia arising in response to acute parietal cell loss.
OBJECTIVE
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.
Nozaki
Koji
K
Nashville VA Medical Center and the Department of Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Ogawa
Masako
M
Williams
Janice A
JA
Lafleur
Bonnie J
BJ
Ng
Vivian
V
Drapkin
Ronny I
RI
Mills
Jason C
JC
Konieczny
Stephen F
SF
Nomura
Sachiyo
S
Goldenring
James R
JR
D000818:Animals; D001284:Atrophy; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D019872:Chief Cells, Gastric / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D030501:Epididymal Secretory Proteins / Q000378:metabolism; D005326:Fetal Proteins / Q000378:metabolism; D005748:Gastric Fundus / Q000378:metabolism* / Q000473:pathology*; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology*; D005755:Gastrins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007437:Intrinsic Factor / Q000378:metabolism; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins; D064126:Minichromosome Maintenance Complex Component 3; D009077:Mucins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000071164:Trefoil Factor-2; D023083:beta-Defensins
D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D030501:Epididymal Secretory Proteins; D005326:Fetal Proteins; D005755:Gastrins; D036341:Intercellular Signaling Peptides and Proteins; D007437:Intrinsic Factor; D008869:Microtubule-Associated Proteins; D064126:Minichromosome Maintenance Complex Component 3; D009077:Mucins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010455:Peptides; D000071164:Trefoil Factor-2; D023083:beta-Defensins; C491312:Bhlha15 protein, mouse; C426184:DEFB126 protein, human; C513269:Mcm3 protein, mouse; C418485:TACC3 protein, mouse; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; C451060:spasmolytic polypeptide