title: Amphiregulin-deficient mice develop spasmolytic polypeptide expressing metaplasia and intestinal metaplasia.
abstract: OBJECTIVE
  The loss of parietal cells from the fundic mucosa leads to the emergence of metaplastic lineages associated with an increased susceptibility to neoplastic transformation. Both intestinal metaplasia (IM) and spasmolytic polypeptide (TFF2/SP) expressing metaplasia (SPEM) have been identified in human stomach, but only SPEM is present in most mouse models of gastric metaplasia. We previously determined that loss of amphiregulin (AR) promotes SPEM induced by acute oxyntic atrophy. We have now examined whether SPEM in the AR-/- mouse predisposes the stomach to gastric neoplasia.
  
  
  METHODS
  Gross pathology of 18-month-old wild-type, AR-/-, and TGF-alpha-/- mice were examined. Ki-67, beta-catenin, Pdx-1, TFF3, and TFF2/SP expression was analyzed by immunohistochemistry. Metaplastic gastric mucosa was analyzed by dual immunostaining for TFF2/SP with MUC2 or TFF3.
  
  
  RESULTS
  By 18 months of age, more than 70% of AR-/- mice developed SPEM while 42% showed goblet cell IM labeled with MUC2, TFF3, and Pdx-1. A total of 28% had invasive gastric lesions in the fundus. No antral abnormalities were observed in AR-/- mice. Metaplastic cell lineages in AR-/- mice showed increases in cell proliferation and cytosolic beta-catenin expression. Dual staining for TFF2/SP with MUC2 or TFF3 showed glands containing both SPEM and IM with intervening cells expressing both TFF2/SP and MUC2 or TFF2/SP and TFF3.
  
  
  CONCLUSIONS
  AR-/- mice develop SPEM, which gives rise to goblet cell IM and invasive fundic dysplastic lesions. The AR-/- mouse represents the first mouse model for spontaneous development of fundic SPEM with progression to IM.
authors.affiliation: Nashville Department of Veterans Affairs Medical Center, Nashville, Tennessee 37232-0443, USA.
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.forename: Hyuk-Joon
authors.initials: HJ
authors.lastname: Lee
authors.forename: Hoyin
authors.initials: H
authors.lastname: Mok
authors.forename: Judith
authors.initials: J
authors.lastname: Romero-Gallo
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.forename: Richard M
authors.initials: RM
authors.lastname: Peek
authors.forename: James R
authors.initials: JR
authors.lastname: Goldenring
mesh_terms: D066258:Amphiregulin; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D005748:Gastric Fundus / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000473:pathology*; D008679:Metaplasia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055262:Mucin-2 / Q000378:metabolism; D009077:Mucins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D051176:beta Catenin / Q000378:metabolism
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D009124:Muscle Proteins; D010455:Peptides; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; C493263:Tff3 protein, mouse; D016211:Transforming Growth Factor alpha; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D051176:beta Catenin; C451060:spasmolytic polypeptide